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The role of dopamine in preparatory and consummatory defensive behaviours Blackburn, James Robert 1989

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THE ROLE OF DOPAMINE IN PREPARATORY AND CONSUMMATORY DEFENSIVE BEHAVIOURS BY JAMES ROBERT BLACKBURN B . S c , M c G i l l U n i v e r s i t y , 1983 M.A., U n i v e r s i t y o f B r i t i s h Columbia, 1985 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY i n THE FACULTY OF GRADUATE STUDIES Department o f Psychology We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA March 1989 (c) James Robert Blackburn, 1989 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. (Signature) James Robert Blackburn Department of Psychology The University of British Columbia Vancouver, Canada Date March 17, 1989  DE-6 (2/88) A b s t r a c t The e f f e c t s of n e u r o l e p t i c drugs on avoidance and f r e e z i n g behaviours o f r a t s were examined i n a s e r i e s o f experiments. In Chapter I i t was found t h a t the a c q u i s i t i o n of a one-way avoidance response was p r e c l u d e d by a dose of h a l o p e r i d o l (0.15 mg/kg) t h a t d i d not prevent escape responses and t h a t d i d not i n i t i a l l y d i s r u p t performance of a p r e v i o u s l y a c q u i r e d response. The a t y p i c a l n e u r o l e p t i c s t h i o r i d a z i n e (10-50 mg/kg) and c l o z a p i n e (1.25-10.0 mg/kg) d i d not p r e c l u d e a c q u i s i t i o n o f the response and had non-s p e c i f i c e f f e c t s on performance o f an a c q u i r e d response. In c o n t r a s t , metoclopramide (5.0 mg/kg), l i k e h a l o p e r i d o l , p r e c l u d e d a c q u i s i t i o n of avoidance responding without i n i t i a l l y d i s r u p t i n g performance. Given the c l i n i c a l p r o f i l e s of these drugs, these r e s u l t s suggest t h a t d i s r u p t i o n o f avoidance responding by n e u r o l e p t i c drugs may be more c l o s e l y r e l a t e d t o t h e i r c a p a c i t y t o produce e x t r a p y r a m i d a l s i d e e f f e c t s than t o t h e i r a b i l i t y t o r e l i e v e p s y c h o t i c symptoms. Chapter I I examined the e f f e c t of metoclopramide on performance of avoidance responses a f t e r v a r i o u s t r a i n i n g regimes. Metoclopramide e f f e c t s were a t t e n u a t e d by a s i n g l e t r a i n i n g s e s s i o n o f 10 t r i a l s , or, i f the tone warning s i g n a l had p r e v i o u s l y been p a i r e d with shock, as few as 5 t r i a l s . No p r o p h y l a c t i c e f f e c t of p r e t r a i n i n g was observed i f the r a t s were g i v e n noncontingent s a f e t y c o n d i t i o n i n g c o n s i s t i n g o f p a i r i n g s of shock t e r m i n a t i o n w i t h the s a f e s i d e of the apparatus p l u s a l i g h t cue. However, metoclopramide had l i t t l e impact i f p r e t r a i n i n g c o n s i s t e d of p r i o r tone-shock p a i r i n g s p l u s the o p p o r t u n i t y t o escape from u n s i g n a l l e d shock i n the avoidance apparatus. These r e s u l t s exclude the p o s s i b i l i t y t h a t a t t e n u a t i o n of metoclopramide e f f e c t s i s due t o o v e r t r a i n i n g of the avoidance response. Chapter I I I e s t a b l i s h e d t h a t f r e e z i n g responses t o shock are p o t e n t i a t e d by metoclopramide, although the magnitude of f r e e z i n g responses t o a c o n d i t i o n a l s t i m u l u s s i g n a l l i n g shock was not enhanced s i g n i f i c a n t l y . F o l l o w i n g up on t h i s d i s c o v e r y , Chapter IV determined t h a t the d i s r u p t i v e e f f e c t of metoclopramide on avoidance responding was enhanced by the presence of a d d i t i o n a l shock or shock cues. I t was concluded t h a t the enhancement of f r e e z i n g by metoclopramide c o n t r i b u t e s t o the d e f i c i t i n avoidance responding observed f o l l o w i n g metoclopramide treatment. These r e s u l t s were i n t e r p r e t e d as s u p p o r t i n g a h y p o t h e s i s t h a t c e n t r a l dopamine systems are i n v o l v e d i n the e x e c u t i o n of p r e p a r a t o r y responses d i r e c t e d towards d i s t a l s t i m u l i , but not i n consummatory responses d i r e c t e d towards d i f f u s e l o c a l or i n t e r n a l cues. I V Table of Contents A b s t r a c t . . . . . . . • • • . i i L i s t o f Tables . . . . . . . . . . v i L i s t o f F i g u r e s . . . . . . . . . . v i i Acknowledgements . . . . . . . . . v i i i I n t r o d u c t i o n . . . . . . . . . . . 1 P r e p a r a t o r y and consummatory d e f e n s i v e behaviours . 4 T h e o r e t i c a l a n a l y s i s of a c t i v e avoidance responding 7 A c q u i s i t i o n and maintenance of avoidance responding 16 E f f e c t s of n e u r o l e p t i c s on response a c q u i s i t i o n . 18 Neural mechanisms i n avoidance behaviour . . . 2 0 Overview . . . . . . . . . . . 2 3 I. E f f e c t s of d i f f e r e n t c l a s s e s of n e u r o l e p t i c drugs on one-way avoidance behaviour . . . . . . 2 7 1.1 - E f f e c t s of h a l o p e r i d o l . . . . . . 28 I.2a - E f f e c t s of t h i o r i d a z i n e . . . . . . 38 I.2b - E f f e c t s of 50 mg/kg t h i o r i d a z i n e . . . 45 1.3 - E f f e c t s of c l o z a p i n e . . . . . . 49 1.4 - E f f e c t s of metoclopramide . . . . . 55 D i s c u s s i o n . . . . . . . . . . . 60 I I . What must a r a t l e a r n i n avoidance t r a i n i n g i n o r d e r t o be p r o t e c t e d from n e u r o l e p t i c drug e f f e c t s ? . 67 11.1 - Days of p r e t r a i n i n g . . . . . . 72 11.2 - E f f e c t of p r i o r WS-AS p a i r i n g s . . . 78 I I . 3 - " S a f e t y " c o n d i t i o n i n g 85 11.4 - Amount of s a f e t y c o n d i t i o n i n g . . . . 92 11.5 - Avoidance v e r s u s escape t r a i n i n g . . . 97 V 11.6 - Escape t r a i n i n g f o l l o w i n g metoclopramide . 104 11.7 - U n s i g n a l l e d escape t r a i n i n g . . . . 109 D i s c u s s i o n . 1(14 I I I . Do n e u r o l e p t i c drugs a l t e r consummatory d e f e n s i v e r e a c t i o n s ? 118 111.1 - Shock-induced f r e e z i n g . . . . . 119 111.2 - CS-induced f r e e z i n g . . . . . . 126 D i s c u s s i o n . . . . . . . . . . . 135 IV. Can f e a r d i s r u p t avoidance responding? . . .139 IV.1 - E f f e c t of non-contingent shock . . . . 142 IV.2 - E f f e c t of shock i n a d i f f e r e n t c o n t e x t . . 147 IV.3 - E f f e c t of a c o n d i t i o n a l s t i m u l u s . . . 153 D i s c u s s i o n . 160 General D i s c u s s i o n . . . . . . . . . 163 T h e o r e t i c a l i n t e r p r e t a t i o n s of dopamine involvement i n avoidance behaviour . . . . . . . 165 Summary and c o n c l u s i o n s . . . . . . . . 183 References . . . . . . . . . . . 185 v i L i s t o f T a b l e s T a b l e I. Summary of n e u r o l e p t i c drug e f f e c t s on p r e p a r a t o r y and consummatory responses . . . 61 v i i L i s t o f F i g u r e s F i g u r e 1. E f f e c t s of h a l o p e r i d o l . . . . . 33 F i g u r e 2 . E f f e c t s of t h i o r i d a z i n e . 42 F i g u r e 3 . E f f e c t s of 50 mg/kg t h i o r i d a z i n e . 47 F i g u r e 4. E f f e c t s of c l o z a p i n e . 53 F i g u r e 5. E f f e c t s of metoclopramide . . . . 58 F i g u r e 6. Days of p r e t r a i n i n g . . . . . . 76 F i g u r e 7 . E f f e c t o f p r i o r WS-AS c o n d i t i o n i n g . 83 F i g u r e 8. E f f e c t of " s a f e t y " c o n d i t i o n i n g . . 90 F i g u r e 9. 10 or 20 " s a f e t y " t r i a l s . . . . . 96 F i g u r e 10 . Avoidance or escape p r e t r a i n i n g . 101 F i g u r e 11 . Escape p r e t r a i n i n g w i t h metoclopramide . . 107 F i g u r e 12 . Escape p r e t r a i n i n g without WS . 113 F i g u r e 13 . F r e e z i n g 30 - 90 s a f t e r shock . . 124 F i g u r e 14 . F r e e z i n g induced by CS+ . . . . . 132 F i g u r e 15 . E f f e c t of p r e t r i a l shock . . . . . 145 F i g u r e 16 . Out of context p r e t r i a l shock . 151 F i g u r e 17 . E f f e c t o f a d d i t i o n a l shock CS+ . . 157 Acknowledgements Throughout the course o f p u t t i n g t h i s t h e s i s t o g e t h e r many people have generously p r o v i d e d a s s i s t a n c e , i d e a s , and i n s p i r a t i o n . I would p a r t i c u l a r l y l i k e t o thank Fred LePiane and Shayne Ka r d e l f o r he l p i n i n s t r u m e n t a t i o n , Chuck Blaha, Jonathan Druhan, Tim Harpur, Jake Jacobs, Mike Mana, Jim Pfaus, Cathy Rankin, Norman White, and my a d v i s o r , Tony P h i l l i p s , f o r many hours of d i s c u s s i o n t h a t l e d t o the development of the ideas put forward here. Above a l l I would l i k e t o thank Linda Johnston f o r her i n s p i r a t i o n , her encouragement, and her l o v e . T h i s t h e s i s i s d e d i c a t e d t o her. I n t r o d u c t i o n 1 THE ROLE OF DOPAMINE IN PREPARATORY AND CONSUMMATORY DEFENSIVE BEHAVIOURS Understanding the c o n t r i b u t i o n of b r a i n dopamine systems t o behaviour has been the o b j e c t i v e o f a g r e a t d e a l of r e s e a r c h i n r e c e n t y e a r s . Although c o n s i d e r a b l e p r o g r e s s has been achieved both t h e o r e t i c a l l y and e m p i r i c a l l y , t h e r e i s s t i l l l i t t l e consensus on even the most b a s i c i s s u e s . For example, i t has been v a r i o u s l y proposed t h a t dopamine f u n c t i o n i s p r i m a r i l y i n v o l v e d i n motor a c t i v i t y (Freed & Zee, 1982), a t t e n t i o n (Solomon e t a l . , 1981; Weiner & Feldon, 1988), m o t i v a t i o n a l a c t i v a t i o n ( C a r l i , Evenden, & Robbins, 1985; Salamone, 1988), l e a r n i n g (Beninger, 1988), reward (Wise, 1982), sensorimotor r e s p o n s i v e n e s s (White, 1986), o r response i n i t i a t i o n ( F i b i g e r , Z i s , & P h i l l i p s , 1975; Posluns, 1962). Rec e n t l y , i t has been proposed t h a t c e n t r a l dopamine systems are p r e f e r e n t i a l l y i n v o l v e d i n p r e p a r a t o r y behaviours (Blackburn, 1985; Blackburn, P h i l l i p s , & F i b i g e r , 1987; Blackburn, P h i l l i p s , Jakubovic, & F i b i g e r , 1989a). P r e p a r a t o r y behaviours, such as f o r a g i n g and hoarding, may be d e f i n e d as responses t h a t l e a d t o and f a c i l i t a t e a separ a t e c l a s s of consummatory behaviours ( C r a i g , 1918; Kon o r s k i , 1967; S h e r r i n g t o n , 1906; Woodworth, 1918). Although the d i s t i n c t i o n between p r e p a r a t o r y and consummatory behaviours i s not always c l e a r - c u t , i t has proven t o be a u s e f u l concept i n e t h o l o g i c a l (e.g., E i b l -E i b e s f e l d t , 1975; Tinbergen, 1951), n e u r o b i o l o g i c a l (e.g., I n t r o d u c t i o n 2 S h e r r i n g t o n , 1906; Wilson & S o l t y s i k , 1985) and t h e o r e t i c a l (e.g., Konorski, 1967; Z e r n i c k i , 1968) a n a l y s e s of behaviour. These two c a t e g o r i e s of motivated behaviour d i f f e r s u b s t a n t i a l l y along s e v e r a l important dimensions, and may be l a r g e l y independent 1. Consummatory a c t s , such as chewing and swallowing, can t y p i c a l l y be r e a d i l y i d e n t i f i e d and d e s c r i b e d : They have r i g i d l y d e f i n e d t o p o g r a p h i e s and c l e a r l y d e f i n e d o b j e c t i v e s . Most o f t e n they s a t i s f y b i o l o g i c a l needs, thus t h e i r t a r g e t s are primary r e i n f o r c e r s . They are t y p i c a l l y c o n t r o l l e d by proximal s t i m u l i . In c o n t r a s t , p r e p a r a t o r y responses, such as f o r a g i n g behaviours, are more f l e x i b l e . They have l e s s immediate o b j e c t i v e s , and have more v a r i a b l e t o p o g r a p h i e s . They do not d i r e c t l y s a t i s f y b i o l o g i c a l needs, thus they are d i r e c t e d towards secondary r e i n f o r c e r s . They are t y p i c a l l y c o n t r o l l e d by d i s t a l s t i m u l i . S e v e r a l d i f f e r e n t p r e p a r a t o r y p a t t e r n s may l e a d t o i d e n t i c a l consummatory r e a c t i o n s . Evidence i n d i c a t e s t h a t dopamine-dependent systems i n the f o r e b r a i n may be i n v o l v e d i n the p o t e n t i a t i o n of non-r e f l e x i v e , t o p o g r a p h i c a l l y f l e x i b l e , p r e p a r a t o r y responses t o d i s t a l , e x t e r o c e p t i v e s t i m u l i . For example, Blackburn et a l . (1989a) analyzed the involvement of dopamine i n 1. The autonomy of these two c l a s s e s of behaviour i s i l l u s t r a t e d by the o b s e r v a t i o n t h a t each can occur i n i s o l a t i o n from the other. S c h a l l e r t , Pendergrass, & F a r r a r (1982) and Konorski (1967) have r e p o r t e d t h a t s a t e d animals remain r e s p o n s i v e t o f e e d i n g - r e l a t e d cues even a f t e r they have ceased i n g e s t i n g f r e e l y - a v a i l a b l e food. In c o n t r a s t , drugs can d i s r u p t p r e p a r a t o r y f e e d i n g responses i n animals t h a t w i l l n o n e t h e l e s s consume undiminished q u a n t i t i e s of food (Blackburn e t a l . , 1987). I n t r o d u c t i o n 3 p r e p a r a t o r y responses e l i c i t e d by an i n c e n t i v e s t i m u l u s c o n s i s t i n g of an extended c o n d i t i o n a l s t i m u l u s t h a t had been p a i r e d r e p e a t e d l y with the d e l i v e r y of a meal. When r a t s were pre s e n t e d with t h i s s t i m u l u s they responded by o r i e n t i n g t o i t , and by e n t e r i n g the f e e d i n g niche i n t o which the meal was about to be d e l i v e r e d . Blackburn e t a l . (1989a) determined t h a t these behaviours were accompanied by an i n c r e a s e i n f o r e b r a i n dopamine a c t i v i t y , as indexed by the r a t i o of the dopamine m e t a b o l i t e 3,4-d i h y d r o x y p h e n y l a c e t i c a c i d t o dopamine (DOPAC/DA r a t i o ) . DOPAC/DA r a t i o s were s i g n i f i c a n t l y i n c r e a s e d i n the nucleus accumbens, and by a s i m i l a r amount i n the s t r i a t u m . S i m i l a r l y , S c h u l t z (1986) demonstrated t h a t dopamine neurons i n the midbrain are a c t i v a t e d when monkeys are presented with i n c e n t i v e s t i m u l i r e l a t e d t o food. Neurons were i d e n t i f i e d as dopaminergic on the b a s i s of t h e i r h i s t o l o g i c a l l o c a t i o n , impulse form, spontaneous d i s c h a r g e r a t e , and response to systemic a d m i n i s t r a t i o n of low doses of the dopamine a g o n i s t apomorphine. When the monkeys were presented w i t h a u d i t o r y and v i s u a l cues t h a t s i g n a l l e d a f e e d i n g t r i a l , the m a j o r i t y (70) of the neurons i n c r e a s e d t h e i r f i r i n g r a t e , and a few (11) became l e s s a c t i v e . When the monkeys reached f o r food, 4 0 neurons became more a c t i v e and 22 became l e s s a c t i v e . However, when food was p l a c e d i n the mouth, onl y 11 neurons showed a c t i v i t y above b a s e l i n e l e v e l s , and 1 became l e s s a c t i v e . Thus, although many dopamine neurons i n c r e a s e d t h e i r a c t i v i t y i n response t o the Introduction 4 incentive cue and during the performance of the preparatory response, very few were activated during the consummatory phase of the feeding t r i a l . These data are consistent with the suggestion that dopamine systems are primarily involved in the preparatory phase of appetitive responding. Further evidence suggests that the dopaminergic a c t i v a t i o n e l i c i t e d by incentive s t i m u l i potentiates forebrain systems c r i t i c a l for the execution of subsequent preparatory responses to appropriate exteroceptive s t i m u l i . In the absence of such potentiation preparatory responses, but not consummatory responses, are diminished or abolished. For example, administration of the dopamine receptor antagonist pimozide was found to severely attenuate the overt preparatory responses e l i c i t e d by presentation of a conditional stimulus that s i g n a l l e d the imminent delivery of a meal, yet did not disrupt the consumption of available food (Blackburn, 1985; Blackburn et a l . , 1987). These r e s u l t s were consistent with previous reports that the dopamine receptor antagonist chlorpromazine disrupts responding in the presence of conditional stimuli s i g n a l l i n g food d e l i v e r y by monkeys (Migler, 1975) and rats (Clody & Carlton, 1980). : • Preparatory and consummatory defensive behaviours Although the d i s t i n c t i o n between preparatory and consummatory responding has most often been discussed i n the context of appetitive behaviours, the preparatory/ I n t r o d u c t i o n 5 consummatory d i s t i n c t i o n may a l s o apply t o d e f e n s i v e b e h a v i o u r s . Indeed, Konorski (1967, c h a p t e r 6) proposed t h a t t h e preparatory/consummatory d i s t i n c t i o n i s orthogonal t o the a p p e t i t i v e / d e f e n s i v e d i s t i n c t i o n . From t h i s p e r s p e c t i v e the hypothesized r o l e f o r dopamine i n p o t e n t i a t i n g p r e p a r a t o r y responses t o d i s t a l e x t e r o c e p t i v e s t i m u l i should apply to d e f e n s i v e as w e l l as t o a p p e t i t i v e p r e p a r a t o r y behaviours. Otherwise, i t would be necessary t o p o s t u l a t e a s p e c i f i c r o l e i n hedonic p r o c e s s i n g f o r dopamine f u n c t i o n (e.g., Wise, 1982). The d i s t i n c t i o n between p r e p a r a t o r y and consummatory d e f e n s i v e behaviours may be o p e r a t i o n a l i z e d by c o n s i d e r i n g avoidance and escape responses. Escape, o c c u r r i n g i n the presence of the primary r e i n f o r c e r ( i n t h i s case a negative r e i n f o r c e r ) , may be considered as a consummatory response. Escape response p a t t e r n s are r e l a t i v e l y i n v a r i a n t and i n f l e x i b l e ( B o l l e s & M c G i l l i s , 1968). In c o n t r a s t , avoidance responding, with more a f l e x i b l e topography, and e l i c i t e d by a warning s i g n a l p r i o r t o d e l i v e r y of the primary r e i n f o r c e r , may be viewed as a p r e p a r a t o r y response. I t has been demonstrated r e p e a t e d l y t h a t moderate doses of n e u r o l e p t i c drugs p r e f e r e n t i a l l y d i s r u p t c o n d i t i o n e d avoidance responding without i n t e r f e r i n g w i t h an animal's a b i l i t y t o execute an escape response (Arnt, 1982; Beninger, 1989; Cook & Weidley, 1957; C o u r v o i s i e r , F o u r n e l , Ducrot, Kolsky, & Koetschet, 1953; Davidson & Weidley, 1976; Herz, 1966). Although h i g h doses of n e u r o l e p t i c drugs w i l l I n t r o d u c t i o n 6 d i s r u p t escape responding, h i g h e r doses are r e q u i r e d t o d i s r u p t escape than are r e q u i r e d t o d i s r u p t avoidance, t y p i c a l l y i n the r a t i o of 3:1 or 5:1, sometimes h i g h e r (Arnt, 1982; van der Heyden & Bradford, 1988). Dopamine-d e p l e t i n g l e s i o n s i n the b r a i n , produced by a p p r o p r i a t e a d m i n i s t r a t i o n of the neurotoxin 6-hydroxydopamine (6-OHDA), produce a s i m i l a r p r e f e r e n t i a l d i s r u p t i o n of avoidance responding compared to t h e i r e f f e c t s on escape (Cooper, Breese, Grant, & Howard, 1973; Cooper, Howard, Grant, Smith, & Breese, 1974; Delacour, E c h a v a r r i a , S e n a u l t , & Houcine, 1977; F i b i g e r , P h i l l i p s , & Z i s , 1974; Heybach, Coover, & L i n t s , 1978; Z i s , F i b i g e r , & P h i l l i p s , 1974). I f we grant t h a t avoidance responses are, by d e f i n i t i o n , p r e p a r a t o r y responses, by v i r t u e of o c c u r r i n g p r i o r t o the occurrence of the primary r e i n f o r c e r , and escape responses are a l s o , by d e f i n i t i o n , consummatory responses, then t o a f i r s t approximation i t f o l l o w s t h a t dopamine i s i n f a c t p r e f e r e n t i a l l y i n v o l v e d i n p r e p a r a t o r y d e f e n s i v e behaviours. However, d e s p i t e the apparent s u r f a c e v a l i d i t y of t h i s a n a l y s i s , a g r e a t many q u e s t i o n s remain unanswered. Fundamentally, g i v e n the m u l t i d i m e n s i o n a l , q u a n t i t a t i v e d e f i n i t i o n s of p r e p a r a t o r y and consummatory responding t h a t have been provided, i t i s not c l e a r i f those f a c t o r s t h a t separate avoidance from escape responding are those onto which an a n a l y s i s of dopamine f u n c t i o n might u s e f u l l y be mapped. A c c o r d i n g l y , t h i s d i s s e r t a t i o n s h a l l i n v e s t i g a t e the c o n t r i b u t i o n of dopamine t o d e f e n s i v e I n t r o d u c t i o n 7 behaviour i n g r e a t e r d e t a i l i n o r d e r t o c l a r i f y the nature of dopamine's c o n t r i b u t i o n t o p r e p a r a t o r y and consummatory responding. C e n t r a l to t h i s a n a l y s i s s h a l l be an attempt to i n t e r p r e t the r o l e of dopamine i n a c t i v e avoidance behaviour. In order t o do t h i s i t i s f i r s t necessary to c o n s i d e r the nature of a c t i v e avoidance responding. T h e o r e t i c a l analyses of a c t i v e avoidance responding D e s p i t e an e x t e n s i v e h i s t o r y of r e s e a r c h , and i t s c e n t r a l r o l e i n the e v o l u t i o n of l e a r n i n g theory, avoidance behaviour i s s t i l l not w e l l understood. The problem of what motivates avoidance behaviour has, by i t s e l f , been a c e n t r a l p o i n t of c o n t r o v e r s y f o r l e a r n i n g and m o t i v a t i o n t h e o r i s t s f o r h a l f a century. Consider a standard avoidance paradigm: An animal i s exposed to a warning s i g n a l (WS) t h a t s i g n a l s the imminent onset of an u n c o n d i t i o n e d a v e r s i v e stimulus (AS), u s u a l l y a shock . Should the animal perform the r e q u i s i t e response d u r i n g the p e r i o d i n which the WS i s presented, the WS i s terminated and the AS i s not presented (avoidance has o c c u r r e d ) . I f no response i s performed, the AS i s a d m i n i s t e r e d u n t i l an escape response i s performed. Escape responding terminates both the AS and the WS. 2. The terms " a v e r s i v e s t i m u l u s " and "warning s i g n a l " are used here because they are o p e r a t i o n a l l y d e f i n e d and t h e o r e t i c a l l y n e u t r a l . The more common d e s i g n a t i o n s of " u n c o n d i t i o n a l s t i m u l u s " and " c o n d i t i o n a l s t i m u l u s " are h i s t o r i c a l a r t e f a c t s of an era when avoidance responses were viewed as P a v l o v i a n c o n d i t i o n e d responses. ( B o l l e s , 1972a). I n t r o d u c t i o n 8 The q u e s t i o n t h a t has so b e d e v i l l e d l e a r n i n g t h e o r i s t s i s why animals continue t o respond i n the presence of the WS. In simple S-R terms ( H u l l , 1937), performance of an escape response w i l l terminate the AS and thereby reduce f e a r , a d r i v e . T h i s d r i v e - r e d u c t i o n w i l l be r e i n f o r c i n g , t h e r e f o r e an animal w i l l be more l i k e l y t o perform the response when i t i s i n the same s t i m u l u s environment. The problem i s why response a c q u i s i t i o n i s enhanced i f the response c a n c e l s AS p r e s e n t a t i o n (Brogden, Lipman, & C u l l e r , 1938) . A simple S-R model should p r e d i c t t h a t the response should e x t i n g u i s h r a p i d l y when the animal r e g u l a r l y avoids the p r e s e n t a t i o n of the AS and t h e r e f o r e f a i l s t o experience the r e i n f o r c e m e n t o f AS t e r m i n a t i o n . The c l a s s i c account of avoidance, s t i l l v e ry i n f l u e n t i a l , i s the two-factor theory o f Mowrer (1947). By t h i s account, (a) the animal l e a r n s a P a v l o v i a n a s s o c i a t i o n between the WS and the AS, which r e s u l t s i n the e l i c i t a t i o n o f f e a r as a c o n d i t i o n e d response by the WS, and (b) i t then l e a r n s t o perform an inst r u m e n t a l response t h a t i s r e i n f o r c e d by t e r m i n a t i o n of the f e a r - e l i c i t i n g WS ( f e a r r e d u c t i o n being r e i n f o r c i n g ) . Two-factor theory has c o n s i d e r a b l e s u r f a c e v a l i d i t y . C e r t a i n l y the experimental c o n t i n g e n c i e s o f the t y p i c a l avoidance paradigm are such as to permit P a v l o v i a n l e a r n i n g t o occur: The onset of the WS i s r e g u l a r l y f o l l o w e d by the onset o f the AS. And evidence i n d i c a t e s t h a t the WS does a c q u i r e p r o p e r t i e s of a c o n d i t i o n e d e x c i t o r of f e a r . For I n t r o d u c t i o n 9 example, Kamin, Brimer, & Black (1963) showed t h a t a f t e r avoidance t r a i n i n g the WS was a b l e t o e l i c i t a c o n d i t i o n e d emotional response. Other evidence a t t e s t s t o the m o t i v a t i n g p r o p e r t i e s of the WS. F i r s t , i f a stimulus i s independently e s t a b l i s h e d as a c o n d i t i o n e d s t i m u l u s f o r shock, then a c q u i s i t i o n of avoidance responding i s t y p i c a l l y more r a p i d l y a c q u i r e d i f t h a t s t i m u l u s i s subsequently used than i f a n e u t r a l or novel s t i m u l u s i s used as the WS (e.g. Anisman, Irwin, Zacharko, & Tombaugh, 1982; De Teledo & Black, 1967; G a l l o n , 1972). What i s more, an e x c i t a t o r y P a v l o v i a n c o n d i t i o n a l stimulus (CS+) a s s o c i a t e d with shock can s u b s t i t u t e f o r the WS i n an avoidance experiment with no d e l e t e r i o u s impact on performance, but an i n h i b i t o r y c o n d i t i o n a l stimulus (CS-) e x p l i c i t l y not a s s o c i a t e d with shock w i l l not e l i c i t avoidance responding i n the same animals (Overmier & Leaf, 1965; Solomon & Turner, 1962). I f these s t u d i e s confirmed the s u f f i c i e n c y of f e a r t o e l i c i t avoidance responding, a study by R e s c o r l a and LoLordo (1965) a p p a r e n t l y confirmed the n e c e s s i t y of f e a r t o motivate avoidance. Dogs were t r a i n e d on a Sidman avoidance schedule. Response r a t e s were i n c r e a s e d i f a c o n d i t i o n e d e x c i t o r of f e a r was presented t o the dogs, but response r a t e s a c t u a l l y d e c l i n e d i f a c o n d i t i o n e d i n h i b i t o r of f e a r was p r e s e n t e d (see a l s o Jacobs & LoLordo, 1980; Weisman & L i t n e r , 1969; Z i e l i n s k i & Cotton, 1982). The f i n a l c o n t e n t i o n of t w o - f a c t o r theory, namely t h a t avoidance i s r e i n f o r c e d by WS t e r m i n a t i o n , was supported by I n t r o d u c t i o n 10 evidence t h a t r a t s would l e a r n a novel response, d i f f e r i n g from the escape response, i n order t o t e r m i n a t e the WS and a v o i d shock (Mowrer & Lamoreaux, 1946). Other s t u d i e s demonstrated t h a t avoidance responding was most r a p i d l y a c q u i r e d i f WS o f f s e t was contiguous w i t h the avoidance response. Performance was impaired i f the WS was a b r i e f s t i m u l u s t h a t terminated before the response o c c u r r e d or i f the WS p e r s i s t e d f o r some time a f t e r the response occurred (Kamin, 1957; Mowrer & Lamoreaux, 1942). D e s p i t e these successes, t w o - f a c t o r t h e o r y has been c h a l l e n g e d on a number of f r o n t s . F i r s t , although i t i s c l e a r t h a t experimental animals do develop f e a r of the WS, the magnitude of t h i s f e a r i s not r e l a t e d t o the v i g o u r of the avoidance response i n any s t r a i g h t f o r w a r d manner. One o b s e r v a t i o n , f i r s t made by Solomon and Wynne (1953), i s t h a t w e l l - t r a i n e d animals do not appear as f r i g h t e n e d d u r i n g WS p r e s e n t a t i o n as do animals with only a s m a l l amount of t r a i n i n g . Brady (1964) and Coover, U r s i n , and Levine (1973a) r e p o r t e d t h a t f e a r , as indexed by plasma l e v e l s of 1 7 - h y d r o x y c o r t i c o s t e r o i d , d e c l i n e s over s u c c e s s i v e avoidance s e s s i o n s . That t h i s r e f l e c t s a d e c l i n e i n f e a r of the WS i s demonstrated by the decreasing e f f e c t i v e n e s s of an avoidance WS as a c o n d i t i o n e d stimulus when t e s t e d i n a c l a s s i c a l c o n d i t i o n i n g paradigm, e i t h e r the s u p p r e s s i o n of ongoing operant responding (the c o n d i t i o n e d emotional response [CER] paradigm; Kamin e t a l . , 1963; Linden, 1969; Mineka & Gino, 1980; Mineka, M i l l e r , Gino, & Giencke, 1981; S t a r r & Mineka, I n t r o d u c t i o n 11 1977), or the i n d u c t i o n of c o n d i t i o n e d f r e e z i n g (Cook, Mineka, & Trumble, 1987). As a f u r t h e r c o m p l i c a t i o n , i t has been observed t h a t decreases i n f e a r need not accompany b e h a v i o u r a l e x t i n c t i o n of avoidance responding. Kamin et a l . (1963) found l i t t l e f e a r e x t i n c t i o n i n r a t s t h a t were e x t i n g u i s h e d i n avoidance to a c r i t e r i o n o f f i v e c o n s e c u t i v e f a i l u r e s t o respond. In the case of response e x t i n c t i o n produced by f l o o d i n g (exposing an animal t o the WS i n the absence of any o p p o r t u n i t y to avoid) t h e r e may be no decrease i n f e a r of the WS (Mineka & Gino, 1979; S h i p l e y , Mock, & L e v i s , 1971) or f e a r may a c t u a l l y i n c r e a s e (C o u l t e r , R i c c i o , & Page, 1969). Another c h a l l e n g e to Mowrer's f o r m u l a t i o n of two-factor theory i n v o l v e s a r e - e v a l u a t i o n of the r o l e of WS o f f s e t . A c c o r d i n g t o Mowrer (1947), t e r m i n a t i o n of the WS serves as a r e i n f o r c i n g event by i t s d r i v e - r e d u c i n g p r o p e r t i e s . However, ot h e r evidence suggests t h a t i t a c t s p r i m a r i l y as a feedback s t i m u l u s t h a t informs the animal t h a t the avoidance response has been completed s u c c e s s f u l l y . V a r i o u s l i n e s of evidence i n d i c a t e the power of feedback from s a f e t y s i g n a l s i n avoidance responding. F i r s t , i f avoidance responding r e s u l t s i n p r e s e n t a t i o n of an e x p l i c i t s a f e t y s i g n a l , avoidance responding i s enhanced. T h i s i s t r u e even i f the response does not terminate the WS ( B o l l e s & Grossen, 1969; Bower, S t a r r , & L a z a r o v i t z , 1965; D'Amato, Fazzaro, & E t k i n , 1968; Keehn & Nakkash, 1959). T h i s f i n d i n g i s an embarrassment f o r t w o - f a c t o r theory, 4 I n t r o d u c t i o n 12 which h o l d s t h a t WS t e r m i n a t i o n motivates avoidance responding. Even more embarrassing i s the f i n d i n g t h a t i f e x p l i c i t s a f e t y s i g n a l s are presented when an animal executes an avoidance response, f e a r of the WS i s subsequently decreased (Cook e t a l . , 1987; Mineka, Cook, & M i l l e r , 1984). Two f a c t o r theory, r e l y i n g on f e a r o f the WS t o motivate avoidance, p r e d i c t s t h a t such a m a n i p u l a t i o n should decrease, r a t h e r than i n c r e a s e , avoidance responding. A second demonstration of the power of s a f e t y s i g n a l s i s t h a t i f a s i g n a l i s a s s o c i a t e d w i t h the absence of shock, and t h a t s i g n a l i s then presented as a consequence of perfo r m i n g an avoidance response, performance of the response i s subsequently enhanced ( R e s c o r l a , 1969; Weisman & L i t n e r , 1969, 1972). T h i r d , r a t s w i l l approach a cue t h a t s i g n a l s the non-occurrence of shock ( B a r t t e r & Masterson, 1980; L e c l e r c , 1985; L e c l e r c & Reberg, 1980). In f a c t , a r a t can be t r a i n e d t o perform a novel operant response t o o b t a i n p r e s e n t a t i o n of a cue e s t a b l i s h e d as a s a f e t y s i g n a l i n the course of avoidance t r a i n i n g (Moot, 1973, c i t e d i n B o l l e s , 1975; M o r r i s , 1975). These o b s e r v a t i o n s are i n l i n e with the p r e d i c t i o n s of i n c e n t i v e m o t i v a t i o n a l i n t e r p r e t a t i o n s of avoidance responding, which h o l d t h a t avoidance a c t u a l l y c o n s i s t s of running towards s a f e t y s i g n a l s r a t h e r than running away from an a v e r s i v e WS (e.g., Toates, 1982). T h i s p o s i t i o n accounts n i c e l y f o r the p e r s i s t e n c e of avoidance i n the absence of the primary m o t i v a t o r (shock) I n t r o d u c t i o n 13 because even when the animal i s a v o i d i n g , and hence not r e c e i v i n g the WS, i t s t i l l r e c e i v e s the s a f e t y s i g n a l which has a c q u i r e d secondary r e i n f o r c i n g p r o p e r t i e s . In l i g h t of the d i f f i c u l t i e s encountered by t w o - f a c t o r theory, i t i s not s u r p r i s i n g t h a t a l t e r n a t i v e accounts of avoidance have a r i s e n i n r e c e n t y e a r s . At one extreme i s t h a t of H e r r n s t e i n (1969), who has accounted f o r avoidance responding s o l e l y i n terms of reinforcement c o n t i n g e n c i e s : Rats perform responses t h a t decrease the p r o b a b i l i t y or frequency of t h e i r being shocked. In support of t h i s a n a l y s i s , H e r r n s t e i n and H i n e l i n e (1966) s u b j e c t e d r a t s t o an avoidance procedure i n which t r i a l s o c c u r r e d randomly i n time, but a response c o u l d reduce the o v e r a l l r a t e of shock (e.g. from a p r o b a b i l i t y of .3 i n a 2 s p e r i o d t o a p r o b a b i l i t y of .1). No other s t i m u l i were presented, so no r e i n f o r c i n g or feedback events were contiguous w i t h responding. Although t h i s experiment demonstrated t h a t a r e d u c t i o n i n shock r a t e alone i s s u f f i c i e n t t o m a i n t a i n avoidance responding, the f a c t t h a t i t took r a t s thousands of shocks t o a c q u i r e the response, as opposed t o a few ( i n the case of one-way avoidance) or a a few dozen ( i n the case of s h u t t l e avoidance), i n d i c a t e s t h a t the r o l e p l a y e d by such c o n t i n g e n c i e s i n other avoidance paradigms may be m a r g i n a l . Other t h e o r i e s of avoidance have emerged from d i f f e r e n t t h e o r e t i c a l p e r s p e c t i v e s . S e v e r a l c o g n i t i v e models have been developed, most n o t a b l y by Seligman & Johnston (1973). I n t r o d u c t i o n 14 By these accounts, f e a r i s c o n d i t i o n e d t o the WS. G r a d u a l l y , however, the animal a c q u i r e s two e x p e c t a n c i e s : F i r s t , t h a t an avoidance response w i l l be f o l l o w e d by an absence of shock; second, t h a t the absence o f an avoidance response w i l l be f o l l o w e d by shock. Given a p r e f e r e n c e f o r no shock, these e x p e c t a n c i e s l e a d t o a h i g h p r o b a b i l i t y of the response being executed. B o l l e s (1970, 1975) begins h i s a n a l y s i s of avoidance behaviour by p o s t u l a t i n g t h a t i n order t o s u r v i v e animals must have a r e p e r t o i r e of s p e c i e s - s p e c i f i c defence r e a c t i o n s (SSDRs) t h a t occur when they are f r i g h t e n e d . In the case of r a t s , these SSDRs are p r i m a r i l y running and f r e e z i n g . In i t s s t r o n g form ( B o l l e s , 1975), the SSDR h y p o t h e s i s h o l d s t h a t i n an avoidance experiment the animal q u i c k l y l e a r n s t h a t some s t i m u l i p r e d i c t shock and oth e r s t i m u l i p r e d i c t s a f e t y . W i t h i n the context of the s t i m u l u s environment, the behaviour of the f r i g h t e n e d r a t i s h e l d t o c o n s i s t e n t i r e l y of SSDRs: "When the t e s t s i t u a t i o n l o o k s l i k e a good p l a c e t o f r e e z e , the animal w i l l f r e e z e i f i t expects shock; when the s i t u a t i o n looks l i k e a good p l a c e t o run, the animal w i l l run i n i t " ( B o l l e s , 1975, p. 365). The development of a c o n s i s t e n t response o c c u r r i n g through avoidance t r a i n i n g i s a t t r i b u t e d t o the punishment of a l l but one SSDR. In t h i s h y p o t h e s i s , B o l l e s has abandoned the n o t i o n of re i n f o r c e m e n t . A l l responses are seen as respondent, r a t h e r t h a t operant. That i s , the response of the animal i s a f u n c t i o n o f i t s l e v e l of f e a r and of the s t i m u l u s I n t r o d u c t i o n 15 environment i n which i t f i n d s i t s e l f , r a t h e r than i t s h i s t o r y o f reinforcement i n the s i t u a t i o n . In most cases any l e a r n i n g t h a t occurs i s s t i m u l u s l e a r n i n g , not response l e a r n i n g ( B o l l e s , 1978). Thus, i f the response t h a t the experimenter has de s i g n a t e d as the avoidance response i n a g i v e n experiment i s an a p p r o p r i a t e SSDR f o r t h a t environment ( f o r example running t o a s a f e p l a c e i n a one-way avoidance experiment) then the animal w i l l q u i c k l y reach a h i g h l e v e l of performance. In c o n t r a s t , i f the d e s i g n a t e d responses i s not an SSDR (such as a l e v e r press) a c q u i s i t i o n can be p a i n f u l l y slow - on the order of hundreds or thousands o f t r i a l s . Thus the SSDR hy p o t h e s i s , u n l i k e any of i t s p r e d e c e s s o r s , can r e a d i l y account f o r v a s t d i f f e r e n c e s i n avoidance a c q u i s i t i o n t h a t are seen when d i f f e r e n t responses are r e q u i r e d . Masterson and Crawford (1982) a l s o make r e f e r e n c e t o the n o t i o n of SSDRs, but r a t h e r than respondents, they see these as r e i n f o r c e r s i n a defence m o t i v a t i o n system a n a l y s i s of avoidance. By t h i s account, avoidance behaviours are consummatory responses, motivated by f e a r and s e r v i n g t o r e i n f o r c e the a c t i v i t i e s t h a t l e d up t o t h e i r e x e c u t i o n . Thus, they demonstrated t h a t r a t s c o u l d e a s i l y l e a r n t o pr e s s a l e v e r t o av o i d shock, so long as the l e v e r p r e s s p e r m i t t e d them t o e x i t the shock compartment (Crawford & Masterson, 1978). Jacobs and LoLordo (1980) suggest t h a t the c r i t i c a l f e a t u r e i n determining avoidance responding i s the presence I n t r o d u c t i o n 16 of a p p r o p r i a t e s u p p o r t i n g s t i m u l i . They contend t h a t apparent c o n s t r a i n t s on avoidance response r e p e r t o i r e s may a c t u a l l y be c o n s t r a i n t s i n the nature of the what those s u p p o r t i n g s t i m u l i can be. S p e c i f i c a l l y , Jacobs and LoLordo determined t h a t some s t i m u l i may be e f f e c t i v e as warning s i g n a l s but not as s a f e t y s i g n a l s (e.g., tone o n s e t ) , or e f f e c t i v e as s a f e t y s i g n a l s but not as warning s i g n a l s (e.g., tone o f f s e t , l i g h t onset, or l i g h t o f f s e t ) . A c q u i s i t i o n and maintenance of avoidance responding Confronted with an unwieldy mass of c o n f l i c t i n g data and theory, i t seems reasonable t o suspect t h a t avoidance, o p e r a t i o n a l l y d e f i n e d , may not be a u n i t a r y b e h a v i o u r a l phenomenon with a s i n g l e n e u r o b i o l o g i c a l s u b s t r a t e (Mineka, 1979). T h i s h y p o t h e s i s would permit the r e s e a r c h e r t o s a l v a g e remnants of s t r o n g t h e o r i e s t h a t can account f o r p o r t i o n s , but not a l l , of the avoidance data. I t i s h i g h l y p l a u s i b l e t h a t a behaviour so q u i c k l y a c q u i r e d , so long r e t a i n e d , and so r e s i s t a n t t o e x t i n c t i o n as avoidance should be m u l t i p l y r e p r e s e n t e d i n the nervous system. One important d i s t i n c t i o n t o be drawn wi t h regard t o avoidance behaviour i s t h a t between response a c q u i s i t i o n and response maintenance. I t i s p r e c i s e l y here t h a t many b e h a v i o u r a l t h e o r i e s of avoidance have had the most t r o u b l e . C o n s i d e r a g a i n a simple S-R account of avoidance responding. P r e s e n t a t i o n of an a v e r s i v e s t i m u l u s (AS) such as shock produces a d r i v e s t a t e . Responses t h a t t e r m i n a t e the AS I n t r o d u c t i o n 17 w i l l be r e i n f o r c e d by r e d u c i n g t h i s d r i v e s t a t e , and w i l l tend t o occur sooner and sooner a f t e r onset o f the AS. I f the AS were c o n s i s t e n t l y preceded by a warning s i g n a l (WS), simple r e i n f o r c e m e n t of the escape h a b i t i n the presence o f the WS c o u l d account f o r responses i n the presence of the WS alone, p r i o r t o AS p r e s e n t a t i o n . Thus, an S-R the o r y of t h i s s o r t can account f o r the a c q u i s i t i o n o f avoidance responding. However, responses o c c u r r i n g p r i o r t o AS p r e s e n t a t i o n cannot be r e i n f o r c e d by AS t e r m i n a t i o n , and thus should e x t i n g u i s h r a p i d l y . T h i s however, i s not the case. For example, Solomon, Kamin, and Wynne (1953) r e p o r t e d t h a t dogs may perform hundreds o f s u c c e s s f u l avoidances a f t e r r e c e i v i n g only a few shocks d u r i n g response a c q u i s i t i o n . The same i s t r u e of r a t s (Seligman & Campbell, 1965). Thus, S-R theory cannot account s a t i s f a c t o r i l y f o r avoidance response maintenance. In c o n t r a s t t o S-R theory, i n Mowrer 1s (1947) two-f a c t o r theory WS p r e s e n t a t i o n can independently produce a d r i v e s t a t e , and thus WS t e r m i n a t i o n can be r e i n f o r c i n g i n the absence of AS t e r m i n a t i o n . Thus, avoidance responding can be maintained even when no shocks are r e c e i v e d . However, as we have seen, l e v e l s o f f e a r d e c l i n e over the course of extended t r a i n i n g on the avoidance response. P a r t l y on the b a s i s of t h i s o b s e r v a t i o n Mineka (1979) and Seligman and Johnston (1973) have suggested t h a t f e a r may p l a y an important r o l e i n the a c q u i s i t i o n o f avoidance I n t r o d u c t i o n 18 responding, but a l e s s c r i t i c a l r o l e i n response maintenance. Other r e c e n t t h e o r i e s have t r e a t e d the maintenance of avoidance as a primary datum f o r which they must account. B o l l e s ' SSDR h y p o t h e s i s holds t h a t once an animal has l e a r n e d t h a t the avoidance apparatus and the s t i m u l i i n i t are f r i g h t e n i n g , i t w i l l emit an SSDR whenever i t i s i n the apparatus. Because the responses do not r e l y on re i n f o r c e m e n t f o r t h e i r e stablishment, they w i l l not e x t i n g u i s h so long as a c e r t a i n l e v e l of f e a r i s e l i c i t e d by the environment. C o g n i t i v e t h e o r i e s h o l d t h a t avoidance i s maintained by the expectancy t h a t f a i l u r e t o emit the avoidance response w i l l r e s u l t i n shock. As Seligman & Johnston (197 3) and Toates (1982) p o i n t out, because t h e r e i s no d i s c o n f i r m a t i o n of t h i s expectancy the c o g n i t i v e t h e o r i s t does not p r e d i c t any change i n the p r o b a b i l i t y of avoidance responding. E f f e c t s of n e u r o l e p t i c s on response a c q u i s i t i o n The d i s t i n c t i o n between the a c q u i s i t i o n and maintenance of avoidance responding i s p a r t i c u l a r l y germane t o the c u r r e n t d i s c u s s i o n , as e x t e n s i v e evidence r e v e a l s t h a t d i s r u p t i o n of dopamine n e u r o t r a n s m i s s i o n p r e f e r e n t i a l l y d i s r u p t s the a c q u i s i t i o n of avoidance responding. I f an animal has l e a r n e d the avoidance response p r i o r t o the d i s r u p t i v e treatment, the avoidance response may be but l i t t l e d i m i n i s h e d . Under a p p r o p r i a t e circumstances i t i s I n t r o d u c t i o n 19 p o s s i b l e t o d i s s o c i a t e completely the e f f e c t of dopamine-d e p l e t i n g l e s i o n s or n e u r o l e p t i c drugs on the a c q u i s i t i o n of avoidance from t h e i r e f f e c t s on performance of a c q u i r e d responses (Anisman e t a l . , 1982; Beninger, P h i l l i p s , & F i b i g e r , 1983; Carey & Kenney, 1987; F i b i g e r e t a l . , 1974, 1975; Ray & Bivens, 1966). In g e n e r a l , the more s l o w l y a g i v e n avoidance response i s a c q u i r e d the more severe the impact of n e u r o l e p t i c treatment (Latz, Bain, & Kornetsky, 1969) . I n i t i a l p r o t e c t i o n from the e f f e c t of n e u r o l e p t i c drugs has a l s o been r e p o r t e d i n cases of p r e v i o u s l y a c q u i r e d a p p e t i t i v e operant responses (Gray & Wise, 1980; Mason, Beninger, P h i l l i p s , & F i b i g e r , 1980; P h i l l i p s & F i b i g e r , 1979; Singh, 1964; Tombaugh, Anisman, & Tombaugh, 1980; Wise, S p i n d l e r , de Wit, & Gerber, 1978). By themselves, these data c o u l d be taken t o imply t h a t dopamine d i s r u p t i o n produces a d e f i c i t i n l e a r n i n g : F o l l o w i n g n e u r o l e p t i c treatment an animal can perform a p r e v i o u s l y l e a r n e d t a s k but cannot l e a r n t o perform a new one (Beninger, 1988). However, a profound d i s r u p t i o n was observed on the f i r s t t r i a l on which pimozide was a d m i n i s t e r e d i n the case of p r e p a r a t o r y c o n d i t i o n e d responding e l i c i t e d by s t i m u l i a s s o c i a t e d w i t h meal d e l i v e r y , even a f t e r 50-80 c o n d i t i o n i n g t r i a l s (Blackburn e t a l . , 1987). D i s r u p t i o n of the same response was of approximately equal magnitude whether r a t s were a d m i n i s t e r e d h a l o p e r i d o l a f t e r 3, 6, 9, or 12 days of c o n d i t i o n i n g (unpublished o b s e r v a t i o n s ) . I f d e f i c i t s i n I n t r o d u c t i o n 20 p r e p a r a t o r y responding are t o be a t t r i b u t e d t o a l t e r e d r e s p o n s i v e n e s s t o e x t e r o c e p t i v e s t i m u l i , r a t h e r than t o l e a r n i n g , t h i s apparent d i s c r e p a n c y between the e f f e c t s of n e u r o l e p t i c drugs on avoidance and c l a s s i c a l l y c o n d i t i o n e d a p p e t i t i v e responding must be r e s o l v e d . Neural mechanisms i n avoidance behaviour An a d d i t i o n a l o b j e c t i v e of t h i s d i s s e r t a t i o n i s t o shed l i g h t on r e l a t i o n s between v a r i o u s n e u r a l systems i n v o l v e d i n d e f e n s i v e behaviour. In a d d i t i o n t o n e u r o l e p t i c treatment, a l t e r a t i o n s i n avoidance behaviour have been found f o l l o w i n g a d m i n i s t r a t i o n of t r a n q u i l i z i n g , a n t i c h o l i n e r g i c , s e r o t o n e r g i c , and o t h e r p h a r m a c o l o g i c a l agents (Barry & M i l l e r , 1965; Cook & Weidley, 1957; Morpurgo, 1965; Ogren, 1986), as a r e s u l t of changes i n c o r t i c o s t e r o i d or ACTH l e v e l (Oei & King, 1980), and f o l l o w i n g sympathectomy (Wynne & Solomon, 1955; Di G i u s t o & King, 1972). D i s r u p t i v e e f f e c t s have a l s o been r e p o r t e d f o l l o w i n g l e s i o n s of d i s c r e t e b r a i n r e g i o n s i n c l u d i n g the caudate nucleus (Green, Beatty, & Schwartzbaum, 1967; S t u d e l s k a & Beatty, 1978), the s u b s t a n t i a n i g r a (Mitcham & Thomas, 1972), the c i n g u l a t e c o r t e x (Peretz, 1960; Thomas & S l o t n i c k , 1962), the hippocampus (Rich & Thompson, 1965), the septum (Kenyon & Kreickhaus, 1965a,b), the amygdala (Goddard, 1964; S a r t e r & Markowitsch, 1985), the dorsomedial nucleus of the thalamus (Olton & Isaacson, 1967; Vanderwolf, 1962, 1963), the ansa l e n t i c u l a r i s (Caruthers, 1968), and I n t r o d u c t i o n 21 the mammillothalamic t r a c t (Krieckhaus, 1964) . However, no s i n g l e s t r u c t u r e can be i d e n t i f i e d as the c r i t i c a l s t r u c t u r e f o r avoidance behaviour, nor i s th e r e a coherent, i n c l u s i v e , w hole-brain model of avoidance. Mineka (1979) has suggested t h a t avoidance, o p e r a t i o n a l l y d e f i n e d , may not be a u n i t a r y b e h a v i o u r a l phenomenon wit h a s i n g l e n e u r o b i o l o g i c a l s u b s t r a t e . However, i t i s t o be hoped t h a t the understanding of avoidance i n g e n e r a l would be enhanced i f a s u b s t a n t i a l advance c o u l d be made i n understanding the c o n t r i b u t i o n o f even a s i n g l e c r i t i c a l n e u r a l system. Although dopamine p l a y s a c r i t i c a l r o l e i n the a c q u i s i t i o n o f avoidance responding, s u b s t a n t i a l doubt e x i s t s c o n c e r n i n g which component or components of the widespread t e l e n c e p h a l i c dopamine p r o j e c t i o n i s most important. There i s a wid e l y h e l d b e l i e f t h a t n i g r o s t r i a t a l dopamine i s r e q u i r e d f o r avoidance responding, i n p a r t i c u l a r the dopaminergic p r o j e c t i o n t o the v e n t r a l s t r i a t u m , but the evidence s u p p o r t i n g t h i s h y p o t h e s i s i s a c t u a l l y v e r y l i m i t e d . E a r l y s t u d i e s w i t h 6-OHDA o f t e n i n v o l v e d i n t r a v e n t r i c u l a r or i n t r a c i s t e r n a l i n f u s i o n of the neu r o t o x i n , l e a d i n g t o g l o b a l d e p l e t i o n of dopamine (e.g., Cooper e t a l . , 1973; Lenard & Beer, 1975). Other s t u d i e s have found avoidance d e f i c i t s a f t e r i n j e c t i n g 6-0HDA i n t o the s u b s t a n t i a n i g r a o r the caudate nucleus but have f a i l e d t o determine whether s t r i a t a l dopamine was d e p l e t e d (Delacour e t a l . , 1977; Heybach e t a l . , 1978; N e i l l , Boggan, & Grossman, 1974). S t i l l o t h e r s have determined t h a t I n t r o d u c t i o n 22 s t r i a t a l dopamine was d e p l e t e d , but d i d not determine whether ot h e r dopamine t e r m i n a l r e g i o n s were a l s o a f f e c t e d ( F i b i g e r e t a l . , 1974; Z i s e t a l . , 1974), or p r o v i d e d o n l y crude anatomical d e t a i l of t h e i r h i s t o l o g i c a l a n a l y s e s (Cooper e t a l . , 1974). Koob, Simon, Herman, and Le Moal (1984) d i d not observe avoidance a c q u i s i t i o n d e f i c i t s f o l l o w i n g s i n g l e b i l a t e r a l i n f u s i o n of 6-OHDA i n t o the p r e f r o n t a l c o r t e x , s u b s t a n t i a n i g r a , nucleus accumbens or s t r i a t u m , but a b o l i s h e d a c q u i s i t i o n w i t h j o i n t i n f u s i o n i n t o the nucleus accumbens p l u s the s t r i a t u m . T h i s was i n t e r p r e t e d as i n d i c a t i n g t h a t d i s r u p t i o n of both the nucleus accumbens and the s t r i a t u m i s r e q u i r e d t o produce avoidance d e f i c i t s . There are two problems w i t h t h i s i n t e r p r e t a t i o n . F i r s t , the double i n f u s i o n r e s u l t e d i n more severe d e p l e t i o n of dopamine i n each t e r m i n a l r e g i o n i n v e s t i g a t e d than d i d any s i n g l e i n f u s i o n . Thus, a s i n g l e s i t e c o u l d be r e s p o n s i b l e f o r the avoidance d e f i c i t , but the d e f i c i t may r e q u i r e more e x t e n s i v e dopamine d e p l e t i o n than t h a t achieved w i t h any s i n g l e l e s i o n . Second, dopamine l e v e l s were o n l y measured i n the p r e f r o n t a l c o r t e x , nucleus accumbens, and the s t r i a t u m . The p o s s i b i l i t y t h a t some oth e r b r a i n r e g i o n s might be i n v o l v e d was not c o n s i d e r e d , even though the area of d e p l e t i o n would have extended t o o t h e r s i t e s as w e l l . I t s hould be noted t h a t o t h e r evidence i m p l i c a t e s the amygdala as the c r i t i c a l s i t e of n e u r o l e p t i c a c t i o n i n avoidance d e f i c i t s . A s h f o r d and Jones (1976) found t h a t I n t r o d u c t i o n 23 a d m i n i s t r a t i o n of 6-OHDA t o the amygdala s u b s t a n t i a l l y impaired a c q u i s i t i o n of a two-way avoidance response, y e t had o n l y a s l i g h t impact on the performance of a p r e v i o u s l y a c q u i r e d response. S i m i l a r l y , i n f u s i o n of n e u r o l e p t i c s drugs i n t o the amygdala delayed a c q u i s i t i o n of a one-way response (Petty, Mott, & Sherman, 1984; Sherman, P e t t y , & Sacquinte, 1982). T h i s , along w i t h a g r e a t d e a l of evidence i m p l i c a t i n g the amygdala as a c r i t i c a l s t r u c t u r e i n avoidance responding (Brady, S c h r e i n e r , G e l l e r , & K l i n g , 1954; Coover, U r s i n , & Levine, 1973b; R i o l o b o s , 1986; Robinson, 1963; Werka, Skar, & U r s i n , 1978; Werka & Z i e l i n s k i , 1978), suggests t h a t the e f f e c t s of n e u r o l e p t i c drugs on avoidance may be mediated a t t h i s s i t e . A l t e r n a t i v e l y , the above evidence c o u l d be i n t e r p r e t e d as i n d i c a t i n g the s i g n i f i c a n c e of the a n a t o m i c a l l y r i c h c o n n e c t i o n between the amygdala and the v e n t r a l s t r i a t u m ( S a r t e r & Markowitsch, 1985). Overview In order t o extend the a n a l y s i s of dopamine f u n c t i o n t o the realm of p r e p a r a t o r y and consummatory d e f e n s i v e behaviour i n g e n e r a l , and t o avoidance responding i n p a r t i c u l a r , t h i s d i s s e r t a t i o n s h a l l examine the e f f e c t s of dopamine a n t a g o n i s t s ( n e u r o l e p t i c drugs) on v a r i o u s components of d e f e n s i v e behaviour. The r e s e a r c h w i l l f a l l i n t o s e v e r a l broad areas, each f o c u s s i n g on a d i f f e r e n t I n t r o d u c t i o n 24 i s s u e c o n c e r n i n g the r o l e o f dopamine i n d e f e n s i v e behaviour. Chapter I w i l l i n v e s t i g a t e the e f f e c t s on avoidance behaviour o f d i f f e r e n t n e u r o l e p t i c drugs b e l i e v e d t o a c t on d i f f e r e n t dopamine subsystems. T h i s w i l l accomplish s e v e r a l o b j e c t i v e s . F i r s t , i t may h e l p t o determine which n e u r a l systems are i n v o l v e d i n avoidance behaviour. Second, g i v e n t h a t n e u r o l e p t i c s have m u l t i p l e b e h a v i o u r a l a c t i o n s i n c l i n i c a l s e t t i n g s , t h i s study may i n d i c a t e which of these e f f e c t s i s most c l o s e l y r e l a t e d t o the d i s r u p t i o n o f avoidance behaviour. T h i r d , i t w i l l permit comparison w i t h a p p e t i t i v e responses: I f those n e u r o l e p t i c s t h a t b l o c k a n t i c i p a t o r y f e e d i n g responses are a l s o those t h a t b l o c k the a c q u i s i t i o n o f avoidance, i t would h e l p t o v a l i d a t e g e n e r a l i z a t i o n s concerning the l a r g e r c l a s s of p r e p a r a t o r y responses. F i n a l l y , i f i t i s p o s s i b l e t o f i n d a drug which a c t s o n l y on a subset o f dopamine t e r m i n a l s i t e s , y e t d i s r u p t s avoidance behaviour i n the same way as l e s s s p e c i f i c a n t a g o n i s t s , i t would be p r e f e r a b l e t o use t h a t drug i n subsequent s t u d i e s of d e f e n s i v e behaviour. For t h i s f i n a l reason, these experiments w i l l be pre s e n t e d a t the o u t s e t of t h i s d i s s e r t a t i o n . The r o l e t h a t dopamine p l a y s i n the a c q u i s i t i o n o f avoidance behaviour w i l l be examined i n f i n e r d e t a i l i n Chapter I I . T h i s i n v e s t i g a t i o n w i l l b egin by de t e r m i n i n g how much t r a i n i n g i t takes r a t s b e f o r e they are a b l e t o execute avoidance responses even under the i n f l u e n c e of I n t r o d u c t i o n 25 n e u r o l e p t i c drugs. T h i s w i l l l e a d i n t o an attempt t o d e f i n e p r e c i s e l y what r a t s must l e a r n i n order t o be p r o t e c t e d from the d i s r u p t i v e e f f e c t s of n e u r o l e p t i c drugs. For example, does the dopamine r e c e p t o r blockade i n t e r f e r e w i t h the a s s o c i a t i o n between the warning s i g n a l and the a v e r s i v e s t i m u l u s ? Does dopamine p l a y a p a r t i c u l a r r o l e i n l e a r n i n g the i n c e n t i v e v a l u e of s a f e t y s i g n a l s i n avoidance t r a i n i n g ? What i s the r e l a t i o n s h i p between l e a r n i n g t o escape and l e a r n i n g t o avoid? By examining the r o l e o f dopamine i n the a c q u i s i t i o n and maintenance of avoidance responding, i t i s hoped t h a t we might not only c l a r i f y the c o n t r i b u t i o n o f dopamine t o avoidance behaviour, but a l s o shed l i g h t on the more g e n e r a l q u e s t i o n of whether d i f f e r e n t p s y c h o l o g i c a l p r o c e s s e s c o n t r o l avoidance a t d i f f e r e n t stages o f a c q u i s i t i o n . Chapter I I I w i l l i n v e s t i g a t e the e f f e c t t h a t dopamine r e c e p t o r blockade has on d e f e n s i v e r e a c t i o n s o t h e r than avoidance. F r e e z i n g i s an important component of the d e f e n s i v e r e p e r t o i r e of r a t s (Blanchard & Blanchard, 1969a), one t h a t may c o n f l i c t with avoidance responding. I t would be i l l u m i n a t i n g t o know whether n e u r o l e p t i c s a l t e r u n c o n d i t i o n e d o r c o n d i t i o n e d responses t o shock. S p e c i f i c a l l y , we s h a l l determine whether n e u r o l e p t i c treatment i n c r e a s e s a r a t ' s tendency t o f r e e z e i n response t o shock, or t o c o n d i t i o n a l s t i m u l i s i g n a l l i n g shock. Chapter IV w i l l c o n s i d e r whether a l t e r e d responses t o shock can account i n p a r t f o r the observed d e f i c i t s i n I n t r o d u c t i o n 2 6 avoidance responding. S p e c i f i c a l l y , evidence s h a l l be pr e s e n t e d t h a t enhanced consummatory f r e e z i n g responses t o shock and s h o c k - r e l a t e d s t i m u l i d i s r u p t those p r e p a r a t o r y responses t o d i s t a l cues t h a t would permit r a t s t o a v o i d shock. The g e n e r a l d i s c u s s i o n w i l l c o n s i d e r the c a p a c i t y of s e v e r a l hypotheses of dopamine f u n c t i o n t o account f o r the r e s u l t s o f the v a r i o u s s t u d i e s , and s h a l l develop the a n a l y s i s o f dopamine's c o n t r i b u t i o n t o p r e p a r a t o r y behaviour i n g e n e r a l . Chapter I 27 I EFFECTS OF DIFFERENT CLASSES OF NEUROLEPTIC DRUGS ON ONE-WAY AVOIDANCE BEHAVIOUR A l a r g e v a r i e t y o f pha r m a c o l o g i c a l substances may be c l a s s i f i e d as dopamine a n t a g o n i s t s ( n e u r o l e p t i c drugs) on the b a s i s o f t h e i r a b i l i t y t o b i n d t o dopamine r e c e p t o r s and t o b l o c k e f f e c t s of dopamine or dopamine a g o n i s t s . However, not a l l n e u r o l e p t i c drugs have the same p h a r m a c o l o g i c a l , b e h a v i o u r a l , o r c l i n i c a l e f f e c t s . The purpose of the experiments i n t h i s chapter i s to determine the e f f e c t of markedly d i f f e r e n t n e u r o l e p t i c compounds on the a c q u i s i t i o n and performance of one-way avoidance behaviour. T h i s s h a l l accomplish f o u r o b j e c t i v e s . F i r s t , i f v a l i d p a r a l l e l s are t o be drawn between d e f e n s i v e and a p p e t i t i v e behaviours, then both c l a s s e s o f behaviour should be a f f e c t e d s i m i l a r l y by d i f f e r e n t c l a s s e s o f n e u r o l e p t i c s . Otherwise, n e u r o l e p t i c - i n d u c e d d i s r u p t i o n of these behaviours would appear t o be under the c o n t r o l of independent dopamine systems. Second, we can determine which c l i n i c a l e f f e c t s o f n e u r o l e p t i c s are most c l o s e l y r e l a t e d t o avoidance d e f i c i t s . T h i s w i l l suggest whether i t i s reasonable t o loo k f o r p a r a l l e l s between p r e p a r a t o r y a p p e t i t i v e responses and avoidance behaviour, on one hand, and human n e u r o l o g i c a l and n e u r o p s y c h i a t r i c d i s o r d e r s , on the other. As w e l l , t h i s approach may p r o v i d e evidence r e l e v a n t t o the e v a l u a t i o n of avoidance responding as an animal model f o r t e s t i n g the Chapter I 2 8 p o t e n t i a l c l i n i c a l e f f i c a c y of novel n e u r o l e p t i c compounds. T h i r d , these p h a r m a c o l o g i c a l i n v e s t i g a t i o n s may p r o v i d e c l u e s as t o which a n a t o m i c a l l y i d e n t i f i e d dopamine subsystems are i n v o l v e d i n avoidance, a q u e s t i o n t h a t has not been r e s o l v e d c l e a r l y through s t u d i e s employing s e l e c t i v e b r a i n l e s i o n s . Fourth, i f i t i s p o s s i b l e t o i d e n t i f y a n e u r o l e p t i c drug which i s more s e l e c t i v e than compounds t h a t have been used i n the p a s t , y e t has a s i m i l a r impact on avoidance responding, i t would be p r e f e r a b l e t o use t h a t drug i n o t h e r s t u d i e s of avoidance behaviour. Experiment 1.1: E f f e c t s of h a l o p e r i d o l H a l o p e r i d o l i s a w i d e l y p r e s c r i b e d a n t i p s y c h o t i c drug whose long-term use i s o f t e n a s s o c i a t e d w i t h u n d e s i r a b l e e x t r a p y r a m i d a l s i d e e f f e c t s (EPSEs). I t has p r e v i o u s l y been shown t o d i s r u p t one-way (e.g., F i b i g e r e t a l . , 1975) and two-way (e.g., Janssen, Niemegeers, & S c h e l l e k e n s , 1965), as w e l l as d i s c r i m i n a t e d and n o n d i s c r i m i n a t e d l e v e r p r e s s (e.g., Davidson & Weidley, 1976; Niemegeers, Verbruggen, & Janssen, 19 69) avoidance behaviour. In the p r e s e n t experiment, the e f f e c t s of h a l o p e r i d o l on one-way avoidance behaviour were examined again, i n order t o p r o v i d e a b a s i s of comparison f o r other n e u r o l e p t i c drugs. Method S u b j e c t s : Male hooded r a t s o b t a i n e d from C h a r l e s R i v e r L a b o r a t o r i e s of Canada were used. A l l r a t s were e x p e r i m e n t a l l y n a i v e , weighed 300 - 600 g a t the s t a r t of Chapter I 29 the experiment and were housed i n d i v i d u a l l y i n a c l i m a t i c a l l y - c o n t r o l l e d colony room on a 12 h l i g h t - d a r k c y c l e i n wire s t a i n l e s s s t e e l cages. Each experimental s e s s i o n o c c u r r e d between 0900 and 1300 h. Apparatus: The avoidance apparatus c o n s i s t e d of a s h u t t l e b o x (25 cm x 78 cm x 33 cm deep) d i v i d e d i n t o two equal h a l v e s by a p a r t i t i o n . Both h a l v e s were p a i n t e d f l a t b l a c k . The p a r t i t i o n c o u l d be opened by r a i s i n g a 13-cm wide g u i l l o t i n e door. A g r i d f l o o r on one s i d e (the "shock" side) c o u l d be e l e c t r i f i e d by a scrambled 1.0 mA d.c. c u r r e n t (BRS/LVE shock g e n e r a t o r ) . A 2900 Hz tone generator (So n a l e r t ) was mounted below the g r i d f l o o r a t the end of the shock s i d e , and a 3.3 ca cue l i g h t (not used i n t h i s experiment) was mounted above the tone generator, near the top of the same w a l l , c e n t r e d 3 4 cm above the g r i d . E l e c t r o m e c h a n i c a l r e l a y s and t i m e r s were used f o r s t i m u l u s c o n t r o l and data c o l l e c t i o n . Avoidance t r a i n i n g : T r a i n i n g s e s s i o n s o c c u r r e d a t approximately the same time f o r s i x c o n s e c u t i v e days. Each r a t r e c e i v e d 10 t r i a l s per s e s s i o n . Each s e s s i o n began by p u t t i n g a r a t i n t o the " s a f e " ( n o n - e l e c t r i f i e d ) s i d e of the s h u t t l e b o x . A f t e r 3 0 s the r a t was p l a c e d on the shock s i d e o f a c i n g away from the g u i l l o t i n e door. The t r i a l began w i t h tone (WS) onset and the opening of the door. I f the r a t moved i n t o the s a f e s i d e d u r i n g the 10-s tone p e r i o d the tone was t u r n e d o f f , the door was lowered, and an avoidance response was recorded. I f the r a t f a i l e d t o a v o i d d u r i n g Chapter I 30 the 10-s tone p e r i o d , the o f f s e t o f the tone was contiguous w i t h the onset o f the footshock (AS). Movement i n t o the s a f e s i d e was f o l l o w e d by lowering the door, and an escape response was recorded. I f no response o c c u r r e d w i t h i n 10 s f o l l o w i n g shock onset, the r a t was pushed g e n t l y i n t o the s a f e s i d e and was assign e d a response l a t e n c y o f 20 s. E n t r y i n t o the s a f e s i d e always i n i t i a t e d the next 30-s i n t e r t r i a l i n t e r v a l . S t a t i s t i c a l a n a l y s i s ; The number of avoidances were analyzed u s i n g a two-way (Group x Day) A n a l y s i s o f V a r i a n c e (ANOVA). Latency s c o r e s were analyzed w i t h a three-way (Group x Day x T r i a l ) ANOVA. In each case s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-Keul 1s pos t hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . Because the treatment of the groups changed between Phase A and Phase B, post hoc t e s t s were o n l y conducted on the Group x Day i n t e r a c t i o n . H a l o p e r i d o l t e s t i n g : Drug e f f e c t s on the a c q u i s i t i o n of avoidance responding were i n v e s t i g a t e d i n Phase A (Days 1 - 3 ) o f each experiment, i n which groups o f r a t s r e c e i v e d i n j e c t i o n s o f drug or v e h i c l e . The v e h i c l e - t r e a t e d r a t s subsequently r e c e i v e d an i n t e r m e d i a t e dose of drug i n Phase B (Days 4 - 6) t o determine e f f e c t s on the performance o f a p r e v i o u s l y a c q u i r e d response. A l l o t h e r groups r e c e i v e d v e h i c l e i n j e c t i o n s i n Phase B. A l l s o l u t i o n s were i n j e c t e d subcutaneously, 60 t o 90 min p r i o r t o t e s t i n g . H a l o p e r i d o l (McNeil Pharmaceutical, S t o u f f v i l l e , O ntario) was d i l u t e d t o 0.075 or 0.150 mg/ml i n d i s t i l l e d Chapter I 31 water. Separate groups of r a t s , d e s i g n a t e d as .075-V and .150-V, r e c e i v e d 0.075 and 0.150 mg/kg h a l o p e r i d o l , r e s p e c t i v e l y , on each day of Phase A. Group V-.150 r e c e i v e d water. In Phase B Groups .075-V and .150-V r e c e i v e d water, and Group V-.150 r e c e i v e d 0.150 mg/kg h a l o p e r i d o l . Each group c o n s i s t e d of 6 r a t s . R e s u l t s The number of avoidances are i l l u s t r a t e d i n the top panel of F i g u r e 1. H a l o p e r i d o l , a t a dose of 0.150 mg/kg, completely b l o c k e d the a c q u i s i t i o n of avoidance responding i n Phase A. A c q u i s i t i o n was a l s o s e v e r e l y d i s r u p t e d f o l l o w i n g treatment w i t h the lower dose (.075 mg/kg), wi t h t h i s group a t t a i n i n g a mean of 3.3 avoidances i n 10 t r i a l s on the t h i r d day. Rats t h a t had a c q u i r e d e f f i c i e n t avoidance behaviour i n Phase A were o n l y moderately a f f e c t e d by h a l o p e r i d o l (0.150 mg/kg) i n the f i r s t s e s s i o n of Phase B (M = 7.2 a v o i d a n c e s ) . However, the d i s r u p t i v e e f f e c t became much more severe on the f i n a l two days of t e s t i n g . The ANOVA i n d i c a t e d a s i g n i f i c a n t e f f e c t of Day [F(5,75) = 45.84, p_ < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(10,75) = 60.88, p < .001], but not a s i g n i f i c a n t e f f e c t of Group [F(2,15) = 3.30, p > .05]. Post hoc t e s t s i n d i c a t e d t h a t Group V-.150 made the most avoidance responses on Days 1 t o 3. On Days 2 and 3 Group .075-V made more avoidances than Group .150-V. There were no between-group d i f f e r e n c e s on Day 4. On Days 5 and 6 Groups .150-V and .075-V performed more avoidance responses than Group V-Chapter I 32 F i g u r e 1. E f f e c t s of h a l o p e r i d o l Top panel i n d i c a t e s mean number of avoidances executed on each day by the r a t s o f the v a r i o u s groups. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A Groups .075-V and .150-V r e c e i v e d 0.075 and 0.150 mg/kg h a l o p e r i d o l , r e s p e c t i v e l y , and Group V-0.150 r e c e i v e d v e h i c l e . In Phase B Groups .075-V and .150-V r e c e i v e d v e h i c l e and Group V-.150 r e c e i v e d 0.150 mg/kg h a l o p e r i d o l . Chapter I 33 CO LU CO z o CL CO LU GC LU CJ <c Q I—i o > 14->- 12--z. LU I— 10-• <c -_l 8-LU -CO fi -o -Q_ A . CO 4 LU -CC 2-HALOPERIDOL Phase A. Phase B. • V - .150 • .075 - V 0 .150 - V 3 4 TEST DAY Chapter I 34 .150. I t i s i n t e r e s t i n g t o note t h a t Groups .075-V and .150-V avoided s i g n i f i c a n t l y more o f t e n on Day 4, t h e i r f i r s t undrugged day, than Group V-.150 had on Day 1. A d d i t i o n a l i n f o r m a t i o n can be gleaned by c o n s i d e r i n g the s c o r e s of i n d i v i d u a l groups a c r o s s the s i x days of the experiment. Group V-.150 avoided s i g n i f i c a n t l y more o f t e n on Days 2 and 3 than on Day 1, as they a c q u i r e d the response. On Day 4 t h e i r performance was s i g n i f i c a n t l y d i s r u p t e d by a d m i n i s t r a t i o n of h a l o p e r i d o l , and t h e i r performance d e t e r i o r a t e d f u r t h e r on Days 5 and 6. In c o n t r a s t , the performance of Groups .150-V and .075-V d i d not change s i g n i f i c a n t l y from Day 1 t o Days 2 and 3, as they d i d not a c q u i r e the response i n Phase A. Group .150-V improved on Day 4, f o l l o w i n g the c e s s a t i o n of h a l o p e r i d o l treatment. T h e i r performance improved f u r t h e r on Day 5. Group .075-V a l s o improved on Day 4, r e l a t i v e t o t h e i r drug t e s t on Day 3, but t h e i r performance d i d not change s i g n i f i c a n t l y between Days 4 and 6. A s i m i l a r p a t t e r n of r e s u l t s h e l d f o r response l a t e n c i e s (see bottom panel of F i g u r e 1). The ANOVA i n d i c a t e d s i g n i f i c a n t e f f e c t s of Group [F(2,15) = 5.24, p_ < .05] and Day [F(5,885) = 101.34, p_ < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(10,885) = 174.43, p_ < .001]. Post hoc examination of the i n t e r a c t i o n i n d i c a t e d t h a t throughout Phase A the l a t e n c i e s of Group V-.150 were s h o r t e s t . Group .075-V had s h o r t e r l a t e n c i e s than Group .150-V on Day 2 and Day 3. On the f i r s t day of Phase B, the Chapter I 35 l a t e n c i e s o f Groups .150-V and .075-V d i d not d i f f e r from those of Group V-.150. On Days 5 and 6 Groups .150-V and ,075-V had s i g n i f i c a n t l y lower l a t e n c i e s than Group V-.150. Note a g a i n t h a t the l a t e n c i e s of Groups .075-V and .150-V were s i g n i f i c a n t l y lower on Day 4 than those of Group V-.150 had been on Day 1. C o n s i d e r i n g the performance of i n d i v i d u a l groups a c r o s s days i n Phase A, the c r i t i c a l f i n d i n g s were (a) a s i g n i f i c a n t improvement i n the response l a t e n c i e s of Group V-.150, (b) no improvement by Group .075-V, and (c) a d e t e r i o r a t i o n i n the response l a t e n c i e s of Group .150-V from Day 1 t o Day 2. In Phase B response l a t e n c i e s o f Groups .150-V and .075-V decreased markedly, r e l a t i v e t o Day 3. Group V-.150 response l a t e n c i e s were i n c r e a s e d f o l l o w i n g 0.150 mg/kg h a l o p e r i d o l on Day 4, and response l a t e n c i e s i n c r e a s e d s u b s t a n t i a l l y by Day 6. Examination of the l a t e n c y s c o r e s f o r i n d i v i d u a l groups a c r o s s days r e v e a l s s e v e r a l i n t e r e s t i n g phenomena. As expected, the l a t e n c i e s f o r Group V-.150 decreased i n Phase A w h i l e these r a t s a c q u i r e d the response, w h i l e those of .075-V d i d not. I n t e r e s t i n g l y , the l a t e n c i e s of Group .150-V a c t u a l l y i n c r e a s e d over the days of Phase A. In Phase B, as expected, the s c o r e s of Groups .150-V and .075-V decreased as they now a c q u i r e d the response, w h i l e those of Group V-.150 i n c r e a s e d s i g n i f i c a n t l y on each s u c c e s s i v e day. Chapter I 3 6 D i s c u s s i o n The p r e s e n t experiment confirmed t h a t h a l o p e r i d o l can prevent a c q u i s i t i o n o f a one-way a c t i v e avoidance response ( F i b i g e r e t a l . , 1975). The experiment a l s o demonstrates s e v e r a l o t h e r p r e v i o u s l y d e s c r i b e d e f f e c t s of n e u r o l e p t i c drugs on avoidance behaviour. F i r s t , although h a l o p e r i d o l prevented a c q u i s i t i o n o f the avoidance response, the drug had r e l a t i v e l y l i t t l e impact on the performance of escape responses o c c u r r i n g a f t e r the onset of shock (Arnt, 1982; Cook & Weidley, 1957; van der Heyden & Bradford, 1988). T h i s was p a r t i c u l a r l y e v i d e n t on Day 1. On Days 2 and 3 the mean response l a t e n c y i n c r e a s e d . As responses were v i r t u a l l y always escape responses, t h i s i n d i c a t e s t h a t the impairment produced by 0.150 mg/kg h a l o p e r i d o l was so extreme t h a t even escape l a t e n c i e s were i n c r e a s e d . Second, d e s p i t e the hig h l e v e l of d e b i l i t a t i o n produced by 0.150 mg/kg d u r i n g Phase A, the same dose had onl y a m i l d e f f e c t on the performance of Group V-.150 on Day 4, a f t e r these r a t s had r e c e i v e d t h r e e days of d r u g - f r e e t r a i n i n g . Thus, t h e r e was a c l e a r d i s s o c i a t i o n between the e f f e c t s of h a l o p e r i d o l on the a c q u i s i t i o n o f avoidance responding and i t s s p a r i n g of a p r e v i o u s l y a c q u i r e d response. T h i s phenomenon has p r e v i o u s l y been noted with both h a l o p e r i d o l (e.g., F i b i g e r e t a l . , 1975) and pimozide (e.g., Beninger e t a l . , 1983). Chapter I 37 T h i r d , the p r o t e c t i v e e f f e c t of p r e - t r a i n i n g was not a b s o l u t e . A d m i n i s t r a t i o n of h a l o p e r i d o l t o Group V-.150 on Day 4 produced a s i g n i f i c a n t decrease i n the number of avoidance responses executed (from 10.0/10 t o 7.2/10). What i s more, t h e r e was a p r o g r e s s i v e d e t e r i o r a t i o n i n performance by t h i s group a c r o s s the t h r e e days they r e c e i v e d h a l o p e r i d o l i n Phase B. Such p r o g r e s s i v e d e t e r i o r a t i o n has p r e v i o u s l y been observed on c o n s e c u t i v e days of n e u r o l e p t i c t e s t i n g (Beninger e t a l . , 1983; Carey & Kenney, 1987) or on repeated t e s t i n g f o l l o w i n g 6-OHDA l e s i o n s of c e n t r a l dopamine neurons (Beer & Lenard, 1975; Cooper e t a l . , 1973; Lenard & Beer, 1975). The v e r y r a p i d d e c l i n e i n performance over t h r e e days of t e s t i n g i n the pr e s e n t experiment was much more extreme than t h a t observed by Beninger e t a l . (1983), and can again be a t t r i b u t e d t o the magnitude of the dose of n e u r o l e p t i c used here. Coupled w i t h the marked i n c r e a s e i n response l a t e n c i e s observed f o r Group .150-V a c r o s s Phase A, i t seems prob a b l e t h a t the dose may have been s u f f i c i e n t l y h i g h t o have had n o n - s p e c i f i c as w e l l as s p e c i f i c e f f e c t s on avoidance responding. A f i n a l f e a t u r e of t h i s s e t of data t h a t warrants comment i s the r a p i d a c q u i s i t i o n of the avoidance response by those r a t s t h a t were switched t o v e h i c l e i n Phase B. De s p i t e t h e i r abysmal performance on the t h i r d d r u g - t e s t day of Phase A, the r a t s i n Group .150-V had lower response l a t e n c i e s and more avoidance responses on Day 4 than Group V-.150 d i d on Day 1. S i m i l a r data have been r e p o r t e d Chapter I 38 p r e v i o u s l y (Beninger, Mason, P h i l l i p s , & F i b i g e r , 1980b; Davidson & Weidley, 1976; F i b i g e r e t a l . , 1975; Posluns, 1962; but see Beninger e t a l . , 1980a). From t h i s we can i n f e r t h a t (a) t h e r e are no s e r i o u s d e l e t e r i o u s e f f e c t s from p r i o r d a i l y i n j e c t i o n s of h a l o p e r i d o l , thus the d e c l i n e i n performance over s u c c e s s i v e days by h a l o p e r i d o l - t r e a t e d r a t s cannot be a t t r i b u t e d t o cumulative r e s i d u a l e f f e c t s of the drug, and (b) although the r a t s of Group .150-V d i d not a v o i d a t a l l on Day 3, they must have a c q u i r e d knowledge r e l e v a n t t o the e x e c u t i o n of the response d u r i n g Phase A. T h i s experiment confirmed t h a t the avoidance paradigm employed here i s a f f e c t e d by n e u r o l e p t i c drugs i n the same manner as i n other p r e v i o u s l y d e s c r i b e d r e s e a r c h . The remainder of Chapter I s h a l l examine the e f f e c t s of o t h e r dopamine a n t a g o n i s t s t o determine whether the avoidance-d i s r u p t i n g p r o p e r t i e s of h a l o p e r i d o l are more c l o s e l y r e l a t e d t o i t s a n t i p s y c h o t i c e f f e c t s or t o i t s a b i l i t y t o produce m o t o r i c s i d e e f f e c t s . Experiment I.2a: E f f e c t s of t h i o r i d a z i n e S o - c a l l e d " a t y p i c a l " n e u r o l e p t i c s are potent a n t i p s y c h o t i c agents. However, compared t o " c l a s s i c a l " n e u r o l e p t i c compounds, such as h a l o p e r i d o l or pimozide, t h e i r long-term use i s i n f r e q u e n t l y a s s o c i a t e d w i t h e x t r a p y r a m i d a l s i d e e f f e c t s (EPSEs), such as t a r d i v e d y s k i n e s i a , a t c l i n i c a l l y e f f e c t i v e doses (Snyder, Greenberg, & Yamamura, 1974; Tamminga, 1983). T h i o r i d a z i n e Chapter I 39 i s one w i d e l y - p r e s c r i b e d a t y p i c a l n e u r o l e p t i c . Thus, i f i t b l o c k s the a c q u i s i t i o n of avoidance behaviour, we might surmise t h a t t h i s e f f e c t of c l a s s i c a l n e u r o l e p t i c compounds i s r e l a t e d t o t h e i r a n t i p s y c h o t i c p r o p e r t i e s , r a t h e r than t o t h e i r a b i l i t y t o induce EPSEs. In c o n t r a s t , i f t h i o r i d a z i n e does not b l o c k avoidance responding, i t would seem u n l i k e l y t h a t the blockade of avoidance i s r e l a t e d t o the a n t i p s y c h o t i c p r o p e r t i e s of n e u r o l e p t i c s . In work wi t h a p p e t i t i v e behaviours, i t has been demonstrated t h a t p r e p a r a t o r y behaviours are b l o c k e d by pimozide, a s o - c a l l e d " c l a s s i c a l " n e u r o l e p t i c drug (Blackburn, 1985; Blackburn e t a l . , 1987). S i m i l a r e f f e c t s have a l s o been observed with h a l o p e r i d o l (unpublished o b s e r v a t i o n s ) . A r e c e n t study examined the e f f e c t s of t h i o r i d a z i n e on p r e p a r a t o r y and consummatory f e e d i n g responses. T h i o r i d a z i n e (10 - 30 mg/kg) had no s i g n i f i c a n t e f f e c t on any measure of p r e p a r a t o r y or consummatory f e e d i n g behaviour (Blackburn, P h i l l i p s , & F i b i g e r , 1989b). Thus, i f avoidance behaviour i s b l o c k e d by t h i o r i d a z i n e , avoidance and p r e p a r a t o r y a p p e t i t i v e responding would appear t o be under the c o n t r o l of d i s t i n c t dopaminergic systems. Method S u b j e c t s , apparatus, procedure, and s t a t i s t i c a l  a n a l y s i s : S u b j e c t s s i m i l a r t o those of Experiment 1.1 were used, and were t e s t e d i n the same apparatus u s i n g the same procedure. Data were again analyzed u s i n g the ANOVA, Chapter I 4 0 f o l l o w e d by Newman-Keul 1s post hoc t e s t , as i n Experiment 1.1. T h i o r i d a z i n e t e s t i n g : T h i o r i d a z i n e (Sandoz Pharmaceuticals, E. Hanover, NJ) was d i s s o l v e d as 3 0 mg of drug i n 0.95 ml of 1% l a c t i c a c i d . When d i s s o l v e d , an a d d i t i o n a l 0.05 ml of 0.1 N NaOH was added t o r a i s e the pH t o 5.75. Separate groups of r a t s , d e s i g n a t e d 10-V, 20-V, and 30-V, r e c e i v e d 10, 20, and 30 mg/kg t h i o r i d a z i n e , r e s p e c t i v e l y , i n Phase A. Group V-20 r e c e i v e d v e h i c l e . In Phase B Groups 10-V, 20-V, and 30-V r e c e i v e d v e h i c l e , w h i l e Group V-20 r e c e i v e d 20 mg/kg t h i o r i d a z i n e . Each group c o n s i s t e d of 9 r a t s . On Day 5 t h e r e was an equipment m a l f u n c t i o n t h a t p r e c l u d e d f u r t h e r t e s t i n g of s e v e r a l r a t s , r e d u c i n g group s i z e s t o 7 on Day 5, and 6 on Day 6. R e s u l t s R e l a t i v e t o c o n t r o l c o n d i t i o n s the a c q u i s i t i o n of avoidance responding was a t t e n u a t e d by 10 - 30 mg/kg t h i o r i d a z i n e . Nonetheless, a l l groups made more avoidance responses over the t h r e e drug-treatment days of Phase A, r e l a t i v e t o t h e i r s cores on Day 1 (see top panel of F i g u r e 2). As w e l l , a d m i n i s t r a t i o n of 20 mg/kg t h i o r i d a z i n e had l i t t l e e f f e c t on the performance of p r e v i o u s l y a c q u i r e d avoidance responding by Group V-20 i n Phase B. These impressions were confirmed by the ANOVA. There were s i g n i f i c a n t e f f e c t s of Group [F(3,32) = 3.28, p < .05] and Day [F(5,140) = 81.29, p < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(15,140) = 1.92, p < .05]. Post hoc Chapter I 41 F i g u r e 2. E f f e c t s of t h i o r i d a z i n e Top panel i n d i c a t e s mean number of avoidances executed on each day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A Groups 10-V, 20-V, and 30-V r e c e i v e d 10, 20 and 30 mg/kg t h i o r i d a z i n e , r e s p e c t i v e l y , and Group V-20 r e c e i v e d v e h i c l e . In Phase B Groups 10-V, 20-V, and 30-V r e c e i v e d v e h i c l e , and Group V-20 r e c e i v e d 20 mg/kg t h i o r i d a z i n e . Chapter I 42 THIORIDAZINE T 1 1 J 1 1 1-1 2 3 4 5 6 TEST DAY Chapter I 43 examination of the i n t e r a c t i o n i n d i c a t e d t h a t Group V-2 0 made more avoidance responses than any o t h e r group on Day 1, more than Groups 20-V or 30-V on Day 2, and more than Group 30-V on Day 3. There were no between-group d i f f e r e n c e s i n Phase B. A s i m i l a r p a t t e r n h e l d f o r the response l a t e n c y s c o r e s (see bottom panel of F i g u r e 2). The anova i n d i c a t e d a s i g n i f i c a n t e f f e c t of Group [F(3,32) = 4.74, p < .01], Day [F(5,1685) = 188.10, p < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(15,1685) = 18.99, p < .001]. Post hoc t e s t s i n d i c a t e d t h a t Group V-2 0 had s h o r t e r l a t e n c i e s than any o t h e r on Days 1 t o 3. When drug c o n d i t i o n s changed on Day 4, Group 3 0-V s t i l l had l o n g e r l a t e n c i e s than any o t h e r group. However, on Days 5 and 6 Group 3 0-V was not s i g n i f i c a n t l y d i f f e r e n t from Group V-20. On these l a s t two days, when Group V-2 0 was r e c e i v i n g 2 0 mg/kg, i t had s i g n i f i c a n t l y l o n g e r l a t e n c i e s than d i d Groups 10-V and 2 0-V. In examining the progress of i n d i v i d u a l groups a c r o s s days, each group improved on Days 2 and 3, r e l a t i v e t o Day 1. Thus, t h i o r i d a z i n e d i d not b l o c k a c q u i s i t i o n of avoidance responding. In Phase B, when they r e c e i v e d v e h i c l e , Groups 10-V and 20-V performed b e t t e r than a t the end o f Phase A. In c o n t r a s t , Group V-2 0 had s i g n i f i c a n t l y l o n g e r response l a t e n c i e s i n Phase B, when they r e c e i v e d 2 0 mg/kg t h i o r i d a z i n e , even though they s t i l l maintained a h i g h number of avoidance responses. Chapter I 44 D i s c u s s i o n I t seems improbable t h a t the i n e f f e c t i v e n e s s of t h i o r i d a z i n e i n t h i s experiment i s due t o the use of i n s u f f i c i e n t doses of the drug. A dose of 2 0 mg/kg i s c l i n i c a l l y e q u i v a l e n t t o a dose of 0.5 mg/kg h a l o p e r i d o l ( B a l d e s s a r i n i , 1985), a dose f a r i n excess of t h a t r e q u i r e d t o completely b l o c k the a c q u i s i t i o n of avoidance responding i n Experiment 1.1 (see a l s o Davidson & Weidley, 1976; F i b i g e r e t a l . , 1975). F u r t h e r , doses below t h i s range have been shown p r e v i o u s l y t o b l o c k dopamine- or amphetamine-induced locomotion (Costal1 & Naylor, 197 6; Ljungberg & Ungerstedt, 1985) and t o i n c r e a s e dopamine t u r n o v e r and r e l e a s e i n the nucleus accumbens (Crow, Deakin, & Longden, 1975; Lane &" Blaha, 1987). Most i m p o r t a n t l y , even though 2 0 mg/kg t h i o r i d a z i n e d i d not prevent a c q u i s i t i o n of a h i g h r a t e of avoidance responding, i t was s u f f i c i e n t t o i n c r e a s e the l a t e n c y t o perform a p r e v i o u s l y a c q u i r e d response: Even though the number of avoidance responses executed by Group V-20 d i d not decrease from Day 3 t o Day 4, t h e i r mean response l a t e n c y i n c r e a s e d s i g n i f i c a n t l y from 2.5 s t o 4.1 s. D e s p i t e these c o n s i d e r a t i o n s , i t i s s t i l l c o n c e i v a b l e t h a t some h i g h e r dose of t h i o r i d a z i n e c o u l d b l o c k a c q u i s i t i o n without d i s r u p t i n g performance of a p r e v i o u s l y a c q u i r e d response as w e l l . A c c o r d i n g l y , an a d d i t i o n a l experiment examined the e f f e c t s of a h i g h e r dose of the drug 1! Chapter I 4 5 Experiment I.2b: E f f e c t s of 50 mg/kg t h i o r i d a z i n e T h i s experiment examined the e f f e c t s o f a h i g h e r dose of t h i o r i d a z i n e than was used i n Experiment I.2a. Method S u b j e c t s , apparatus, procedure, and s t a t i s t i c a l  a n a l y s i s : S u b j e c t s s i m i l a r t o those of Experiment 1.1 were used, and were t e s t e d i n the same apparatus u s i n g the same procedure. Data were again analyzed u s i n g the ANOVA, f o l l o w e d by Newman-Keul 1s post hoc t e s t , as i n Experiment 1.1. T h i o r i d a z i n e t e s t i n g : T h i o r i d a z i n e (Sandoz Pharmaceuticals, E. Hanover, NJ) was d i s s o l v e d by s o n i c a t i o n i n d i s t i l l e d water. Group 50-V (n = 6) r e c e i v e d 50 mg/kg t h i o r i d a z i n e i n Phase A, and v e h i c l e i n Phase B. Group V-50 (n = 6) r e c e i v e d v e h i c l e i n Phase A, and 50 mg/kg i n Phase B. R e s u l t s As shown i n the top panel of F i g u r e 3, r a t s r e c e i v i n g 50 mg/kg t h i o r i d a z i n e a t t a i n e d a mean l e v e l o f 5.2 avoidance responses i n 10 t r i a l s by the end of Phase A. I t i s noteworthy t h a t t h i s l e v e l of performance was e q u i v a l e n t t o t h a t observed i n Phase B f o r the group t h a t had p r e v i o u s l y r e c e i v e d 50 mg/kg i n Phase A. The ANOVA i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t e f f e c t o f Day [F(5,50) = 16.17, p < .001] and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(5,50) = 27.43, p < .001], but no s i g n i f i c a n t e f f e c t o f Group [F < Chapter I 46 F i g u r e 3. E f f e c t s o f 50 mg/kg t h i o r i d a z i n e Top panel i n d i c a t e s mean number of avoidances executed on each day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A Group 50-V r e c e i v e d 50 mg/kg t h i o r i d a z i n e , and Group V-50 r e c e i v e d v e h i c l e . In Phase B Group 50-V r e c e i v e d v e h i c l e and Group V-50 r e c e i v e d 50 mg/kg t h i o r i d a z i n e . Chapter I 47 CO LU CO o CL CO LU QZ LU CJ z <c Q l-H O > 10-8-6-4 -2 ->-CJ 12H ji" 10-1 <: —1 8H 6 4-2-LU CO z o CL CO LU THIORIDAZINE Phase A. Phase B Phase A • V-50 o 50-V Phase B 3 4 TEST DAY —t— 5 i 6 Chapter I 48 1]. Post hoc examination of the i n t e r a c t i o n i n d i c a t e d t h a t Group V-50 made more avoidance responses than Group 50-V on Days 1 t o 3, whereas Group 50-V made more responses than Group V-50 on Days 5 and 6. There was no between-group d i f f e r e n c e on Day 4. The performance o f Group V-50 on Days 4 t o 6 d i d not d i f f e r from t h a t of Group 50-V on Days 2 and 3. That i s , t h e r e was no d i s s o c i a t i o n between the e f f e c t s of t h i o r i d a z i n e on the a c q u i s i t i o n and performance o f avoidance responding. The same p a t t e r n i s seen f o r the response l a t e n c i e s (see bottom panel o f F i g u r e 3). The ANOVA i n d i c a t e d a s i g n i f i c a n t e f f e c t o f Day [F(5,590) = 26.21, p < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(5,590) = 75.79, p < .001], but no s i g n i f i c a n t e f f e c t of Group [F < 1]. Post hoc t e s t s i n d i c a t e d t h a t the performance of Group V-50 was s u p e r i o r t o t h a t o f Group 50-V on Days 1 t o 3. When drug c o n d i t i o n s were r e v e r s e d , Group 50-V had s h o r t e r l a t e n c i e s than Group V-50 on Days 4 t o 6. Again, a n a l y s i s of response l a t e n c i e s i n d i c a t e d t h a t the performance of Group V-50 on Days 4 t o 6 d i d not d i f f e r from t h a t of Group 50-V on Days 2 and 3. D i s c u s s i o n T h i s experiment demonstrated t h a t , i n s u f f i c i e n t l y h i g h doses, t h i o r i d a z i n e can s i g n i f i c a n t l y a t t e n u a t e avoidance responding. However, i n marked c o n t r a s t t o the e f f e c t of h a l o p e r i d o l , the d i s r u p t i v e e f f e c t of high-dose t h i o r i d a z i n e was i d e n t i c a l d u r i n g a c q u i s i t i o n of avoidance and d u r i n g performance of a p r e v i o u s l y a c q u i r e d response. T h i s p r o f i l e Chapter I 49 of r e s u l t s suggests t h a t t h i o r i d a z i n e had a much l e s s s p e c i f i c e f f e c t on avoidance than d i d h a l o p e r i d o l . As non-s p e c i f i c performance d e f i c i t s are a l s o observed w i t h a wide v a r i e t y of p h a r m a c o l o g i c a l agents, such as b a r b i t u r a t e s , i t i s u n l i k e l y t h a t such e f f e c t s p r o v i d e important c l u e s c o n c e r n i n g the s p e c i f i c r o l e f o r dopamine i n avoidance responding. The i n a b i l i t y of t h i o r i d a z i n e t o prevent the a c q u i s i t i o n of avoidance responding p a r a l l e l s i t s l a c k of e f f e c t on a p p e t i t i v e responding. T h i o r i d a z i n e (10 - 30 mg/kg) had no s i g n i f i c a n t e f f e c t on any measure of f e e d i n g behaviour (Blackburn, e t a l . , 1989b). Thus, the p r e s e n t experiments do not i n d i c a t e any p h a r m a c o l o g i c a l d i s s o c i a t i o n between the a p p e t i t i v e and d e f e n s i v e p r e p a r a t o r y responding. Experiment 1.3: E f f e c t s of c l o z a p i n e C l o z a p i n e , l i k e t h i o r i d a z i n e , i s an a t y p i c a l n e u r o l e p t i c compound. However, u n l i k e t h i o r i d a z i n e , a p h e n o t h i a z i n e d e r i v a t i v e , c l o z a p i n e i s a s u b s t i t u t e d p i p e r i d i n e . I f the absence of a c l a s s i c a l p r o f i l e of n e u r o l e p t i c drug a c t i o n on avoidance observed w i t h t h i o r i d a z i n e i s t o h o l d f o r a t y p i c a l n e u r o l e p t i c s i n g e n e r a l , then i t should a l s o be found f o r c l o z a p i n e . Doses of c l o z a p i n e i n the range of 0.0625 t o 15 mg/kg have been shown t o attenuate amphetamine induced behaviours ( C o s t a l l & Naylor, 1976; Ljungberg & Ungerstedt, 1985; Robertson & MacDonald, 1984). Higher doses (10 - 2 0 mg/kg) Chapter I 50 have been used t o show a l t e r a t i o n s i n v e n t r a l tegmental area dopamine u n i t a c t i v i t y and i n c r e a s e d r e l e a s e of dopamine i n the nucleus accumbens (Blaha & Lane, 1987; Chiodo & Bunney, 1985; White & Wang, 1983). P r e l i m i n a r y t e s t i n g of the compound i n t h i s l a b o r a t o r y i n d i c a t e d t h a t doses of 2 0 or 3 0 mg/kg produced profound motor d e b i l i t a t i o n i n r a t s . A c c o r d i n g l y , e f f e c t s i n a lower range (1.25 t o 10.0 mg/kg) were examined. Method S u b j e c t s , apparatus, procedure. and s t a t i s t i c a l  a n a l y s i s : S u b j e c t s s i m i l a r t o those of Experiment 1.1 were used, and were t e s t e d i n the same apparatus u s i n g the same procedure. Data were again analyzed u s i n g the ANOVA, f o l l o w e d by Newman-Keul 1s pos t hoc t e s t , as i n Experiment 1.1. C l o z a p i n e t e s t i n g : C l o z a p i n e (Sandoz Pharmaceuticals, E. Hanover, NJ) was d i s s o l v e d as 10.0 mg of drug i n 0.98 ml of 1% l a c t i c a c i d . When d i s s o l v e d , an a d d i t i o n a l 0.02 ml of 0.1 N NaOH was added to r a i s e the pH t o 5.0. Separate groups r e c e i v e d 1.25 (n = 6), 2.5 (n = 8), 5.0 (n = 8), 7.5 (n = 8), and 10.0 (n = 6) mg/kg c l o z a p i n e i n Phase A, and v e h i c l e i n Phase B. Group V-5.0 (n — 6) r e c e i v e d v e h i c l e i n Phase A, and 5.0 mg/kg c l o z a p i n e i n Phase B. One r a t , from Group 5.0-V, became i l l a f t e r Day 2 and was excluded from f u r t h e r t e s t i n g . Chapter I 51 R e s u l t s As was the case w i t h t h i o r i d a z i n e , c l o z a p i n e slowed but d i d not completely b l o c k the a c q u i s i t i o n of avoidance responding (see top panel of F i g u r e 4). The ANOVA i n d i c a t e d a s i g n i f i c a n t e f f e c t of Day [F(5,176) = 115.15, p_ < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(25,176) = 4.44, p_ < .001], but not a s i g n i f i c a n t e f f e c t of Group [F(5,36) = 1.45, p_ > .20]. Post hoc t e s t s showed t h a t a l l groups improved from Day 1 t o Day 3, i n d i c a t i n g a c q u i s i t i o n of the response. On Day 1 Group V-5.0 made s i g n i f i c a n t l y more avoidances than Groups 5.0-V or 7.5-V, whereas on Days 2 and 3 o n l y Groups 2.5-V and 10-V were s i g n i f i c a n t l y worse than Group V-5.0. In Phase B t h e r e were no between-group d i f f e r e n c e s on Days 4 or 6, but on Day 5 Group 7.5-V avoided s i g n i f i c a n t l y more o f t e n than group V-5.0. L a t e n c i e s f o r the c l o z a p i n e t e s t s are shown i n the bottom panel of F i g u r e 4. The ANOVA i n d i c a t e d a s i g n i f i c a n t e f f e c t of Day [F(5,2084) = 368.23, p_ < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(25,2084) = 18.91, p_ < .001], but not a s i g n i f i c a n t Group e f f e c t [F(5,36) = 1.37, p_ > .20]. Examination of the i n t e r a c t i o n r e v e a l e d t h a t Group V-5.0 had the s h o r t e s t l a t e n c i e s of any group throughout Phase A. Nonetheless, each group improved from Day 1 t o Day 2. Thus, although c l o z a p i n e had a d i s r u p t i v e e f f e c t , i t d i d not prevent a c q u i s i t i o n of the response. When Group V-5.0 r e c e i v e d 5.0 mg/kg i n Phase B they had the l o n g e s t l a t e n c i e s of any group. Thus, t h e r e was no d i s s o c i a t i o n between the Chapter I 52 F i g u r e 4. E f f e c t s o f c l o z a p i n e Top panel i n d i c a t e s mean number of avoidances executed on each day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A Groups 1.25-V, 2.5-V, 5.0-V, 7.5-V, and 10.0-V r e c e i v e d 1.25, 2.5, 5.0, 7.5, and 10.0 mg/kg c l o z a p i n e , r e s p e c t i v e l y , and Group V-5.0 r e c e i v e d v e h i c l e . In Phase B Groups 1.25-V, 2.5-V, 5.0-V, 7.5-V, and 10-V r e c e i v e d v e h i c l e and Group V-5.0 r e c e i v e d 5.0 mg/kg c l o z a p i n e . Chapter I CLOZAPINE 10-8-6-4 -2-Phase A. Phase B i  12 —' 8 LU <5 6-4-2-Phase A. Phase B. 3 , 4 TEST DAY 6 Chapter I 54 e f f e c t s o f c l o z a p i n e on a c q u i s i t i o n and performance. A l l groups t h a t had r e c e i v e d c l o z a p i n e i n Phase A showed f u r t h e r improvement when they were switched t o v e h i c l e on Day 4. In c o n t r a s t , l a t e n c i e s were l o n g e r f o r Group V-5.0 on Day 4 ( f o l l o w i n g i n j e c t i o n o f 5.0 mg/kg c l o z a p i n e ) than they had been on Day 3, i n d i c a t i n g d i s r u p t i o n o f avoidance response performance by c l o z a p i n e . D i s c u s s i o n The n o n - s p e c i f i c p a t t e r n of r e s u l t s observed f o l l o w i n g a d m i n i s t r a t i o n of t h i o r i d a z i n e was even more pronounced i n the case o f c l o z a p i n e . Doses t h a t f a i l e d t o b l o c k a c q u i s i t i o n of avoidance responding i n t e r f e r e d s i g n i f i c a n t l y w i t h the performance of p r e v i o u s l y a c q u i r e d responses. In f a c t , the mean l a t e n c y (7.7 s) f o r Group V-5.0 on Day 4, f o l l o w i n g a d m i n i s t r a t i o n of 5.0 mg/kg c l o z a p i n e , was s i m i l a r t o t h a t f o r Group 5.0-V on Day 3 (6.7 s ) . Once again, t h i s p r o f i l e of r e s u l t s d i f f e r s s u b s t a n t i a l l y from t h a t observed w i t h h a l o p e r i d o l , and suggests t h a t the d i s r u p t i o n of avoidance responding by t h i s compound i s not c o n s i s t e n t with the primary impact of dopamine d i s r u p t i o n observed w i t h c l a s s i c a l n e u r o l e p t i c s or 6-OHDA l e s i o n s o f c e n t r a l dopamine neurons. A l a c k of s p e c i f i c e f f e c t s on p r e p a r a t o r y responding was a l s o observed i n the case of a p p e t i t i v e responding. C l o z a p i n e (5.0 mg/kg) was found t o have a s e r i o u s impact on consummatory f e e d i n g behaviour, and so was not t e s t e d f o r Chapter I 55 i t s e f f e c t s on p r e p a r a t o r y responding (unpublished o b s e r v a t i o n s ) . Experiment 1.4 E f f e c t s o f metoclopramide In c o n t r a s t t o the s t r o n g a n t i p s y c h o t i c , weak EPSE p r o f i l e o f the a t y p i c a l n e u r o l e p t i c s , the a n t i p s y c h o t i c a c t i o n of the s u b s t i t u t e d benzamide metoclopramide i s d i s p u t e d (Doongaji, Desai, & Satoskar, 198 6; Nakra, Bond, & Lader, 1975; St a n l e y , L a u t i n , Rotrosen, Gershon, & K l e i n b e r g , 1980) whereas i t s long term use i s a s s o c i a t e d w i t h severe EPSEs (Bateman, Rawlins, & Simpson, 1985; H a r r i n g t o n e t a l . , 1983; Indo & Ando, 1982). Thus, the ph a r m a c o l o g i c a l p r o f i l e of metoclopramide stands i n d i r e c t c o n t r a s t t o the a n t i p s y c h o t i c e f f i c a c y and m i l d EPSE p r o f i l e o f the a t y p i c a l n e u r o l e p t i c s . In an examination of i t s impact on p r e p a r a t o r y and consummatory a p p e t i t i v e responses, i t was found t h a t metoclopramide (2.5 - 7.5 mg/kg) s e v e r e l y a t t e n u a t e d p r e p a r a t o r y responses t o a c o n d i t i o n a l s t i m u l u s s i g n a l l i n g d e l i v e r y of a meal. However, consummatory responding was only a f f e c t e d by the h i g h e s t dose (Blackburn e t a l . , 1989b). Thus, i f metoclopramide i s found t o d i s r u p t the a c q u i s i t i o n of avoidance responding, we w i l l have demonstrated i t s c a p a c i t y t o attenuate both a p p e t i t i v e and d e f e n s i v e p r e p a r a t o r y behaviours. Chapter I 56 Method S u b j e c t s , apparatus, procedure. and s t a t i s t i c a l  a n a l y s i s : S u b j e c t s s i m i l a r t o those of Experiment 1.1 were used, and were t e s t e d i n the same apparatus u s i n g the same procedure. Data were again analyzed u s i n g the ANOVA, f o l l o w e d by Newman-Keul 1s post hoc t e s t , as i n Experiment 1.1. Metoclopramide t e s t i n g : Metoclopramide-HCl (Sigma Chemical Co., S t . L o u i s , MO) was d i s s o l v e d as 7.5 mg of the s a l t weight i n 1.0 ml of s a l i n e . Separate groups r e c e i v e d 2.5, 5.0, and 7.5 mg/kg metoclopramide i n Phase A, and s a l i n e i n Phase B. Group V-5.0 r e c e i v e d s a l i n e i n Phase A, and 5.0 mg/kg metoclopramide i n Phase B. Each group c o n s i s t e d of 6 r a t s . R e s u l t s Metoclopramide, a t doses of 5.0 and 7.5 mg/kg, completely blocked the a c q u i s i t i o n of avoidance responding i n Phase A. In Phase B, the i n i t i a l impact of 5.0 mg/kg on the performance of Group V-5.0 was n e g l i g i b l e , but a s i g n i f i c a n t d i s r u p t i o n was observed over the t h r e e days of t e s t i n g . The number of avoidances are i l l u s t r a t e d i n the top panel of F i g u r e 5. The ANOVA i n d i c a t e d s i g n i f i c a n t e f f e c t s of Group [F(3,20) = 22.68, p < .001] and Day [F(5,100) = 69.29, p < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(15,100) = 16.74, p < .001]. Post hoc t e s t s i n d i c a t e d t h a t whereas Groups V-5.0 and 2.5-V improved a c r o s s Phase A, Groups 5.0-V and 7.5-V showed no s i g n s of Chapter I 57 F i g u r e 5. E f f e c t s of metoclopramide Top panel i n d i c a t e s mean number of avoidances executed on each day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A Groups 2.5-V, 5.0-V, and 7.5-V r e c e i v e d 2,5, 5.0, and 7.5 mg/kg metoclopramide, r e s p e c t i v e l y , and Group V-5.0 r e c e i v e d v e h i c l e . In Phase B Groups 2.5-V, 5.0-V, and 7.5-V r e c e i v e d v e h i c l e and Group V-5.0 r e c e i v e d 5.0 mg/kg metoclopramide. Chapter I 58 METOCLOPRAMIDE TEST DAY Chapter I 59 a c q u i r i n g the response. Group V-5.0 had the most avoidances on Day 1. On Days 2 and 3 Groups V-5.0 and 2.5-V made more avoidances than Groups 5.0-V or 7.5-V. T h i s was a l s o t r u e on Day 4. There were no between-group d i f f e r e n c e s on Day 5. On Day 6 Group V-5.0 performed fewer avoidances than any oth e r group. A s i m i l a r p a t t e r n of r e s u l t s h e l d f o r response l a t e n c i e s (see bottom panel of F i g u r e 5 ) . The ANOVA i n d i c a t e d s i g n i f i c a n t e f f e c t s of Group [F(3,20) = 6.86, p_ <.01] and Day [F(5,1180) = 171.77, p_ < .001], and a s i g n i f i c a n t Group x Day i n t e r a c t i o n [F(15,1180) = 54.07, p_ < .001]. Post hoc examination of the i n t e r a c t i o n i n d i c a t e d t h a t throughout Phase A Group V-5.0 l a t e n c i e s were s h o r t e s t , and Group 2.5-V had s h o r t e r l a t e n c i e s than Groups 5.0-V and 7.5-V. On the f i r s t day of Phase B, the l a t e n c i e s of Group 5.0-V and 7.5-V remained the l o n g e s t . However, by Day 5 Groups 5.0-V and 7.5-V were s i g n i f i c a n t l y f a s t e r than Groups V-5.0 and 2.5-V. T h i s was a l s o the, case on Day 6, when Group V-5.0 had the l o n g e s t l a t e n c i e s . Looking a t i n d i v i d u a l groups a c r o s s days, the c r i t i c a l f i n d i n g was t h a t Groups 5.0-V and 7.5-V showed no s i g n of a c q u i s i t i o n a c r o s s Phase A, whereas the l a t e n c i e s of Groups V-5.0 and 2.5-V decreased s u b s t a n t i a l l y . In Phase B Groups 5.0-V and 7.5-V improved s i g n i f i c a n t l y , r e l a t i v e t o Day 3. Although the behaviour of Group V-5.0 was o n l y m a r g i n a l l y d i s r u p t e d by 5.0 mg/kg metoclopramide on Day 4, response l a t e n c i e s i n c r e a s e d s i g n i f i c a n t l y by Day 6. Chapter I 60 D i s c u s s i o n of Chapter I The r e s u l t s o f these experiments i n d i c a t e t h a t although h a l o p e r i d o l , c l o z a p i n e , t h i o r i d a z i n e , and metoclopramide a l l impair avoidance responding, t h e r e are important q u a l i t a t i v e d i f f e r e n c e s i n the way they do so. Even though the a t y p i c a l n e u r o l e p t i c s t h i o r i d a z i n e and c l o z a p i n e slowed a c q u i s i t i o n of avoidance responding, they d i d not completely b l o c k i t . C r i t i c a l l y , the d e l e t e r i o u s e f f e c t s they had on a c q u i s i t i o n were a l s o e v i d e n t i n r a t s t h a t had r e c e i v e d p r i o r d r u g - f r e e t r a i n i n g . That i s , t h e r e was no d i s s o c i a t i o n between the e f f e c t s o f these drugs on the a c q u i s i t i o n of avoidance responding and t h e i r e f f e c t s on the performance o f an a c q u i r e d response. Together, these r e s u l t s suggest t h a t doses o f t h i o r i d a z i n e and c l o z a p i n e h i g h enough t o d i s r u p t avoidance responding had a g e n e r a l d i s r u p t i v e e f f e c t on motor performance. In marked c o n t r a s t , h a l o p e r i d o l and metoclopramide completely b l o c k e d a c q u i s i t i o n o f avoidance responding a t doses t h a t had, i n i t i a l l y , o n l y a n e g l i g i b l e impact on performance. T h i s p a t t e r n of r e s u l t s p a r a l l e l s t h a t observed f o r a a p p e t i t i v e responses (see Table I ) . Blackburn e t a l . (1989b) found t h a t metoclopramide attenuated p r e p a r a t o r y f e e d i n g responses a t a dose as low as 2.5 mg/kg, but d i d not have any d i s c e r n a b l e impact on consummatory f e e d i n g behaviour a t doses lower than 7.5 mg/kg. T h i s i s s i m i l a r t o the e f f e c t s o f metoclopramide observed here on d e f e n s i v e behaviour, where i t a b o l i s h e d avoidance responding without Chapter I 61 Table I Summary of n e u r o l e p t i c drug e f f e c t s on p r e p a r a t o r y and consummatory responses P r e p a r a t o r y Consummatory Drug Type Defen Appet Defen Appet Pimozide c l a s s i c a l _ 0 0 H a l o p e r i d o l c l a s s i c a l - - 0 T h i o r i d a z i n e a t y p i c a l 0 0 0 0 C l o z a p i n e a t y p i c a l 0 0 -Metoclopramide ™ 0 0 Defen: Defensive behaviour. Appet: A p p e t i t i v e behaviour. - decrease. 0 no e f f e c t . ? not t e s t e d . E f f e c t s of pimozide on d e f e n s i v e behaviours from Beninger a l . (1983), on a p p e t i t i v e behaviours from Blackburn e t a l . (1987) . E f f e c t s of t h i o r i d a z i n e and metoclopramide on a p p e t i t i v e behaviours, Blackburn e t a l . , 1989b. E f f e c t s of h a l o p e r i d o l and c l o z a p i n e on a p p e t i t i v e behaviours, unpublished o b s e r v a t i o n s . Other o b s e r v a t i o n s from p r e s e n t r e p o r t . Chapter I 62 p r e v e n t i n g escape. In c o n t r a s t , the a t y p i c a l n e u r o l e p t i c t h i o r i d a z i n e had no s i g n i f i c a n t e f f e c t on any measure of p r e p a r a t o r y or consummatory f e e d i n g behaviour a t doses from 10 t o 30 mg/kg, j u s t as i t had n e g l i g i b l e e f f e c t s on d e f e n s i v e behaviours i n t h a t dose range. C l o z a p i n e , which had pronounced n o n - s p e c i f i c e f f e c t s on d e f e n s i v e behaviour a t 5.0 mg/kg, markedly d i s r u p t e d consummatory f e e d i n g responses a t 10.0 mg/kg, the lowest dose t e s t e d . The s i m i l a r l y of these p a t t e r n s of r e s u l t s suggest t h a t the pro c e s s t h a t i s be i n g d i s r u p t e d by n e u r o l e p t i c s i n the a c q u i s i t i o n o f avoidance behaviour may be e q u i v a l e n t t o the dopamine-mediated process u n d e r l y i n g p r e p a r a t o r y a p p e t i t i v e responding. C l i n i c a l l y , these f i n d i n g s are of i n t e r e s t i n l i g h t o f the widespread use of n e u r o l e p t i c drugs t o a l l e v i a t e p s y c h o t i c symptoms. D i s r u p t i o n of avoidance behaviour has been c o r r e l a t e d with the a n t i p s y c h o t i c potency of v a r i o u s n e u r o l e p t i c s (Davidson & Weidley 1976; Arn t 1982), and has been used as a screen f o r d e t e c t i n g drugs w i t h p o t e n t i a l a n t i p s y c h o t i c a c t i v i t y (e.g., I o r i o , B a r n e t t , L e i t z , Houser, & Korduba, 1983; Janssen e t a l . , 1965). However, as noted by A r n t (1982), i t has never been e s t a b l i s h e d whether the d i s r u p t i o n of avoidance responding by n e u r o l e p t i c s i s r e l a t e d t o t h e i r a n t i - p s y c h o t i c e f f i c a c y , t h e i r a b i l i t y t o induce EPSEs, or both. The p a t t e r n of r e s u l t s observed i n the c u r r e n t s e t of experiments suggests t h a t the a b i l i t y of c l a s s i c a l Chapter I 6 3 n e u r o l e p t i c s t o b l o c k the a c q u i s i t i o n of avoidance responding s e l e c t i v e l y may c o r r e l a t e more c l o s e l y with t h e i r a b i l i t y t o induce EPSEs than w i t h t h e i r a b i l i t y t o r e l i e v e p s y c h o t i c symptoms. C l a s s i c a l n e u r o l e p t i c s l i k e h a l o p e r i d o l are e f f e c t i v e a n t i p s y c h o t i c agents but, l i k e metoclopramide, they can induce EPSEs wi t h extended use. U n l i k e metoclopramide, a t y p i c a l n e u r o l e p t i c s are e f f e c t i v e a n t i p s y c h o t i c agents t h a t have a low p r o b a b i l i t y of i n d u c i n g EPSEs. While i t i s c l e a r t h a t our understanding of the mechanisms by which n e u r o l e p t i c drugs d i s r u p t avoidance responding i s f a r from complete, and t h a t f u r t h e r s t u d i e s w i l l be r e q u i r e d t o e l u c i d a t e the p s y c h o l o g i c a l and p h y s i o l o g i c a l mechanisms t h a t u n d e r l i e these behaviours, the p r e s e n t experiments suggest t h a t c a u t i o n should be e x e r c i s e d i n u s i n g the d i s r u p t i o n of avoidance responding as an animal model f o r a s s e s s i n g the a n t i p s y c h o t i c p o t e n t i a l of new p h a r m a c o l o g i c a l agents. In f a c t , these data suggest t h a t avoidance d i s r u p t i o n may be more a p p r o p r i a t e as an animal model f o r EPSEs. At the same time, these data i n d i c a t e t h a t u nderstanding the d i s r u p t i o n of p r e p a r a t o r y a p p e t i t i v e and d e f e n s i v e behaviours may be i n t i m a t e l y r e l a t e d t o an understanding of e x t r a p y r a m i d a l pathology, such as parkinsonism ( F i b i g e r e t a l . , 1975). One f a c t o r t h a t may account f o r the d i f f e r e n t e f f e c t s of these v a r i o u s drugs on avoidance responding i s t h a t although a t y p i c a l n e u r o l e p t i c s are e f f e c t i v e dopamine Chapter I 64 a n t a g o n i s t s , they are a l s o potent a n t i c h o l i n e r g i c s (Snyder e t a l . , 1974). Although c o n t r o v e r s i a l , e a r l i e r s t u d i e s have suggested t h a t normal b a s a l f o r e b r a i n f u n c t i o n i s maintained by a balance between c h o l i n e r g i c systems and n i g r o s t r i a t a l dopaminergic a c t i v i t y (Klawans, 1968). An a l t e r n a t i v e h y p o t h e s i s t h a t may account f o r the d i f f e r e n t i a l e f f e c t s of a t y p i c a l n e u r o l e p t i c s and metoclopramide i s t h a t these compounds may a c t s e l e c t i v e l y on a n a t o m i c a l l y d i s t i n c t s i t e s i n the f o r e b r a i n . Evidence from r e c e p t o r b i n d i n g ( A l t a r , Wasley, Neale, & Stone, 1986; B o r i s o n & Diamond, 1983; Howard, Large, Wedley, & P u l l a r , 1978), b e h a v i o u r a l pharmacology (Ljungberg & Ungerstedt, 1985; Robertson & MacDonald, 1984, 1985), e l e c t r o p h y s i o l o g y (Chiodo & Bunney, 1985; White & Wang, 1983), and i n v i v o e l e c t r o c h e m i s t r y (Blaha & Lane, 1987; Lane & Blaha, 1987) i n d i c a t e s t h a t a t y p i c a l n e u r o l e p t i c s may a c t p r e f e r e n t i a l l y a t s i t e s i n the mesolimbic dopamine system, i n c l u d i n g the nucleus accumbens, whereas metoclopramide may have a s e l e c t i v e a c t i o n on dopamine f u n c t i o n i n the s t r i a t u m . A n a t o m i c a l l y d i s t i n c t s i t e s of a c t i o n f o r a t y p i c a l n e u r o l e p t i c s and metoclopramide would be c o n s i s t e n t with the h y p o t h e s i s t h a t the a n t i p s y c h o t i c e f f e c t s of n e u r o l e p t i c s are mediated by the mesolimbic dopamine system, i n c l u d i n g the nucleus accumbens, whereas EPSEs are induced by d i s r u p t i o n of dopamine f u n c t i o n i n the s t r i a t u m . By t h i s l i n e of r e asoning, the present s t u d i e s i m p l i c a t e the s t r i a t u m as the c r i t i c a l s i t e of n e u r o l e p t i c a c t i o n i n Chapter I 65 p r o d u c i n g avoidance d e f i c i t s . Although t h i s i s c o n s i s t e n t w i t h the c o n c l u s i o n of many p r e v i o u s r e s e a r c h e r s , i t should be r e c a l l e d from the i n t r o d u c t i o n t h a t the evidence s u p p o r t i n g t h i s c o n c l u s i o n has been very l i m i t e d : Those s t u d i e s t h a t have examined the e f f e c t s of 6-OHDA l e s i o n s i n d i s c r e t e t e r m i n a l r e g i o n s have e i t h e r f a i l e d t o c o n f i r m t h a t s t r i a t a l dopamine was i n f a c t d e p l e t e d , or d i d not determine whether ot h e r dopamine t e r m i n a l r e g i o n s were a l s o a f f e c t e d . Evidence t h a t the amygdala may be a c r i t i c a l s i t e f o r dopaminergic modulation of avoidance (Ashford & Jones, 1976; P e t t y e t a l . , 1984; Sherman e t a l . , 1982) i s i m p o s s i b l e t o i m p o s s b i l e w i t h the present r e s u l t s i n the absence of data c o n c e r n i n g the a f f i n i t y of t h i s s i t e f o r a t y p i c a l n e u r o l e p t i c s and metoclopramide. Thus, w h i l e the r e s u l t s of the p r e s e n t study are e n t i r e l y c o n s i s t e n t w i t h the h y p o t h e s i s t h a t n e u r o l e p t i c e f f e c t s on avoidance behaviour and p r e p a r a t o r y f e e d i n g responses are mediated by the n i g r o s t r i a t a l dopamine system, they cannot be taken as s t r o n g evidence on t h i s p o i n t g i v e n the c u r r e n t s t a t e of knowledge co n c e r n i n g the a c t i o n s of these drugs. These r e s u l t s do permit us t o i d e n t i f y metoclopramide as a p h a r m a c o l o g i c a l agent t h a t has the f u l l impact of c l a s s i c a l n e u r o l e p t i c drugs on d e f e n s i v e as w e l l as p r e p a r a t o r y responding. Because i t appears t o have o n l y a subset of the c l i n i c a l and n e u r o b i o l o g i c a l e f f e c t s of these drugs, i t appears t o be an i d e a l agent f o r i d e n t i f y i n g more p r e c i s e l y the c o n t r i b u t i o n of dopamine t o p r e p a r a t o r y Chapter I 66 b e h a v i o u r s . For t h i s reason, metoclopramide w i l l be used e x c l u s i v e l y throughout the remaining experiments of t h i s d i s s e r t a t i o n . Chapter I I 67 II WHAT MUST A RAT LEARN IN AVOIDANCE TRAINING IN ORDER TO BE PROTECTED FROM NEUROLEPTIC DRUG EFFECTS? Both the performance and the a c q u i s i t i o n o f a wide range of avoidance behaviours can be d i s r u p t e d by treatment w i t h n e u r o l e p t i c drugs. Most s t u d i e s have used o v e r t r a i n e d r a t s (Janssen e t a l . , 1965, p r e t r a i n e d t h e i r r a t s f o r approximately 3 000 m u l t i - t r i a l s e s s i o n s b e f o r e drug t e s t i n g ! ) but t e s t i n g has been conducted on naive animals as w e l l . For example, a c q u i s i t i o n of bar pre s s avoidance was d i s r u p t e d by chlorpromazine (Davidson & Weidley, 1976), and by h a l o p e r i d o l ( S e t l e r , Sarua, & McKenzie, 1976). A c q u i s i t i o n o f one-way avoidance by r a t s has been d i s r u p t e d by chlorpromazine (Posluns, 1962), h a l o p e r i d o l ( F i b i g e r e t a l . , 1975; Chapter 1), pimozide (Beninger e t a l . , 1980a,b; Beninger e t a l . , 1983), and metoclopramide (Chapter 1). A c q u i s i t i o n of a two-way response by mice was d i s r u p t e d by pimozide (Anisman e t a l . , 1982). D e s p i t e the conspicuous a b i l i t y o f n e u r o l e p t i c drugs t o d i s r u p t the performance of a p r e v i o u s l y a c q u i r e d a c t i v e avoidance response, t h e r e i s s t r o n g evidence t h a t they have a q u a l i t a t i v e l y g r e a t e r e f f e c t on the a c q u i s i t i o n of a new response: Simply showing a l a r g e r percentage decrease i n responding among naive animals f o l l o w i n g a d m i n i s t r a t i o n of a gi v e n dose o f drug c o u l d be an a r t e f a c t o f s h i f t i n g a s h a r p l y r i s i n g a c q u i s i t i o n curve t o the r i g h t . However, s e v e r a l Chapter I I 68 s t u d i e s have demonstrated t h a t doses of n e u r o l e p t i c drugs t h a t can prevent a q u i s i t i o n o f a new response over many days may have almost no e f f e c t on the performance of a p r e v i o u s l y a c q u i r e d response (Anisman e t a l . , 1982; Beninger e t a l . , 1983; Carey & Kenney, 1987; F i b i g e r e t a l . , 1975; Ray & Bivens, 1966). For example, i n Experiment 1.4 i t was demonstrated t h a t a dose of metoclopramide t h a t l i m i t e d avoidance t o a mean of 0.2/10 responses on the t h i r d day of a c q u i s i t i o n o n l y decreased p r e v i o u s l y a c q u i r e d responding, from 9.8/10 s u c c e s s f u l responses on the t h i r d day of drug-f r e e a c q u i s i t i o n t o 8.8/10 responses on the f i r s t drugged day. Nonetheless, i t i s important t o note t h a t the performance of a p r e v i o u s l y a c q u i r e d response may d e t e r i o r a t e over s e v e r a l s e s s i o n s of n e u r o l e p t i c t e s t i n g ( H i l l e g a a r t , A h l e n i u s , Magnusson, & Fowler, 1987; Niemegeers e t a l . , 1969; Chapter 1). Beninger e t a l . (1983) observed p r o g r e s s i v e d e t e r i o r a t i o n of p r e v i o u s l y a c q u i r e d responding over repeated s e s s i o n s o f pimozide t e s t i n g . The cumulative s e s s i o n - t o -s e s s i o n d i s r u p t i o n was r e v e r s e d by i n t e r p o l a t i n g two drug-f r e e r e t r a i n i n g s e s s i o n s between each avoidance s e s s i o n with pimozide. A c q u i s i t i o n of avoidance has a l s o been s t u d i e d f o l l o w i n g s e l e c t i v e d i s r u p t i o n of c e n t r a l dopamine n e u r o t r a n s m i s s i o n by a p p r o p r i a t e a d m i n i s t r a t i o n o f 6-OHDA. The c o n s i s t e n t outcome of a l l such s t u d i e s has been the marked a t t e n u a t i o n of a c q u i s i t i o n of e i t h e r one-way or two-way avoidance; Chapter I I 69 a c q u i s i t i o n was a b o l i s h e d w i t h more extreme l e v e l s o f dopamine d e p l e t i o n (Cooper e t a l . , 1973, 1974; Delacour e t a l . , 1977; F i b i g e r e t a l . , 1974; Heybach e t a l . , 1978; Z i s et a l . , 1974). S e v e r a l s t u d i e s have i n d i c a t e d t h a t 6-OHDA l e s i o n s can a l s o d i s r u p t performance of a p r e v i o u s l y a c q u i r e d response (Beer & Lenard, 1975; Cooper e t a l . , 1973; Lenard & Beer, 1975; N e i l l e t a l . , 1974). However, no d e f i c i t was observed when r a t s r e c e i v e d e x t e n s i v e t r a i n i n g p r i o r t o the l e s i o n ( F i b i g e r e t a l . , 1975). As was the case w i t h n e u r o l e p t i c t e s t i n g , when d e f i c i t s have been observed f o l l o w i n g 6-OHDA l e s i o n s they have t y p i c a l l y become more severe over s u c c e s s i v e t e s t s e s s i o n s (Beer & Lenard, 1975; Cooper e t a l . , 1973; Lenard & Beer, 1975). T h i s d e t e r i o r a t i o n i s not simply a f u n c t i o n o f p r o g r e s s i v e d e t e r i o r a t i o n o f dopamine neurons, as the e f f e c t i s seen even when a d e l a y i s imposed between time of l e s i o n and the onset of t e s t i n g . I f , however, the response i s f o l l o w e d f o r an extended p e r i o d of time t h e r e may be rec o v e r y (Beer & Lenard, 1975; Lenard & Beer, 1975). For these cases i t has not been e s t a b l i s h e d whether the recovery i s due t o repeated t e s t i n g o r t o n e u r a l compensation. What i s c l e a r from both the ph a r m a c o l o g i c a l and the l e s i o n s t u d i e s i s t h a t i f an animal has had s u f f i c i e n t avoidance t r a i n i n g p r i o r t o d i s r u p t i o n of dopamine ne u r o t r a n s m i s s i o n , the impact of the treatment on performance i s markedly a t t e n u a t e d . What i s u n c l e a r i s what c o n s t i t u t e s s u f f i c i e n t t r a i n i n g i n t h i s c o ntext. Chapter I I 70 Kimble and Perlmuter (1970) have suggested t h a t when responses are w e l l p r a c t i c e d they become "automatized", t h a t i s , they are a u t o m a t i c a l l y executed i n the presence of the WS without r e g a r d t o t h e i r consequences. I t i s c o n c e i v a b l e t h a t dopamine i s i n v o l v e d i n the p r o d u c t i o n of " v o l u n t a r y " responses, but i s not r e q u i r e d f o r an animal t o execute such automatized responses. Second, as reviewed i n the I n t r o d u c t i o n , v a r i o u s t h e o r i s t s o f avoidance responding have suggested t h a t f e a r i s r e q u i r e d f o r the a c q u i s i t i o n o f avoidance responding, but may not be r e q u i r e d f o r the maintenance of avoidance responding (Mineka, 1979; Seligman & Johnston, 1973). T h i s i s c o n s i s t e n t w i t h the f i n d i n g t h a t b e h a v i o u r a l and p h y s i o l o g i c a l i n d i c e s of f e a r may d e c l i n e d u r i n g extended avoidance t r a i n i n g . Perhaps dopamine mediates f e a r , o r the c a p a c i t y f o r f e a r t o e f f e c t responding. T h i s h y p o t h e s i s i s r e l a t e d t o a s i m i l a r p r o p o s a l t h a t dopamine i s i n v o l v e d i n mediat i n g reward, or the c a p a c i t y f o r reward t o e f f e c t b ehaviours (Beninger, 1988; F i b i g e r & P h i l l i p s , 1986; P h i l l i p s & F i b i g e r 1979; Wise, 1982, 1985). These hypotheses, proposing t h a t n e u r o l e p t i c s are i n e f f e c t i v e a g a i n s t e s t a b l i s h e d avoidance responses because responding has become automatized or because f e a r has di m i n i s h e d , would be c h a l l e n g e d by evidence t h a t the d i s r u p t i v e e f f e c t s of dopaminergic i n t e r f e r e n c e d i m i n i s h b e f o r e f e a r of the WS su b s i d e s . Chapter I I 71 Other p o t e n t i a l r o l e s f o r dopamine i n the a c q u i s i t i o n of avoidance responding have been excluded by e a r l i e r r e s e a r c h . I t has been c l e a r l y e s t a b l i s h e d t h a t n e u r o l e p t i c - t r e a t e d animals are not d e f i c i e n t i n a s s o c i a t i n g the WS and the AS. S p e c i f i c a l l y , n e u r o l e p t i c - t r e a t e d r a t s t h a t f a i l t o a v o i d s t i l l show b e h a v i o u r a l s i g n s of f e a r d u r i n g t e s t i n g ( F i b i g e r e t a l . , 1975; Posluns, 1962). F u r t h e r , i f r a t s are t r a i n e d i n a d r u g - f r e e s t a t e a f t e r having f a i l e d t o a c q u i r e an avoidance response under the i n f l u e n c e of a n e u r o l e p t i c , they may show savings (Beninger e t a l . , 1980b; Davidson & Weidley, 1976; F i b i g e r e t a l . , 1975; Posluns, 1962; but see Beninger e t a l . , 1980a). In f a c t , r a t s t h a t f a i l t o a v o i d w h i l e t r e a t e d with n e u r o l e p t i c s can subsequently a c q u i r e an avoidance response or d i s p l a y o t h e r a p p r o p r i a t e responses t o s h o c k - r e l a t e d s t i m u l i even i f no f u r t h e r shocks are presented (Beninger e t a l . , 1980a,b; Beninger, MacLennan, & P i n e l , 1980c). A l l these f i n d i n g s i n d i c a t e t h a t the r a t s must have l e a r n e d the s i g n a l v a l u e of the WS even as they f a i l e d t o a c q u i r e the avoidance response. F u r t h e r evidence t h a t n e u r o l e p t i c drugs do not i n t e r f e r e w i t h the est a b l i s h m e n t of a WS-AS a s s o c i a t i o n comes from a study conducted by Anisman e t a l . (1982) who determined t h a t (a) P a v l o v i a n p a i r i n g of the WS and the AS p r i o r t o t r a i n i n g f a c i l i t a t e s the a c q u i s i t i o n of avoidance responding, and t h a t (b) when a dose of pimozide s u f f i c i e n t t o b l o c k the a c q u i s i t i o n of avoidance responding i s a d m i n i s t e r e d a t the time o f WS-AS p a i r i n g s i t does not Chapter I I 72. d i s r u p t the f a c i l i t a t o r y e f f e c t s of such p a i r i n g s . Thus, n e u r o l e p t i c drugs do not prevent the form a t i o n o f a P a v l o v i a n WS-AS a s s o c i a t i o n when a d m i n i s t e r e d d u r i n g c o n d i t i o n i n g . On the o t h e r hand, Anisman e t a l . (1982) found, i n an a d d i t i o n a l experiment, t h a t i f pimozide i s ad m i n i s t e r e d a t the time of avoidance t r a i n i n g then no f a c i l i t a t o r y e f f e c t s o f p r i o r WS-AS p a i r i n g s are observed. Apparently some pro c e s s o t h e r than l e a r n i n g the WS-AS r e l a t i o n s h i p must be d i s r u p t e d on the a c q u i s i t i o n day. The experiments of Chapter 2 were aimed a t i d e n t i f y i n g more p r e c i s e l y what the r a t s had t o l e a r n b e f o r e n e u r o l e p t i c drugs would not d i s r u p t t h e i r performance of p r e v i o u s l y a c q u i r e d avoidance responses. C h a r a c t e r i z i n g the e f f e c t s o f n e u r o l e p t i c drugs on avoidance a c q u i s i t i o n more f u l l y should r u l e out dopamine-dependence o f c e r t a i n f a c t o r s t h a t may be c r i t i c a l i n avoidance response a c q u i s i t i o n . Experiment II.1 - Days o f p r e t r a i n i n g P r e v i o u s s t u d i e s have examined the e f f e c t s of v a r i o u s amounts of p r e t r a i n i n g on the e f f e c t s o f h a l o p e r i d o l o r pimozide on the performance o f avoidance responding w i t h i n c o n s i s t e n t r e s u l t s . F i b i g e r e t a l . (1975) found t h a t two days o f p r e t r a i n i n g d i d not prevent d i s r u p t i o n o f responding by 0.15 mg/kg h a l o p e r i d o l , although r a t s c o n t i n u e d t o perform f l a w l e s s l y when g i v e n t h i s dose a f t e r nine days o f t r a i n i n g . In c o n t r a s t , Beninger e t a l . (1983) found p r o t e c t i o n from the e f f e c t s of 0.5 or 1.0 mg/kg pimozide Chapter I I 7 3 f o l l o w i n g two days of t r a i n i n g . T h i s d i f f e r e n c e may be a t t r i b u t a b l e t o the ve r y severe impact of 0.15 mg/kg h a l o p e r i d o l on avoidance a c q u i s i t i o n . I t would be i n t e r e s t i n g t o determine the impact of low l e v e l s o f p r e t r a i n i n g on the e f f e c t of a dose of metoclopramide known t o be s u f f i c i e n t t o b l o c k a c q u i s i t i o n , but which d i d not produce severe n o n - s p e c i f i c e f f e c t s . In a d d i t i o n t o p r o v i d i n g u s e f u l p a r a m e t r i c data, the q u e s t i o n of how l i t t l e t r a i n i n g i s r e q u i r e d t o p r o t e c t r a t s from the d e l e t e r i o u s e f f e c t s of n e u r o l e p t i c s i s d i r e c t l y r e l e v a n t t o important t h e o r e t i c a l i s s u e s d i s c u s s e d above. I f p r o t e c t i o n from the d i s r u p t i v e e f f e c t s o f n e u r o l e p t i c s i s observed w i t h i n a few t r i a l s of the onset of t r a i n i n g , i t would appear i m p l a u s i b l e t h a t the n e u r o l e p t i c s are i n e f f e c t i v e because responding has become automatized or because f e a r has d i m i n i s h e d . As a f i r s t step toward determining the minimum amount of t r a i n i n g r a t s need t o become l e s s s u s c e p t i b l e t o the e f f e c t s of n e u r o l e p t i c drugs, Experiment II.1 determined the e f f e c t of v a r y i n g the numbers of days of p r e t r a i n i n g on the impact of metoclopramide on avoidance. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of Chapter 1 were used and were t e s t e d i n the same apparatus. Procedure: Rats were randomly a s s i g n e d t o one of f o u r groups (n = 6 per group). D i f f e r e n t groups r e c e i v e d i n c r e a s i n g numbers of d a i l y d r u g - f r e e s e s s i o n s o f avoidance Chapter I I 74 t r a i n i n g i n Phase A, each c o n s i s t i n g of 10 t r i a l s , p r i o r t o t h r e e s e s s i o n s i n Phase B i n which each r e c e i v e d 5.0 mg/kg metoclopramide. S p e c i f i c a l l y , Group Zero r e c e i v e d no days of p r e t r a i n i n g , Group One r e c e i v e d one day of p r e t r a i n i n g , Group Two r e c e i v e d two days of p r e t r a i n i n g , and Group Three r e c e i v e d t h r e e days of p r e t r a i n i n g . Avoidance t r a i n i n g was conducted i n the same manner as i n the experiments of Chapter 1, and metoclopramide was prepared and a d m i n i s t e r e d as i n Experiment 1.4. A n a l y s i s of v a r i a n c e r e v e a l e d t h a t t h e r e were no d i f f e r e n c e s between Groups One, Two, and Three on t h e i r r e s p e c t i v e f i r s t days of p r e t r a i n i n g on e i t h e r avoidance or l a t e n c y s c o r e s (Fs < 1). S t a t i s t i c a l a n a l y s i s : The number of avoidances a c r o s s the t h r e e days of metoclopramide t e s t i n g i n Phase B were analyzed u s i n g a two-way ( T r a i n i n g x Day) ANOVA. Latency s c o r e s were analyzed with a three-way ( T r a i n i n g x Day x T r i a l ) ANOVA. In each case s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-Keul 1s post hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . R e s u l t s The number of avoidances are i l l u s t r a t e d i n the top panel of F i g u r e 6. Over the t h r e e days of drug t e s t i n g t h e r e was a m a r g i n a l l y s i g n i f i c a n t e f f e c t of T r a i n i n g [F(3,20) = 2.75, p_ < .07]. There was a s i g n i f i c a n t main e f f e c t of T e s t Day [£(2,40) = 5.60, p < .01], and a s i g n i f i c a n t T r a i n i n g x Day i n t e r a c t i o n [F(6,40) = 4.84, p> < .001]. Post hoc t e s t s i n d i c a t e d t h a t on the f i r s t t e s t day Chapter I I 75 F i g u r e 6. Days of p r e t r a i n i n g Top panel i n d i c a t e s mean number of avoidances executed on each day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . In Phase A groups were t r a i n e d f o r sero t o t h r e e days f o l l o w i n g s a l i n e i n j e c t i o n s . In Phase B a l l r a t s r e c e i v e d 5.0 mg/kg metoclopramide on each t e s t day. Chapter I I 7 6 DAYS OF PRETRAINING co LU CO 10 o CO 1 LU oc LL1 U O 6^ 4J 2\ Phase A. Phase B. >- 12H w io^ i— 8^ LU § 6^  o CO 4 1 LU 0 1 2H Phase A. Phase B. 3 4 TEST DAY 6 Chapter I I 77 (Day 4) Groups One, Two, and Three each avoided s i g n i f i c a n t l y more o f t e n than Group Zero, and t h a t Group Three avoided s i g n i f i c a n t l y more o f t e n than Group One. On the second t e s t day (Day 5) Group Two avoided more o f t e n than Group One. On the f i n a l t e s t day t h e r e were no s i g n i f i c a n t between-group d i f f e r e n c e s . Looking a c r o s s days, the number of avoidance responses i n Phase B d i d not change s i g n i f i c a n t l y f o r Groups Zero, One, or Two. However, the performance of Group Three d e t e r i o r a t e d through the course of Phase B: There were fewer avoidance responses on Days 5 and 6 than on Day 4. Latency scores r e v e a l e d f u r t h e r d i f f e r e n c e s between groups i n the drug t e s t s (see bottom panel of F i g u r e 6). There was a m a r g i n a l l y s i g n i f i c a n t e f f e c t of T r a i n i n g [F(3,20) = 2.92, p_ < .06], a s i g n i f i c a n t main e f f e c t of T e s t Day [F(2,580) = 15.45, p_ < .001], and a s i g n i f i c a n t T r a i n i n g x Day i n t e r a c t i o n [F(6,580) = 7.47, p_ < .001]. On the f i r s t drug day (Day 4) the l a t e n c i e s of each group d i f f e r e d from those of each other group. The l a t e n c i e s of Group Three were lowest, those of Group Two were next lowest, f o l l o w e d by those of Group One. L a t e n c i e s of Group Zero were h i g h e s t . On the second drug t e s t day (Day 5) the l a t e n c i e s of Groups Two and Three were lowest, those of Groups Zero and One being h i g h e r . On Day 3 the l a t e n c i e s of Group Zero were agai n the h i g h e s t . Looking a c r o s s the days of Phase B, the l a t e n c i e s of Groups One and Three i n c r e a s e d on Days 5 Chapter I I 78 and 6, f o l l o w i n g the f i r s t drug t e s t on Day 4, w h i l e the sc o r e s o f Groups Zero and Two d i d not change a c r o s s days. D i s c u s s i o n C o n s i d e r a b l e p r o t e c t i o n from the d i s r u p t i v e e f f e c t s of metoclopramide was observed a f t e r o n l y a . s i n g l e day of p r e t r a i n i n g , and even g r e a t e r p r o t e c t i o n was seen a f t e r two days o f p r e t r a i n i n g . A dose o f metoclopramide t h a t l i m i t e d n a i v e r a t s t o 0.7/10 avoidance responses on Day 4 p e r m i t t e d r a t s w i t h two days of p r e t r a i n i n g t o a v o i d 6.7/10 times. I t i s remarkable t h a t a f t e r a s i n g l e day of p r e t r a i n i n g Group One was not only s i g n i f i c a n t l y s u p e r i o r t o Group Zero, the r a t s of t h i s group a c t u a l l y avoided more o f t e n on Day 4, wh i l e drugged, than they had wh i l e undrugged on Day 3 (4.2/10 vs . 1.7/10 avo i d a n c e s ) . T h i s r e s u l t demonstrates t h a t i t was not necessary f o r r a t s t o have achieved a s u b s t a n t i a l l e v e l of a c q u i s i t i o n i n order f o r the n e u r o l e p t i c t o have a s u b s t a n t i a l l y d i m i n i s h e d impact on performance. Experiment II.2 - E f f e c t o f p r i o r WS-AS p a i r i n g s A c q u i s i t i o n of one-way avoidance responding has been r e p o r t e d t o be f a c i l i t a t e d by g i v i n g the animals WS-AS p a i r i n g s p r i o r t o the commencement of t r a i n i n g (De Toledo & Black, 1967). A c q u i s i t i o n of two-way avoidance may a l s o be f a c i l i t a t e d i n t h i s manner, though with l e s s c o n s i s t e n t r e s u l t s ( G a l l o n , 1972; Overmier & Leaf, 1965; Weiss, Kriekhaus, & Conte, 1968). Anisman e t a l . (1982) found t h a t Chapter I I 79 although p r i o r WS-AS p a i r i n g s c o u l d f a c i l i t a t e l a t e r a c q u i s i t i o n of two-way responding by mice, such p a i r i n g s were not i n themselves s u f f i c i e n t t o p r o v i d e p r o t e c t i o n from the e f f e c t s of n e u r o l e p t i c treatment. A p p a r e n t l y P a v l o v i a n a s s o c i a t i o n of the WS and the AS i s a component of avoidance t h a t an animal may use i n the a c q u i s i t i o n of avoidance responding, but t h i s component i s not i n i t s e l f s u f f i c i e n t t o permit avoidance responding t o occur i n the absence of dopaminergic n e u r o t r a n s m i s s i o n , nor i s i t mediated by dopaminergic mechanisms. By i n s t i l l i n g t h i s a s s o c i a t i o n i n r a t s p r i o r t o g i v i n g them avoidance t r a i n i n g we might g a i n a more a c c u r a t e view of the amount of avoidance t r a i n i n g per se t h a t the r a t s r e q u i r e b e f o r e t h e i r performance w i l l not be d i s r u p t e d by n e u r o l e p t i c treatment. By doing so, we improve our chances of i s o l a t i n g the dopamine-dependent component of avoidance a c q u i s i t i o n . Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages a t l e a s t one week p r i o r t o the b e g i n n i n g of t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t p e r i o d . T h i s procedure appeared t o reduce the e m o t i o n a l i t y of the r a t s d u r i n g h a n d l i n g and t e s t i n g . Avoidance t r a i n i n g was conducted i n the same apparatus as i n the experiments d e s c r i b e d e a r l i e r . The p a i r i n g s of tone and footshock were presented i n a s e p a r a t e P l e x i g l a s chamber, 2 6 c m x 3 0 c m x 4 0 cm h i g h . The g r i d f l o o r was Chapter I I 8 0 connected t o the same shock generator as was the avoidance apparatus. The w a l l s of t h i s compartment were l i n e d w i t h brown s h e l f paper, making them t r a n s l u c e n t . A hinged P l e x i g l a s c e i l i n g remained t r a n s p a r e n t . A tone ge n e r a t o r i d e n t i c a l t o t h a t i n the avoidance apparatus was c e n t r e d 8 cm above the shock g r i d , and a 3.3 ca cue l i g h t (not used i n t h i s experiment) was mounted above the tone generator, near the top of the same w a l l , c e n t r e d 37 cm above the g r i d . Procedure: Rats were randomly a s s i g n e d t o one of fo u r groups (n = 6 per group). The two C o n d i t i o n e d groups r e c e i v e d 10 WS-AS p a i r i n g s i n the P l e x i g l a s c o n d i t i o n i n g chamber. Each p a i r i n g c o n s i s t e d o f a 10 s p r e s e n t a t i o n of the tone, f o l l o w e d by a 1.5 s, 1.0 mA footshock. Two C o n t r o l groups were simply put i n the c o n d i t i o n i n g compartment and then removed. On the next day, a l l f o u r groups r e c e i v e d f i v e avoidance t r a i n i n g t r i a l s u s i n g the procedure d e s c r i b e d i n Chapter 1. On these t r a i n i n g t r i a l s the r a t s t h a t had r e c e i v e d the WS-AS p a i r i n g s tended t o a v o i d more o f t e n than those t h a t had not (1.5/5 vs. 0.9/5 avoidances; p <.09). There were no d i f f e r e n c e s between the groups t h a t r e c e i v e d metoclopramide or s a l i n e on the t e s t day. On the Te s t day, the t h i r d day, one Co n d i t i o n e d group and one C o n t r o l group r e c e i v e d 5.0 mg/kg metoclopramide 60 -90 min p r i o r t o t r a i n i n g , w h i l e the other C o n d i t i o n e d group and the othe r C o n t r o l group r e c e i v e d s a l i n e . A l l r a t s were t e s t e d f o r t e n avoidance t r i a l s . Chapter I I 81 S t a t i s t i c a l a n a l y s i s : The data were analyzed u s i n g a two-way (Drug treatment x C o n d i t i o n i n g ) ANOVA. Latency s c o r e s were analyzed w i t h a three-way (Drug x C o n d i t i o n i n g x T r i a l ) ANOVA. In each case s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-Keul 1s post hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . R e s u l t s Those r a t s t h a t r e c e i v e d s a l i n e performed v e r y w e l l on the t e s t day r e g a r d l e s s of whether or not tone-shock p a i r i n g s had been a d m i n i s t e r e d p r i o r t o t r a i n i n g . Of those r a t s t h a t were i n j e c t e d with metoclopramide, those t h a t had not r e c e i v e d tone-shock p a i r i n g s showed d i s r u p t i o n o f performance r e l a t i v e t o s a l i n e c o n t r o l s . However, those r a t s t h a t had r e c e i v e d tone-shock p a i r i n g s p r i o r t o t r a i n i n g performed w e l l d u r i n g avoidance t e s t i n g d e s p i t e i n j e c t i o n o f the n e u r o l e p t i c (compare Group Conditioned-Met t o Group C o n t r o l - M e t ) . Examination of the number of avoidance responses (see top panel o f F i g u r e 7) i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t e f f e c t o f Drug [F(l,20) = 19.10, p_ < .001], a s i g n i f i c a n t e f f e c t o f p r i o r C o n d i t i o n i n g [F(l,20) = 7.62, p_ < .05], and a s i g n i f i c a n t Drug x C o n d i t i o n i n g i n t e r a c t i o n [ F ( l,20) = 6.40, p_ < .05]. Post hoc t e s t s i n d i c a t e d t h a t the C o n t r o l group r e c e i v i n g metoclopramide avoided l e s s f r e q u e n t l y than any oth e r group. There were no other s i g n i f i c a n t between-group d i f f e r e n c e s . Chapter I I 82 F i g u r e 7. E f f e c t o f p r i o r WS-AS c o n d i t i o n i n g Top p a n e l i n d i c a t e s mean number of avoidances on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . On Day 1 C o n d i t i o n e d Groups r e c e i v e d 10 non-contingent p a i r i n g s of tone and shock, w h i l e C o n t r o l Groups d i d not. On Day 2 a l l groups r e c e i v e d 5 avoidance t r a i n i n g t r i a l s . On the t e s t day a l l r a t s were t e s t e d f o r 10 t r i a l s . On the t e s t day Met Groups r e c e i v e d 5.0 mg/kg metoclopramide, and S a l Groups r e c e i v e d s a l i n e . Chapter I I 83 EFFECT OF PRIOR WS-AS CONDITIONING O SAL • I MET Control Conditioned Chapter I I 84 A n a l y s i s o f the l a t e n c y s c o r e s r e v e a l e d a s i m i l a r p a t t e r n of r e s u l t s (see bottom panel of F i g u r e 7). There was a s i g n i f i c a n t e f f e c t of Drug [F(l,20) = 21.99, p < .001], but not a s i g n i f i c a n t e f f e c t o f C o n d i t i o n i n g [F(l,20) = 2.41, p > .1]. The Drug x C o n d i t i o n i n g i n t e r a c t i o n was m a r g i n a l l y s i g n i f i c a n t [F(l,20) = 4.27, p < .051]. The post hoc t e s t s i n d i c a t e d t h a t Group C o n t r o l - S a l had s h o r t e r avoidance l a t e n c i e s than d i d Group Control-Met, whereas t h e r e was no d i f f e r e n c e between the sco r e s o f the two Co n d i t i o n e d groups. D i s c u s s i o n These r e s u l t s c o n f i r m the f i n d i n g of Anisman e t a l . (1982) t h a t p r i o r WS-AS p a i r i n g s i n c r e a s e d the amount of p r o t e c t i o n from the e f f e c t s of n e u r o l e p t i c drugs t h a t animals r e c e i v e from a small amount of avoidance t r a i n i n g . M etoclopramide-treated r a t s t h a t r e c e i v e d o n l y f i v e avoidance t r a i n i n g t r i a l s f o l l o w i n g a p r i o r c o n d i t i o n i n g s e s s i o n c o n s i s t i n g o f 10 WS-AS p a i r i n g s were a b l e t o execute almost t w i c e as many avoidance responses as s i m i l a r l y drugged r a t s t h a t had not r e c e i v e d such p a i r i n g s p r i o r t o the t r a i n i n g s e s s i o n (8.2/10 vs. 4.3/10 s u c c e s s f u l avoidance r e s p o n s e s ) , 1 U n l i k e the study by Anisman e t a l . , the pre s e n t experiment does not determine whether such WS-AS 1. The performance of the r a t s i n s e v e r a l groups, p a r t i c u l a r l y those i n Group Conditioned-Met, are h i g h e r than may have been p r e d i c t e d from the r e s u l t s o f Experiment I I . 1 . T h i s may be a r e s u l t of the h a n d l i n g the r a t s r e c e i v e d p r i o r t o c o n d i t i o n i n g or t o othe r extraneous f a c t o r s . These d i f f e r e n c e s h i g h l i g h t the danger of drawing s t r o n g comparisons between the r e s u l t s of groups from d i f f e r e n t experiments. Chapter I I 85 p a i r i n g s are s u f f i c i e n t f o r p r o v i d i n g p r o t e c t i o n from n e u r o l e p t i c e f f e c t s , although Experiment II.5 s h a l l c o n f i r m t h a t they are not. Together with the r e s u l t s of Experiment I I . 1 , these r e s u l t s argue s t r o n g l y a g a i n s t the n o t i o n t h a t the p r o t e c t i o n from metoclopramide e f f e c t s observed i n Experiment 1.4 a f t e r t h r e e days of t r a i n i n g was the r e s u l t of o v e r l e a r n i n g through e x t e n s i v e response r e p e t i t i o n . Indeed, the r a t s of Group Conditioned-Met managed on l y an average of 1.7 avoidance responses on the t r a i n i n g day. One r a t of t h i s group avoided on every t e s t t r i a l d e s p i t e having avoided o n l y once on the t r a i n i n g day. The a b i l i t y of r a t s t o become capable of w i t h s t a n d i n g n e u r o l e p t i c e f f e c t s i n so few t r i a l s suggests t h a t , r a t h e r than becoming a h a b i t through i n c r e m e n t a l l e a r n i n g , the avoidance response i s a problem t h a t the r a t s have s o l v e d . Experiment II.3 - S a f e t y c o n d i t i o n i n g During one-way avoidance t r a i n i n g , an animal may l e a r n not o n l y t h a t the l o c a t i o n where the shock i s t o be d e l i v e r e d i s t o be avoided, but a l s o t h a t the a l t e r n a t i v e l o c a t i o n i s a s a f e p l a c e t o be. W i t h i n the framework of i n c e n t i v e -m o t i v a t i o n theory (e.g., Bindra, 1968; B o l l e s , 1972b; Toates, 1986), avoidance can thus be seen as approach t o a p l a c e with a c q u i r e d i n c e n t i v e v a l u e . The v a l i d i t y o f t h i s i n t e r p r e t a t i o n i s supported by evidence t h a t feedback cues p o t e n t i a t e avoidance a c q u i s i t i o n ( B o l l e s & Grossen, Chapter I I 86 1969; Bower e t a l . , 1965; D'Amato e t a l . , 1968; Keehn & Nakkash, 1959; Modaresi, 1978; Weisman & L i t n e r , 1972). I f n e u r o l e p t i c drugs i n t e r f e r e with l e a r n i n g the i n c e n t i v e v a l u e of cues, then such treatment c o u l d d i s r u p t a c q u i s i t i o n of avoidance responding. T h i s i n t e r p r e t a t i o n i s c o n s i s t e n t w i t h the h y p o t h e s i s t h a t c e n t r a l dopamine systems mediate i n c e n t i v e m o t i v a t i o n (Blackburn e t a l . , 1987, 1989a; Crow, 1973; F i b i g e r & P h i l l i p s , 1986; Mogenson & P h i l l i p s , 1976). I f t h i s i s the case, then c o n d i t i o n i n g r a t s t o a s s o c i a t e the s a f e s i d e of the box w i t h the t e r m i n a t i o n of shock should be s u f f i c i e n t t o p r o v i d e p r o t e c t i o n from the e f f e c t s of metoclopramide. An a d d i t i o n a l e f f e c t of p a i r i n g shock o f f s e t w i t h s a l i e n t cues i s t h a t f e a r of the WS i s d i m i n i s h e d , r e l a t i v e t o l e v e l s i n r a t s t h a t do not r e c e i v e such feedback (Cook e t a l . , 1987; Mineka e t a l , 1984; Weisman & L i t n e r , 1972). I f dopamine blockade i n t e r f e r e d w i t h emotional p r o c e s s i n g of f e a r - r e l a t e d s t i m u l i , w h i l e p e r m i t t i n g i n f o r m a t i o n p r o c e s s i n g t o c o ntinue, then performance c o u l d a c t u a l l y d e t e r i o r a t e as a r e s u l t of such s a f e t y c o n d i t i o n i n g . These hypotheses were t e s t e d i n the f o l l o w i n g two experiments. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages a t l e a s t one week p r i o r t o the b e g i n n i n g of t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t Chapter I I 87 p e r i o d . For t h i s experiment an a d d i t i o n a l 3.3 ca cue l i g h t was mounted i n the s a f e s i d e o f the box, a t the top of the w a l l o p p o s i t e the g u i l l o t i n e door l e a d i n g t o the shock s i d e . Procedure: Rats were randomly a s s i g n e d t o one of f o u r groups. Each group of r a t s r e c e i v e d 10 non-contingent WS-AS p a i r i n g s i n the shock s i d e o f the avoidance apparatus. Immediately f o l l o w i n g each WS-AS p a i r i n g the r a t s of the two "S a f e t y " l e a r n i n g groups were removed manually t o the s a f e s i d e o f the box. Beginning 3 s a f t e r shock t e r m i n a t i o n the cue l i g h t i n the sa f e s i d e of the box was i l l u m i n a t e d u n t i l 5 s b e f o r e the onset of the next t r i a l . T h i s procedure was designed t o g i v e the non-shock s i d e o f the avoidance apparatus equal s t a t u s as a s a f e t y s i g n a l as i t would normally a c q u i r e i n 10 escape t r i a l s . The cue l i g h t onset would have p r o v i d e d an a d d i t i o n a l s a l i e n t s a f e t y s i g n a l towards which the r a t s c o u l d d i r e c t avoidance responses on the t e s t day. L i g h t onset p a i r e d w i t h shock o f f s e t has p r e v i o u s l y been demonstrated t o a c t as an e f f i c i e n t i n h i b i t o r of f e a r (Jacobs & LoLordo, 1980; Weisman & L i t n e r , 1972). The r a t s of the two C o n t r o l groups were t r a n s f e r r e d manually t o a P l e x i g l a s c a r r y i n g cage immediately a f t e r r e c e i v i n g the a v e r s i v e footshock. T h i s procedure gave a l l r a t s equal exposure t o post-shock h a n d l i n g , and might have e s t a b l i s h e d e i t h e r the h a n d l i n g o r the P l e x i g l a s compartment as a s a f e t y s i g n a l , but i t would not have p r o v i d e d the Chapter I I 88 c o n t r o l r a t s w i t h a cue towards which they c o u l d d i r e c t t h e i r , responses on the t e s t day. On the t e s t day r a t s o f Group "Safety"-Met and Group Control-Met (each n = 8) r e c e i v e d 5.0 mg/kg metoclopramide, w h i l e r a t s of Groups " S a f e t y " - S a l and C o n t r o l - S a l (each n = 7) r e c e i v e d s a l i n e . On each t r i a l i l l u m i n a t i o n o f the l i g h t i n the s a f e s i d e of the box was contiguous w i t h onset o f the WS. The cue l i g h t was e x t i n g u i s h e d 5 s p r i o r t o the s t a r t of the next t r i a l . S t a t i s t i c a l a n a l y s i s : The data were an a l y z e d u s i n g the ANOVA and Newman-Keul's post hoc t e s t , as d e s c r i b e d i n Experiment I I . 2 . R e s u l t s The performance of a l l groups was s u r p r i s i n g l y uniform. Even the c o n t r o l group t h a t r e c e i v e d metoclopramide performed reasonably w e l l on the t e s t day. However, the experiment a f f o r d s no evidence t h a t p u t t i n g the "Safety"-Met group i n t o the s a f e s i d e a t the o u t s e t o f the i n t e r t r i a l i n t e r v a l enhanced p r o t e c t i o n from metoclopramide's e f f e c t s . The number of avoidances are shown i n the top panel o f F i g u r e 8. The ANOVA i n d i c a t e d t h a t t h e r e was a m a r g i n a l l y s i g n i f i c a n t e f f e c t o f Drug [F(l,26) = 3.76, p_ < .07], no s i g n i f i c a n t e f f e c t of C o n d i t i o n i n g [F(l,26) = 1.12, p_ > .20], and no s i g n i f i c a n t Drug x C o n d i t i o n i n g i n t e r a c t i o n (F < 1). The l a t e n c y scores are shown i n the bottom panel o f F i g u r e 8. The ANOVA i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t Chapter I I 89 F i g u r e 8. E f f e c t o f " s a f e t y " c o n d i t i o n i n g Top panel i n d i c a t e s mean number of avoidances executed on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . A l l groups i n i t i a l l y r e c e i v e d 10 non-contingent p a i r i n g s of tone and shock i n the shock s i d e o f the avoidance apparatus on the c o n d i t i o n i n g day. " S a f e t y " Groups were p l a c e d i n the s a f e s i d e o f the box and were presented w i t h a cue l i g h t f o l l o w i n g each shock o f f s e t , w h i l e C o n t r o l Groups were p l a c e d i n a P l e x i g l a s c a r r y i n g cage. On the f o l l o w i n g day Met Groups were t e s t e d f o l l o w i n g a d m i n i s t r a t i o n o f 5.0 mg/kg metoclopramide, w h i l e " S a f e t y " Groups r e c e i v e d s a l i n e . Chapter II 90 Chapter I I 91 main e f f e c t of Drug [F(l,26) = 10.87, p_ < .01], but no s i g n i f i c a n t e f f e c t of C o n d i t i o n i n g (F < 1), and no s i g n i f i c a n t Drug x C o n d i t i o n i n g i n t e r a c t i o n (F < 1). D i s c u s s i o n The r e s u l t s of t h i s experiment f a i l e d t o support the h y p o t h e s i s t h a t s a f e t y c o n d i t i o n i n g would enhance avoidance performance and would p r o v i d e p r o t e c t i o n from the impact of metoclopramide on avoidance a c q u i s i t i o n . In n e i t h e r the case of undrugged or metoclopramide-treated r a t s d i d p a i r i n g s h o c k - t e r m i n a t i o n w i t h placement i n t o the s a f e s i d e of the apparatus and exposure t o the cue l i g h t enhance subsequent e n t r y i n t o the s a f e s i d e , toward the i l l u m i n a t e d cue l i g h t . T h i s i s c o n s i s t e n t w i t h the a s s e r t i o n of B o l l e s (1975) t h a t one-way avoidance i s l e a r n e d too r a p i d l y f o r s a f e t y l e a r n i n g t o p l a y a s i g n i f i c a n t r o l e i n i t s a c q u i s i t i o n . I n t e r p r e t a t i o n of t h i s f i n d i n g i s complicated by the s u r p r i s i n g l y good performance by the r a t s of the c o n t r o l groups, f o r whom shock t e r m i n a t i o n was p a i r e d w i t h placement i n t o a n e u t r a l P l e x i g l a s c a r r y i n g cage t h a t was not p r e s e n t on the t e s t day. I t i s c o n c e i v a b l e t h a t the s a f e t y and c o n t r o l groups d i d not d i f f e r because the c r i t i c a l f a c t o r i n the s a f e t y treatment was the p a i r i n g of shock t e r m i n a t i o n w i t h h a n d l i n g and removal from the shock s i d e of the avoidance apparatus. Such treatment may have been s u f f i c i e n t t o decrease f e a r c o n d i t i o n i n g t o the WS and the shock s i d e of the box, somehow l e a d i n g t o enhanced performance on the t e s t day. Although i n t r i g u i n g , t h i s Chapter I I 92 h y p o t h e s i s i s i m p o s s i b l e t o e v a l u a t e i n the absence of a c o n t r o l group t h a t r e c e i v e d no shock t e r m i n a t i o n - h a n d l i n g p a i r i n g s . In the absence of such a c o n t r o l , i t i s e q u a l l y r e asonable t o suggest t h a t the s u r p r i s i n g l y h i g h l e v e l of performance by the r a t s not r e c e i v i n g s a f e t y c o n d i t i o n i n g was due t o some u n i d e n t i f i e d extraneous f a c t o r . As a r e s u l t , such a c o n t r o l was i n c o r p o r a t e d i n t o the d e s i g n of Experiment I I . 4 . Experiment II.4 - Amount of s a f e t y c o n d i t i o n i n g The f a i l u r e t o see a s i g n i f i c a n t enhancement of performance as a r e s u l t of s a f e t y c o n d i t i o n i n g i n the p r e v i o u s experiment c o u l d c o n c e i v a b l y be a r e s u l t of the use of an i n s u f f i c i e n t number of p a i r i n g s . A c c o r d i n g l y , i n the p r e s e n t experiment one group was t e s t e d a f t e r h a v ing r e c e i v e d 2 0 p a i r i n g s of shock t e r m i n a t i o n and the s a f e t y cues over two days, i n a d d i t i o n t o groups r e c e i v i n g treatment i d e n t i c a l t o t h a t of Groups "Safety"-Met and " S a f e t y " - S a l from the p r e v i o u s experiment. The p r e v i o u s experiment a l s o f a i l e d t o compare the e f f e c t s of such s a f e t y c o n d i t i o n i n g t o a c o n t r o l c o n d i t i o n i n which r a t s d i d not r e c e i v e p a i r i n g s of shock t e r m i n a t i o n and h a n d l i n g . Such a c o n t r o l was p r e s e n t i n t h i s experiment. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages a t l e a s t one week p r i o r t o the b e g i n n i n g of Chapter I I 93 t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t p e r i o d . Procedure: Rats were randomly a s s i g n e d t o one of f o u r groups (n = 6 per group). On a f i r s t day of treatment, r a t s of each group were allowed t o e x p l o r e the avoidance apparatus w i t h the g u i l l o t i n e door removed f o r 10 min. Subsequently, two groups o f r a t s (10+Sal and 10+Met) each r e c e i v e d 10 non-c o n t i n g e n t WS-AS p a i r i n g s i n the shock s i d e of the avoidance apparatus. Each shock t e r m i n a t i o n was f o l l o w e d immediately by manual placement i n the s a f e s i d e of the avoidance apparatus and the onset o f the s a f e t y l i g h t , as d e s c r i b e d i n Experiment I I . 3 . Thus, treatment of these two groups was e q u i v a l e n t t o t h a t of Groups "Safety"-Met and " S a f e t y " - S a l from the p r e v i o u s experiment. Rats o f a t h i r d group (0+Met) d i d not r e c e i v e any p a i r i n g s o f the WS and the AS on t h i s day, and remained i n t h e i r home cages. Rats o f a f o u r t h group (2 0+Met) r e c e i v e d 2 0 p a i r i n g s o f shock o f f s e t and s a f e t y s i g n a l over two days o f c o n d i t i o n i n g p r i o r t o t e s t i n g . On the t e s t day, r a t s o f the c o n t r o l group (0+Met), one of the 10 s a f e t y p a i r i n g groups (10+Met), and of the 20 p a i r i n g group (2 0+Met) each r e c e i v e d an i n j e c t i o n o f 5.0 mg/kg metoclopramide. The other 10 s a f e t y p a i r i n g group (10+Sal) was a d m i n i s t e r e d s a l i n e . S t a t i s t i c a l a n a l y s i s : The number of avoidances were analyzed u s i n g a one-way (Group) ANOVA. Latency s c o r e s were analyzed w i t h a two-way (Group x T r i a l ) ANOVA. In each case Chapter I I 94 s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-Keul 1s po s t hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . R e s u l t s In t h i s experiment, a minimal amount of p r o t e c t i o n was observed f o l l o w i n g 10 s a f e t y c o n d i t i o n i n g t r i a l s , and no a d d i t i o n a l amount of p r o t e c t i o n was observed f o l l o w i n g 2 0 t r i a l s . The number of avoidances are shown i n the top panel of F i g u r e 9. The ANOVA i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t e f f e c t of Group [F(3,20) = 8.58, p < .001]. The p o s t hoc t e s t r e v e a l e d t h a t the 10+Sal group avoided more o f t e n than any group t h a t r e c e i v e d metoclopramide. There were no s i g n i f i c a n t d i f f e r e n c e s between the t h r e e metoclopramide groups. S i m i l a r e f f e c t s are observed i n a n a l y s i s of the l a t e n c y s c o r e s (see bottom panel of F i g u r e 9). There was a s i g n i f i c a n t e f f e c t of Group [F(3,20) = 10.52, p < .001]. The p o s t hoc t e s t i n d i c a t e d t h a t Group 10-Sal had s h o r t e r l a t e n c i e s than any of the t h r e e groups t h a t r e c e i v e d metoclopramide, which d i d not d i f f e r between themselves. D i s c u s s i o n As was the case i n Experiment I I . 3 , the p r e s e n t experiment f a i l e d t o p r o v i d e any evidence t h a t p a i r i n g shock t e r m i n a t i o n w i t h the s a f e s i d e of the compartment f a c i l i t a t e d the development of p r o t e c t i o n from the d i s r u p t i v e e f f e c t s of metoclopramide treatment. T h i s was the case even though the s a f e compartment should have been r e a d i l y d i s t i n g u i s h e d on the b a s i s of the cue l i g h t , and Chapter I I 95 F i g u r e 9. 10 or 20 " s a f e t y " t r i a l s Top panel i n d i c a t e s mean number of avoidances executed on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . Group 10+Sal and Group 10+Met r e c e i v e d one c o n d i t i o n i n g s e s s i o n o f 10 s a f e t y p a i r i n g s , Group Safe+20 r e c e i v e d two. Group 0+Met was p l a c e d i n the shock s i d e but r e c e i v e d no ot h e r programmed events. S a f e t y p a i r i n g s c o n s i s t e d o f non-co n t i n g e n t p a i r i n g s o f tone and shock i n the shock s i d e o f the avoidance apparatus f o l l o w e d by placement of the r a t i n the s a f e s i d e o f the box and p r e s e n t a t i o n o f the cue l i g h t . On the t e s t day Group 10+Sal r e c e i v e d s a l i n e , w h i l e a l l other groups r e c e i v e d 5.0 mg/kg metoclopramide. Chapter I I 96 10 or 20 "SAFTEY" CONDITIONING TRIALS 10 - i CO UJ CO E 8H OL CO LU OC LU O z a 1 6-Z UJ _J LU CO z 2 CO UJ cc 10-8 6 4-2-O+Met 10+Sal 10+Met 20+Met Chapter I I 97 d e s p i t e the presence of the cue l i g h t as an a d d i t i o n a l s a l i e n t s a f e t y cue. In c o n t r a s t , i n Experiment II.2 r a t s showed s u b s t a n t i a l p r o t e c t i o n from metoclopramide e f f e c t s a f t e r o n l y 10 tone-shock p a i r i n g s and f i v e avoidance t r a i n i n g t r i a l s . T h i s was l e s s exposure t o the tone-shock contingency, and s u b s t a n t i a l l y l e s s exposure t o the shock o f f s e t - s a f e compartment contingency than t h a t o b t a i n e d by Group 2 0+Met i n the p r e s e n t experiment. In l i g h t o f these f i n d i n g s i t seems u n l i k e l y t h a t l e a r n i n g of the i n c e n t i v e v a l u e of the s a f e t y cues c o u l d be the c r i t i c a l f a c t o r i n v o l v e d i n o b t a i n i n g p r o t e c t i o n from metoclopramide e f f e c t s . Experiment I I . 5 - Avoidance v e r s u s escape t r a i n i n g One c u r i o u s o b s e r v a t i o n made d u r i n g the course of Experiment II.2 was t h a t some r a t s were capable of a v o i d i n g on the t e s t day d e s p i t e the a d m i n i s t r a t i o n of metoclopramide even though they had executed as few as a s i n g l e avoidance response on the avoidance a c q u i s i t i o n day. T h i s e f f e c t , i f r e a l , would exclude the p o s s i b i l i t y t h a t p r o t e c t i o n from n e u r o l e p t i c e f f e c t s i s due t o the avoidance response becoming automatized through e x t e n s i v e o v e r t r a i n i n g . Nor c o u l d such p r o t e c t i o n be a t t r i b u t e d t o the incremental e s t a b l i s h m e n t of a n e u r o l e p t i c - r e s i s t a n t e x p e c t a t i o n t h a t the avoidance responses r e s u l t s i n no shock being a d m i n i s t e r e d . Such an e f f e c t would a l s o seem t o exclude the p o s s i b i l i t y t h a t n e u r o l e p t i c s d i s r u p t a c q u i s i t i o n of Chapter I I 98 avoidance responding by p r e v e n t i n g the g e n e r a l i z a t i o n of an escape response t o an avoidance s i t u a t i o n . In order t o see i f r a t s needed t o avoid d u r i n g WS p r e s e n t a t i o n i n order t o a c q u i r e p r o t e c t i o n from metoclopramide e f f e c t s , i n Experiment II.5 r a t s r e c e i v i n g standard avoidance t r a i n i n g were compared t o r a t s f o r whom responding was prevented d u r i n g WS p r e s e n t a t i o n . P r i o r experience with escapable shock i n the avoidance apparatus has p r e v i o u s l y been shown t o enhance subsequent avoidance l e a r n i n g (De Teledo & Black, 1967; Radlow, 1958). Method Su b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages a t l e a s t one week p r i o r t o the b e g i n n i n g of t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t p e r i o d . Avoidance and escape were conducted i n the standard avoidance apparatus, and the tone-shock p a i r i n g s were admin i s t e r e d i n the P l e x i g l a s boxes d e s c r i b e d i n Experiment II.2 Procedure: Rats were randomly a s s i g n e d t o one of s i x groups (n = 6 per group). On the f i r s t day each group of r a t s r e c e i v e d 10 non-contingent tone-shock p a i r i n g s i n the P l e x i g l a s compartment, as d e s c r i b e d i n Experiment I I . 2 . On the next day, the t r a i n i n g day, the two C o n t r o l groups r e c e i v e d no treatment. The Avoidance groups both r e c e i v e d f i v e standard avoidance t r a i n i n g t r i a l s . The number of avoidances and the response l a t e n c i e s d i d not d i f f e r between Chapter I I 99 these two groups (Fs < 1). The Escape Groups both r e c e i v e d f i v e t r a i n i n g t r i a l s which were s i m i l a r t o avoidance t r i a l s i n a l l r e s p e c t s except t h a t the g u i l l o t i n e door remained shut d u r i n g WS p r e s e n t a t i o n , p r e v e n t i n g avoidance. The door was o n l y opened a t the onset of the AS. The mean l a t e n c y t o escape f o l l o w i n g shock onset was 3.1 s f o r Group Escape-Sal and 3.5 s f o r Group Escape-Met (F < 1). On the t e s t day (the t h i r d day) one of each p a i r of groups r e c e i v e d s a l i n e , the o t h e r 5.0 mg/kg metoclopramide. S t a t i s t i c a l a n a l y s i s : The data were analyzed u s i n g the ANOVA and Newman-Keul 1s post hoc t e s t , as d e s c r i b e d i n Experiment I I . 2 . R e s u l t s The r a t s r e c e i v i n g p r i o r avoidance t r a i n i n g were a b l e t o a v o i d on the t e s t day d e s p i t e metoclopramide treatment, whereas those who r e c e i v e d no p r i o r t r a i n i n g were not. Importantly, those r e c e i v i n g escape t r a i n i n g were as good or b e t t e r than those r e c e i v i n g avoidance t r a i n i n g . The number of avoidance responses performed by each group are i l l u s t r a t e d i n the top panel of F i g u r e 10. There was a s i g n i f i c a n t e f f e c t of T r a i n i n g [F(2,30) = 62.01, p < .001], a s i g n i f i c a n t e f f e c t of Drug [F(l,30) = 20.19, p < .001], and a s i g n i f i c a n t T r a i n i n g x Drug i n t e r a c t i o n [F(2,30) = 3.78, p < .05]. The post hoc t e s t s r e v e a l e d t h a t o n l y i n the case of the C o n t r o l groups was the performance of the metoclopramide-t r e a t e d group s i g n i f i c a n t l y worse than t h a t of the s a l i n e -t r e a t e d group. F o l l o w i n g avoidance or escape Chapter I I 100 F i g u r e 10. Avoidance o r escape p r e t r a i n i n g Top panel i n d i c a t e s mean number of avoidances on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . Rats of a l l groups r e c e i v e d 10 non-contingent p a i r i n g s o f tone and shock, w h i l e C o n t r o l Groups d i d not. On the day p r i o r t o t r a i n i n g Avoidance Groups r e c e i v e d 5 avoidance t r a i n i n g t r i a l s , Escape Groups r e c e i v e d 5 escape t r a i n i n g t r i a l s , and C o n t r o l Groups were not t r a i n e d . On the t e s t day a l l r a t s were t e s t e d f o r 10 t r i a l s . Met Groups r e c e i v e d 5.0 mg/kg metoclopramide w h i l e S a l Groups r e c e i v e d s a l i n e . Chapter I I 101 AVOIDANCE OR ESCAPE PRETRAINING Control Avoidance Escape Chapter I I 102 t r a i n i n g , r a t s were p r o t e c t e d from the a v o i d a n c e - d i s r u p t i n g e f f e c t s o f metoclopramide. A comparison of the performance o f the two s a l i n e - t r e a t e d groups r e v e a l e d t h a t n a i v e r a t s d i s p l a y e d fewer avoidances than those t h a t had r e c e i v e d p r i o r avoidance or escape p r e t r a i n i n g . The l a t e n c y s c o r e s , i l l u s t r a t e d i n the bottom panel of F i g u r e 10, r e v e a l a s i m i l a r p a t t e r n o f r e s u l t s . However, i n t h i s case the e f f e c t s can be a t t r i b u t e d t o s i g n i f i c a n t main e f f e c t s o f T r a i n i n g [F(2,30) = 34.28, p < .001] and Drug [F(l,30) = 15.41, p < .001]. There was no s i g n i f i c a n t T r a i n i n g x Drug i n t e r a c t i o n (F < 1). I t i s i n t e r e s t i n g t o note t h a t post hoc examination of the T r a i n i n g e f f e c t r e v e a l e d t h a t those r a t s r e c e i v i n g escape t r a i n i n g had s h o r t e r response l a t e n c i e s on the t e s t day than r a t s t h a t had r e c e i v e d p r i o r avoidance t r a i n i n g . D i s c u s s i o n The r e s u l t s of t h i s experiment i n d i c a t e t h a t r a t s can a c q u i r e the c a p a c i t y t o perform an avoidance response d e s p i t e metoclopramide treatment i n the absence o f any p r i o r o p p o r t u n i t y t o execute an avoidance response. E x e c u t i o n of f i v e escape responses i n the same apparatus, u s i n g the same WS, had an i d e n t i c a l e f f e c t t o t h a t observed when r a t s were ab l e t o make avoidance responses. T h i s i s an important f i n d i n g , as i t r u l e s out s e v e r a l p o s s i b l e hypotheses c o n c e r n i n g the o r i g i n of the p r o t e c t i o n from n e u r o l e p t i c e f f e c t s . F i r s t , i t excludes the p o s s i b i l i t y t h a t the avoidance response becomes i n s e n s i t i v e t o n e u r o l e p t i c Chapter I I 103 e f f e c t s through o v e r t r a i n i n g of the avoidance response per se: A v o i d i n g p r i o r t o shock onset was a novel response f o r the r a t s i n Group Escape-Met on the t e s t day. Second, the animals c o u l d not have had i n c r e m e n t a l l y - e s t a b l i s h e d e x p e c t a t i o n s t h a t performing the avoidance response p r i o r t o shock onset would r e s u l t i n the non-occurrence of shock. T h i s suggests t h a t dopamine i s i n t e r a c t i n g w i t h c o g n i t i v e mechanisms, as opposed t o response r e i n f o r c e m e n t mechanisms, i n the e s t a b l i s h m e n t of behaviour. T h i r d , because the r a t s had o n l y ever escaped from shock, dopamine blockade c o u l d not have d i s r u p t e d the g e n e r a l i z a t i o n of the escape response i n t o an avoidance response. In a d d i t i o n t o the important comparison between the performance of r a t s t h a t had p r e v i o u s l y r e c e i v e d escape or avoidance p r e t r a i n i n g , t h i s experiment a l s o i n d i c a t e s , i n agreement w i t h Anisman e t a l . (1982) t h a t p r o v i d i n g r a t s w i t h 10 WS-AS p a i r i n g s i s not s u f f i c i e n t t o p r o v i d e p r o t e c t i o n from n e u r o l e p t i c e f f e c t s . Group Control-Met had r e c e i v e d 10 such p a i r i n g s , but u n l i k e group Avoidance-Met i t d i d not r e c e i v e a d d i t i o n a l avoidance t r a i n i n g p r i o r t o the t e s t day. On the t e s t day, the performance of Group Control-Met was s u b s t a n t i a l l y and s i g n i f i c a n t l y worse than t h a t of Group Avoidance-Met (1.7 vs. 7.8 avoidance r e s p o n s e s ) . Chapter I I 104 Experiment II.6 - Escape t r a i n i n g f o l l o w i n g metoclopramide I t i s apparent from Experiment II.5 t h a t c r i t i c a l i n f o r m a t i o n r e g a r d i n g the avoidance t a s k may be a c q u i r e d d u r i n g escape t r i a l s i f dopamine f u n c t i o n i s normal, and t h a t once t h i s i n f o r m a t i o n i s encoded i t can subsequently i n f l u e n c e the performance of r a t s t r e a t e d w i t h dopamine a n t a g o n i s t s . I f t h i s i s the case then metoclopramide treatment d u r i n g escape t r a i n i n g should a t t e n u a t e the p r o t e c t i v e e f f e c t s of t r a i n i n g a g a i n s t d i s r u p t i o n o f avoidance a c q u i s i t i o n by a n e u r o l e p t i c . T h i s h y p o t h e s i s was t e s t e d i n Experiment I I . 6 . Su b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages at l e a s t one week p r i o r t o the b e g i n n i n g of t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t p e r i o d . Tone-shock p a i r i n g s were presented i n the same boxes as i n Experiment I I . 2 . Procedure: Rats were randomly a s s i g n e d t o one of t h r e e groups (n = 8 per group). On the f i r s t day r a t s o f each group r e c e i v e d 10 non-contingent WS-AS p a i r i n g s i n the P l e x i g l a s compartment, as d e s c r i b e d i n Experiment I I . 2 . On the next day the C o n t r o l group r e c e i v e d no treatment, whereas Groups E s c - S a l and Esc-Met r e c e i v e d f i v e escape t r a i n i n g t r i a l s , as d e s c r i b e d i n Experiment I I . 5 . For Group E s c - S a l t h i s escape t r a i n i n g o c c u r r e d f o l l o w i n g a d m i n i s t r a t i o n o f s a l i n e , whereas f o r Group Esc-Met t r a i n i n g o c c u r r e d f o l l o w i n g a d m i n i s t r a t i o n of 5.0 mg/kg Chapter I I 105 metoclopramide. The escape l a t e n c i e s f o r these two groups d i d not d i f f e r on the t r a i n i n g day (F < 1). On the t e s t day (the t h i r d day) the r a t s o f each group r e c e i v e d 5.0 mg/kg metoclopramide and were t e s t e d f o r 10 avoidance t r i a l s . S t a t i s t i c a l a n a l y s i s : The data were analyzed u s i n g the ANOVA and Newman-Keul 1s post hoc t e s t , as d e s c r i b e d i n Experiment I I . 4 . R e s u l t s The r a t s r e c e i v i n g escape t r a i n i n g f o l l o w i n g s a l i n e a d m i n i s t r a t i o n (Esc-Sal) were a b l e t o a v o i d s u c c e s s f u l l y on the t e s t day d e s p i t e a d m i n i s t r a t i o n of metoclopramide. T h i s r e p l i c a t e s the major f i n d i n g o f Experiment I I . 5 . However, r a t s t h a t r e c e i v e d i d e n t i c a l escape t r a i n i n g f o l l o w i n g metoclopramide a d m i n i s t r a t i o n (Group Esc-Met) were not p r o t e c t e d from the e f f e c t s of metoclopramide on the f o l l o w i n g day. The number of avoidances executed by these two groups, as w e l l as by the c o n t r o l group t h a t r e c e i v e d no escape t r a i n i n g , are i l l u s t r a t e d i n the top panel o f F i g u r e 11. The ANOVA i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t d i f f e r e n c e between the number of avoidance responses executed by r a t s of the t h r e e groups [F(2,21) = 23.47, p_ < .001]. Post hoc t e s t i n g r e v e a l e d t h a t the group t h a t r e c e i v e d escape t r a i n i n g f o l l o w i n g s a l i n e (Group Esc-Sal) avoided s i g n i f i c a n t l y more o f t e n than the other two groups on the t e s t day. The l a t e n c y s c o r e s are shown i n the bottom pan e l of F i g u r e 11. Again, t h e r e was a s i g n i f i c a n t e f f e c t o f Group Chapter I I 106 F i g u r e 11. Escape p r e t r a i n i n g w i t h metoclopramide Top panel i n d i c a t e s mean number of avoidances on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . Rats of a l l groups i n i t i a l l y r e c e i v e d 10 non-contingent p a i r i n g s of tone and shock. On the day p r i o r t o t e s t i n g Group Cont-S a l was not t r a i n e d and Esc Groups r e c e i v e d 5 escape t r a i n i n g t r i a l s . Group Esc^Met r e c e i v e d 5.0 mg/kg metoclopramide, and Group E s c - S a l r e c e i v e d s a l i n e on t h i s day. On the t e s t day a l l r a t s r e c e i v e d 5.0 mg/kg metoclopramide. Chapter I I 107 ESCAPE PRETRAINING WITH METOCLOPRAMIDE co LU CO z o CL CO LU OC LU O z < Q O io-. 8-6 2 -O z LU _ J LU CO z o OL CO LU or 12-j 10-8-6 4 2 Cont-Sal Esc-Sal Esc-Met Chapter I I 108 [F(2,21) = 13.83, p_ < .001], Post hoc t e s t s i n d i c a t e d t h a t the group t r a i n e d under s a l i n e (Group Esc-Sal) had lower l a t e n c i e s than e i t h e r of the ot h e r two groups. D i s c u s s i o n The performance of Group Esc-Met i n t h i s experiment confirmed the major f i n d i n g of Experiment I I . 5 , s p e c i f i c a l l y t h a t f i v e escape t r i a l s were s u f f i c i e n t t r a i n i n g t o p r o v i d e p r o t e c t i o n from the d i s r u p t i v e e f f e c t s o f metoclopramide on the performance of avoidance behaviours. In a d d i t i o n , they extend the p r e v i o u s f i n d i n g s t o demonstrate t h a t such escape t r a i n i n g i s not e f f e c t i v e when g i v e n t o n e u r o l e p t i c - t r e a t e d r a t s . T h i s l a t t e r f i n d i n g i s c o n s i s t e n t w i t h the f i n d i n g t h a t metoclopramide-treated r a t s are i n c a p a b l e o f a c q u i r i n g an avoidance response over s e v e r a l days of t r a i n i n g (Experiment 1.4). In each case the r a t s are exposed t o the same warning and a v e r s i v e s t i m u l i , i n each case they e x i t from the compartment a f t e r the onset of the shock. And i n each case they e x p e r i e n c e these events under the i n f l u e n c e o f metoclopramide. What remains s u r p r i s i n g i s the a b i l i t y of n e u r o l e p t i c - t r e a t e d r a t s t o a v o i d on the day f o l l o w i n g escape t r a i n i n g i f they were not g i v e n metoclopramide p r i o r t o these t r i a l s . The two groups r e c e i v i n g escape t r a i n i n g were exposed t o i d e n t i c a l experimental c o n t i n g e n c i e s , and t h e i r responses were i n d i s t i n g u i s h a b l e d u r i n g the t r a i n i n g t r i a l s . Yet on the t e s t day onl y Group E s c - S a l was a b l e t o b e n e f i t from the experience of the t r a i n i n g day. Chapter I I 109 I t i s c o n c e i v a b l e t h a t a c r i t i c a l f a c t o r f o r t h i s outcome was the long d e l a y between tone p r e s e n t a t i o n s and shock onset on escape t r a i n i n g t r i a l s . The r a t s may have been attempting t o a v o i d d u r i n g t h i s p e r i o d , even though they were unable t o en t e r the s a f e compartment because of the c l o s e d g u i l l o t i n e door. Experiment II.7 was conducted t o exclude t h i s p o s s i b i l i t y . Experiment II.7 - U n s i g n a l l e d escape t r a i n i n g Although the r a t s r e c e i v i n g escape t r a i n i n g i n the p r e v i o u s two experiments were unable t o a v o i d shock, they were exposed t o the WS f o r the standard 10 s p e r i o d . I t was noted t h a t over the f i v e t r a i n i n g t r i a l s the r a t s t y p i c a l l y came t o stand by the c l o s e d g u i l l o t i n e door, s n i f f i n g and clawing a t i t . That i s , they appeared t o be attempting t o av o i d , even though they c o u l d not. Perhaps subsequent r e i n f o r c e m e n t of these attempts when escape u l t i m a t e l y o c c u r r e d was the c r i t i c a l component of the procedure which r e q u i r e d dopaminergic mediation. A c c o r d i n g l y , an a d d i t i o n a l experiment examined the e f f e c t o f p r e t r a i n i n g escape responses when no WS was present, and when the r a t s would not have time t o o r i e n t t o the door p r i o r t o shock onset. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of p r e v i o u s experiments were used. A l l r a t s were housed i n s i n g l e cages a t l e a s t one week p r i o r t o the be g i n n i n g of t e s t i n g , and were handled a t l e a s t t h r e e times d u r i n g t h a t Chapter I I 110 p e r i o d . Tone-shock p a i r i n g s were presented i n the same boxes as i n Experiment I I . 2 . Procedure: Rats were randomly a s s i g n e d t o one of t h r e e groups (n = 6 per group). As d e s c r i b e d f o r Experiment I I . 6 , each group of r a t s each r e c e i v e d 10 non-contingent WS-AS p a i r i n g s i n the P l e x i g l a s compartment on the f i r s t day of the experiment. On the next day Group Cont-Sal r e c e i v e d no treatment, whereas Groups E s c - S a l and Esc-Met r e c e i v e d f i v e escape t r a i n i n g t r i a l s . In the p r e s e n t experiment the escape t r a i n i n g procedure was m o d i f i e d t o l i m i t the o p p o r t u n i t y of the r a t s t o perform any response p r i o r t o shock onset. F i r s t , the WS (tone) was not presented a t a l l on the escape t r a i n i n g day. Second, the i n t e r v a l between p l a c i n g the r a t i n the shock s i d e of the compartment and the onset of shock was reduced from 10 s t o 1 s. As i n Experiments II.5 and II. 6 , shock onset was synchronous w i t h the opening of the g u i l l o t i n e door. Those r a t s t h a t r e c e i v e d s a l i n e p r i o r t o escape t r a i n i n g (Group Esc-Sal) had a mean response l a t e n c y of 2.1 s, those t h a t r e c e i v e d metoclopramide (Group Esc-Met) had a mean l a t e n c y of 3.3 s [F(l,10) = 5.64, p < .05]. On the t e s t day a l l r a t s r e c e i v e d 5.0 mg/kg metoclopramide and were t e s t e d f o r 10 standard avoidance t r i a l s . S t a t i s t i c a l a n a l y s i s : The data were analyzed u s i n g the ANOVA and Newman-Keul's post hoc t e s t , as d e s c r i b e d i n Experiment I I . 4 . Chapter I I 111 R e s u l t s As shown i n the top p o r t i o n o f F i g u r e 12, r a t s t h a t had r e c e i v e d the reduced form of escape t r a i n i n g w h i l e undrugged were a b l e t o a v o i d on 7.3/10 t r i a l s on the t e s t day d e s p i t e metoclopramide treatment. In c o n t r a s t , those t h a t r e c e i v e d the escape t r a i n i n g under the i n f l u e n c e o f metoclopramide were o n l y a b l e t o a v o i d 1.5/10 times, no more than u n t r a i n e d c o n t r o l s (1.5/10 t r i a l s ) . The ANOVA i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t d i f f e r e n c e between the number of avoidance responses executed by r a t s of the t h r e e groups on the t e s t day as a f u n c t i o n of t h e i r t r a i n i n g [F(2,15) = 12.71, p_ < .001]. Post hoc t e s t s r e v e a l e d t h a t the group t h a t r e c e i v e d escape t r a i n i n g f o l l o w i n g metoclopramide treatment avoided s i g n i f i c a n t l y more o f t e n than e i t h e r of the ot h e r two groups. The l a t e n c y s c o r e s are shown i n the bottom panel of F i g u r e 12. Again, t h e r e was a s i g n i f i c a n t e f f e c t o f T r a i n i n g [F(2,15) = 7.26, p < .01]. Post hoc t e s t s i n d i c a t e d t h a t the group t r a i n e d under s a l i n e (Group Esc-Sal) had lower response l a t e n c i e s than the other two groups. D i s c u s s i o n Once again, as i n Experiment I I . 6 , we observe t h a t i f r a t s are t r a i n e d f o r f i v e escape t r i a l s p r i o r t o being t e s t e d on avoidance, they show remarkable r e s i l i e n c e t o the e f f e c t s of metoclopramide treatment, but on l y i f they r e c e i v e d the escape t r a i n i n g i n the absence of the drug. I f Chapter I I 112 F i g u r e 12. Escape p r e t r a i n i n g without WS Top panel i n d i c a t e s mean number of avoidances on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . Rats of a l l groups i n i t i a l l y r e c e i v e d 10 non-contingent p a i r i n g s of tone and shock. On the day p r i o r t o t e s t i n g Group Cont-S a l was not t r a i n e d and Esc Groups r e c e i v e d 5 escape t r a i n i n g t r i a l s w i t h the WS absent, and a del a y o f o n l y 1 s between placement i n the shock s i d e o f the box and shock onset. On the t r a i n i n g day Group Esc-Met r e c e i v e d 5.0 mg/kg metoclopramide, and Group E s c - S a l r e c e i v e d s a l i n e . On the t e s t day a l l r a t s r e c e i v e d 5.0 mg/kg metoclopramide. Chapter I I 113 ESCAPE PRETRAINING WITHOUT WS CO LU CO z O CL CO LU CC LU O z o >-O z L U _J LU CO z o CL CO LU OC 10 8-6-0 12-10-8 -6 4 2 Cont-Sal Esc-Sal Esc-Met Chapter I I 114 r a t s r e c e i v e i d e n t i c a l t r a i n i n g i n a s e s s i o n where they have been a d m i n i s t e r e d metoclopramide t h e i r performance i s i n d i s t i n g u i s h a b l e from t h a t of r a t s who have r e c e i v e d no p r i o r t r a i n i n g . In t h i s case, escape t r a i n i n g amounted t o l i t t l e more than dumping the r a t s i n t o the shock s i d e of the compartment, t u r n i n g on the shock, and l e t t i n g them run out a g a i n . Yet something t h a t happened d u r i n g those f i v e t r i a l s gave the r a t s the knowledge or experience they needed t o perform avoidance responses w h i l e drugged on the f o l l o w i n g day. D i s c u s s i o n of Chapter I I The experiments i n t h i s chapter demonstrate j u s t how l i t t l e t r a i n i n g i s r e q u i r e d t o a t t e n u a t e the e f f e c t s of metoclopramide on avoidance behaviour d r a m a t i c a l l y . F o l l o w i n g a d m i n i s t r a t i o n of metoclopramide a r a t w i t h no p r i o r t r a i n i n g w i l l not respond t o the WS by a v o i d i n g . I t remains i n the compartment u n t i l the shock comes on and e l i c i t s an escape response. In c o n t r a s t , r a t s t h a t have executed as few as f i v e escape responses, even i n the absence of the s t i m u l u s t h a t normally s i g n a l s shock, are subsequently a b l e t o i n i t i a t e avoidance responses s u c c e s s f u l l y d e s p i t e a d m i n i s t r a t i o n of the same dose of metoclopramide. The r e s u l t s of Experiments II.6 and II.7 i n d i c a t e t h a t the animals are f a i l i n g t o l e a r n something w h i l e drugged. A f t e r a l l , the escape groups i n those experiments were t r e a t e d i d e n t i c a l l y on the t e s t day, and on the t r a i n i n g day Chapter I I 115 the o n l y d i f f e r e n c e i n the treatment of the two groups was t h a t one r e c e i v e d metoclopramide w h i l e the o t h e r r e c e i v e d s a l i n e . Yet the performance of the two groups d i f f e r e d markedly d u r i n g the t e s t , when they were t r e a t e d i d e n t i c a l l y . Although t h i s suggests t h a t the metoclopramide produces a l e a r n i n g d e f i c i t , the drugged r a t s do not seem unaware of where t o go. They can, a f t e r a l l , perform s u c c e s s f u l escape responses r e l i a b l y and w i t h s h o r t l a t e n c i e s . S i m i l a r l y , n e i t h e r n e u r o l e p t i c - t r e a t m e n t nor 6-OHDA l e s i o n s of the s u b s t a n t i a n i g r a d i s r u p t the a b i l i t y of rodents t o l e a r n the a p p r o p r i a t e cues towards which they should d i r e c t responses i n a d i s c r i m i n a t e d escape procedure ( C o r r a d i n i , Tombaugh, & Anisman, 1984; P r i c e & F i b i g e r , 1975; but see Ranje & Ungerstedt, 1977). Yet t h i s knowledge i s not s u f f i c i e n t t o a l l o w them t o execute the response w h i l e drugged. Indeed, c o n d i t i o n i n g them on the a s s o c i a t i o n between shock t e r m i n a t i o n and the p l a c e where they are supposed t o go does no t h i n g t o enhance t h e i r subsequent a b i l i t y t o a v o i d . I t may f u r t h e r be argued t h a t n e u r o l e p t i c treatment i s u n l i k e l y t o d i s r u p t avoidance a c q u i s i t i o n by p r e v e n t i n g l e a r n i n g of the i n c e n t i v e v a l u e of s a f e t y cues on the grounds t h a t s a f e t y l e a r n i n g t y p i c a l l y takes dozens or hundreds of t r i a l s , not f i v e as i n s e v e r a l experiments here. There i s a v a r i a n t of the i n c e n t i v e l e a r n i n g d e f i c i t t h a t i s not r u l e d out by the r e s u l t s of Experiments II.3 and I I . 4 . T h i s i s Beninger's r e c e n t p r o p o s a l t h a t dopamine i s i n v o l v e d i n t r a n s f e r r i n g the i n c e n t i v e m o t i v a t i o n a l Chapter I I 116 p r o p e r t i e s o f the reward t o the s a f e t y r e l a t e d s i g n a l . A c c o r d i n g t o Beninger (1989) "animals can l e a r n where s a f e t y i s but cannot l e a r n t o go t h e r e when dopaminergic n e u r o t r a n s m i s s i o n i s bl o c k e d " (p. 275). Although t h i s f o r m u l a t i o n c o n t r a d i c t s the a s s e r t i o n of B o l l e s (1975) t h a t s a f e t y l e a r n i n g i s not necessary f o r one-way avoidance a c q u i s i t i o n , Beninger's h y p o t h e s i s i s not r e f u t e d by the o b s e r v a t i o n t h a t escape t r a i n i n g i s s u f f i c i e n t t o e s t a b l i s h avoidance responding on l y i f i t occurs when animals are undrugged. However, the a s s e r t i o n t h a t the e f f e c t s of dopaminergic blockade are p r i m a r i l y on l e a r n i n g , r a t h e r than performance (Beninger, 1988, 1989), does c o n t r a d i c t the f i n d i n g t h a t w e l l - a c q u i r e d a p p e t i t i v e p r e p a r a t o r y responses are d i s r u p t e d by an i n i t i a l a d m i n i s t r a t i o n of n e u r o l e p t i c (Blackburn e t a l . , 1987, 1989b). E i t h e r Beninger's a n a l y s i s a p p l i e s o n l y t o d e f e n s i v e behaviours, or e l s e we must a l s o look f o r e f f e c t s o f n e u r o l e p t i c s on performance. I f the metoclopramide-treated r a t s a re l e a v i n g the escape t r a i n i n g s e s s i o n with d e f i c i e n t knowledge, perhaps the f a i l u r e i s i n response l e a r n i n g , as opposed t o s t i m u l u s l e a r n i n g (see B o l l e s , 1978). Even a r e t a r d a t i o n o f l e a r n i n g c o u l d have had d i s r u p t i v e e f f e c t s i n t h i s s i t u a t i o n where r a t s had onl y f i v e l e a r n i n g t r i a l s . I t i s s t i l l p o s s i b l e , f o l l o w i n g Experiment I I . 7, t o argue t h a t the escape responses emitted by the drugged and undrugged r a t s were not the same responses, g i v e n the d i f f e r e n c e s i n response l a t e n c i e s Chapter I I 117 between the two groups d u r i n g t r a i n i n g . I t might be argued t h a t the s a l i n e - t r e a t e d r a t s had the o p p o r t u n i t y t o a s s o c i a t e a v o l u n t a r y response w i t h s a f e t y , but t h a t the escape responses of drugged r a t s were i n v o l u n t a r y , and thus they c o u l d not a c q u i r e t h i s a s s o c i a t i o n . I t i s d i f f i c u l t t o see what advantage t h a t k i n d of a n a l y s i s p r o v i d e s us w i t h . Perhaps we are approaching t h i s q u e s t i o n from the wrong d i r e c t i o n . Instead of a s k i n g why drugged r a t s do not execute avoidance responses when the WS i s presented, perhaps we should ask how i n f a c t they do respond t o the WS. In order t o do t h i s we s h a l l l e a v e avoidance responding f o r a w h i l e and take a c l o s e r look a t how metoclopramide-treated r a t s do i n f a c t respond t o shock and t o s h o c k - r e l a t e d s t i m u l i . We s h a l l r e t u r n t o avoidance i n Chapter 4 w i t h t h i s newly a c q u i r e d knowledge. Chapter I I I 118 I I I DO NEUROLEPTIC DRUGS ALTER CONSUMMATORY DEFENSIVE REACTIONS? In examination of the e f f e c t s of n e u r o l e p t i c drugs on a p p e t i t i v e behaviour i t was p o s s i b l e t o d i s s o c i a t e profound d i s r u p t i o n of p r e p a r a t o r y responding from minimal d i s r u p t i o n of consummatory f e e d i n g behaviour. T h i s has been e s t a b l i s h e d f o r metoclopramide (Blackburn e t a l . , 1989b) as w e l l as f o r pimozide (Blackburn e t a l . , 1987). S i m i l a r l y , i n the case of d e f e n s i v e behaviour i t has o f t e n been r e p o r t e d t h a t n e u r o l e p t i c drugs can b l o c k p r e p a r a t o r y avoidance responses a t doses t h a t do not d i s r u p t consummatory escape responses. S t u d i e s o f the e f f e c t s of n e u r o l e p t i c s on oth e r consummatory d e f e n s i v e responses t o c o n d i t i o n a l or u n c o n d i t i o n a l f e a r -r e l a t e d s t i m u l i have been n e g l i g i b l e . One of the primary responses of rodents t o f e a r - r e l a t e d s t i m u l i i s f r e e z i n g . F r e e z i n g was d e s c r i b e d by Konorski (1967) as a " p a s s i v e f e a r r e f l e x " of s m a l l animals t h a t are s u b j e c t t o p r e d a t i o n . A s i m i l a r n o t i o n i s conveyed i n the d e s c r i p t i o n of f r e e z i n g as a s p e c i e s - s p e c i f i c defense r e a c t i o n , o r SSDR ( B o l l e s , 1970, 1975; Masterson & Crawford, 1982). In both cases the su g g e s t i o n i s t h a t f r e e z i n g i s an ad a p t i v e response t h a t has evolved t o l i m i t the v i s i b i l i t y of animals t o nearby p r e d a t o r s . T h i s h y p o t h e s i s i s supported by f i n d i n g s t h a t f r e e z i n g i s r e l i a b l y e l i c i t e d i n r a t s by the presence o f a t h r e a t e n i n g p r e d a t o r . Blanchard, Mast, and Blanchard (1975) have shown t h a t the presence of a moving dog Chapter I I I 119 or c a t can r a p i d l y induce v i r t u a l l y complete i m m o b i l i t y . Even the movement of an otherwise n e u t r a l s t i m u l u s ( i . e . , a c i r c u l a r white card) e l i c i t s s u b s t a n t i a l f r e e z i n g behaviour. F r e e z i n g can be r e l i a b l y e l i c i t e d by shock. Even a s i n g l e 1-s, 1.3 mA footshock can i n c r e a s e l e v e l s of f r e e z i n g (or "crouching") over a 3-hr p e r i o d (Blanchard, Dielman, & Blanchard, 1968), 1 and the amount of f r e e z i n g i s an i n c r e a s i n g monotonic f u n c t i o n of shock i n t e n s i t y (Blanchard & Blanchard, 1969a; Fanselow St B o l l e s , 1979) . The f o l l o w i n g experiments examined the e f f e c t of metoclopramide on the f r e e z i n g r e a c t i o n s of r a t s . Experiment I I I . l examines the r e a c t i o n s of r a t s f o l l o w i n g f ootshocks, and Experiment III.2 extends t h i s study t o f r e e z i n g e l i c i t e d by c o n d i t i o n a l s t i m u l i p a i r e d w i t h shock. Experiment I I I . l - Shock-induced f r e e z i n g F r e e z i n g has been i d e n t i f i e d as a response by r a t s t o a s i n g l e footshock (e.g. Blanchard e t a l . , 1968; Blanchard & Blanchard, 1969a; Blanchard, Fukunaga, & Blanchard, 1976; Fanselow, 1980; Fanselow & B o l l e s , 1979), as w e l l as a f t e r a 1. "Crouching", as d e f i n e d by Blanchard & Blanchard, 1969a, i s not i d e n t i c a l t o " f r e e z i n g " , as d e f i n e d by B o l l e s & C o l l i e r (197.6) , Fanselow (1980) , or i n the experiments presented below. I t i s a more i n c l u s i v e term t h a t i n c l u d e s p e r i o d s d e s i g n a t e d as " i n a c t i v i t y " by B o l l e s & C o l l i e r and here. Although t h i s r e s u l t s i n c o n s i d e r a b l y h i g h e r b a s e l i n e l e v e l s of " c r o u c h i n g " than " f r e e z i n g " , i t appears t h a t the two d e f i n i t i o n s l e a d t o s i m i l a r e xperimental f i n d i n g s . Chapter I I I 120 s e r i e s o f shocks (Blanchard & Blanchard, 1969a; B o l l e s & R i l e y , 1973; Fanselow & B o l l e s , 1979). The p r e s e n t study examined the f r e e z i n g responses of r a t s a f t e r they had r e c e i v e d 1, 2, and a s e r i e s o f 7 f o o t s h o c k s . Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of the experiments of Chapters I and I I were used. A l l t e s t i n g was conducted i n the P l e x i g l a s shock compartment d e s c r i b e d i n Experiment I I . 2 . The brown s h e l f paper was removed from one w a l l t o permit viewing of the r a t s . A v i d e o camera, s t a t i o n e d approximately 50 cm from the P l e x i g l a s compartment, recorded the behaviour of the r a t s d u r i n g t e s t s e s s i o n s . A t i t l e g e n e r a t o r a f f i x e d t o the v i d e o camera pr e s e n t e d t r i a l time t o an accuracy of 0.1 s. * Procedure: Rats were assi g n e d randomly t o one of two groups (n = 7 per group). Rats of Group S a l were a d m i n i s t e r e d s a l i n e , r a t s of Group Met were a d m i n i s t e r e d 5.0 mg/kg metoclopramide. S i x t y t o n i n e t y minutes a f t e r i n j e c t i o n , a s i n g l e r a t was p l a c e d i n the P l e x i g l a s compartment. No shocks or other events o c c u r r e d i n the f i r s t 10 min t h a t the r a t was i n the compartment. At the end of t h i s h a b i t u a t i o n p e r i o d the r a t r e c e i v e d a 1.0-s, 1.0-mA footshock. A second shock was presented 2 min a f t e r the f i r s t . A s e r i e s of f i v e a d d i t i o n a l shocks began 2 min a f t e r the second, on a v a r i a b l e - t i m e (VT) 60 s schedule. Rats remained i n the compartment f o r 40 min f o l l o w i n g the f i n a l shock. Chapter I I I 121 R e a c t i o n s t o shock were score d from the v i d e o t a p e u s i n g a time sampling technique adapted from B o l l e s and C o l l i e r (1976). The experimenter scored r a t behaviours (a) i n a b a s e l i n e p e r i o d comprising the two minutes p r i o r t o the f i r s t shock, (b) i n the two minutes f o l l o w i n g the f i r s t shock, (c) i n the two minutes f o l l o w i n g the second shock, and (d) i n the two minutes a f t e r the r a t had experienced the f i n a l shock. Every 5 s, timed from shock onset (or from 2 min p r i o r t o the f i r s t shock), the behaviour of the r a t was c l a s s i f i e d i n t o one of f o u r e xhaustive c a t e g o r i e s : F r e e z i n g (immobile except f o r b r e a t h i n g and movements r e l a t e d t o h e a r t b e a t , t y p i c a l l y accompanied by conspicuous muscle r i g i d i t y and l a y i n g back of the e a r s ) , A c t i v e (locomoting, moving the body a x i s or limbs, or s n i f f i n g accompanied by head movements), Grooming ( s t e r e o t y p e d face washing or s e l f - d i r e c t e d o r a l a c t i o n s ) , or I n a c t i v e (absence of marked body a x i s or head movements, but presence of s n i f f i n g or o r a l a c t i v i t y , w i t h the ears i n t h e i r normal, u p r i g h t p o s i t i o n . T r a n s i t o r y p e r i o d s of i m m o b i l i t y between a c t i o n s were c l a s s i f i e d as I n a c t i v e . ) Data a n a l y s i s : Only the f r e e z i n g responses were analyzed s t a t i s t i c a l l y . In o r d e r t o maximize the r e l e v a n c e of the a n a l y s i s t o the r e a c t i o n s of r a t s t o shock d u r i n g avoidance t r a i n i n g the a n a l y s i s was r e s t r i c t e d t o responses of the r a t s b e g i n n i n g 3 0 s a f t e r the onset of each of the f o u r 2-min p e r i o d s and f o r the 1 min t h e r e a f t e r , even though behaviour was scored over the e n t i r e 2-min p e r i o d . The Chapter I I I 122 p a t t e r n o f r e s u l t s was s u b s t a n t i a l l y the same d u r i n g t h i s middle minute as i t was over the e n t i r e 2-min p e r i o d . The number of f r e e z i n g s c o r e s the r a t s r e c e i v e d d u r i n g the p e r i o d s b e f o r e the f i r s t shock ( b a s e l i n e ) , a f t e r the f i r s t shock, a f t e r the second shock, and a f t e r the f i n a l shock were analyzed u s i n g a two-way (Group x Period) ANOVA. S i g n i f i c a n t e f f e c t s were f u r t h e r examined u s i n g Newman-Keul1s-post hoc t e s t a t a .05 l e v e l o f s i g n i f i c a n c e . R e s u l t s The number of f r e e z i n g responses recorded i n each of the f o u r o b s e r v a t i o n p e r i o d s are i l l u s t r a t e d i n F i g u r e 13. Note t h a t i n each 1 min p e r i o d recorded t h e r e were 12 o b s e r v a t i o n s t h a t o c c u r r e d a t 5-s i n t e r v a l s . The ANOVA conducted on the f r e e z i n g s c o r e s i n d i c a t e d t h a t t h e r e was a s i g n i f i c a n t main e f f e c t o f Group [F(l,12) = 7.59, p_ < .05], a s i g n i f i c a n t e f f e c t o f P e r i o d [F(3,36) = 33.26, p_ < .001], and a s i g n i f i c a n t Group x P e r i o d i n t e r a c t i o n [F(3,36) = 2.83, p_ < . 05] . Post hoc a n a l y s i s of the i n t e r a c t i o n r e v e a l e d t h a t the number of f r e e z i n g responses by Group Met i n c r e a s e d s i g n i f i c a n t l y i n the f i r s t post-shock i n t e r v a l , r e l a t i v e t o the b a s e l i n e s c o r e s of zero f r e e z i n g responses. F u r t h e r i n c r e a s e s o c c u r r i n g a f t e r subsequent shocks were not s i g n i f i c a n t . In c o n t r a s t , the f r e e z i n g responses o f Group S a l d i d not d i f f e r s i g n i f i c a n t l y from the B a s e l i n e p e r i o d u n t i l a f t e r the second shock. Comparing the two groups, Group Met had s i g n i f i c a n t l y h i g h e r f r e e z i n g s c o r e s than Chapter I I I 123 F i g u r e 13. F r e e z i n g 30 - 90 s a f t e r shock Number of f r e e z i n g responses by r a t s 30 t o 90 s a f t e r footshock. Behaviours were score d every 5 s, f o r a t o t a l o f 12 o b s e r v a t i o n s per p e r i o d , d u r i n g the b a s e l i n e p e r i o d , i n the p e r i o d a f t e r the f i r s t shock, i n the p e r i o d a f t e r the second shock, and a f t e r a s e r i e s of f i v e a d d i t i o n a l shocks. P r i o r t o t e s t i n g Group S a l was i n j e c t e d w i t h s a l i n e , Group Met was i n j e c t e d w i t h 5.0 mg/kg metoclopramide. Chapter I I I 124 FREEZING 30 - 90 sec AFTER SHOCK 100 - i Base First Second Seventh Chapter I I I 125 Group S a l a f t e r the f i r s t and second shocks, but s c o r e s d i d not d i f f e r s i g n i f i c a n t l y a f t e r the f i n a l shock. D i s c u s s i o n T h i s experiment demonstrated t h a t the f r e e z i n g responses of r a t s i n c r e a s e d from a b a s e l i n e of zero t o a h i g h l e v e l over the course of 1, 2, and then 7 b r i e f f o o t s h o c k s . A moderate dose of metoclopramide enhanced the onset of f r e e z i n g so t h a t s i g n i f i c a n t f r e e z i n g o c c u r r e d a f t e r the f i r s t shock, whereas i n undrugged r a t s s i g n i f i c a n t f r e e z i n g was not observed u n t i l a f t e r the second shock. I t should be noted t h a t the l a c k of s i g n i f i c a n t f r e e z i n g by s a l i n e - t r e a t e d r a t s f o l l o w i n g the f i r s t shock was p robably an a r t e f a c t of the s h o r t o b s e r v a t i o n time employed. Post-shock f r e e z i n g responses have been observed f o l l o w i n g a s i n g l e footshock s i m i l a r t o t h a t used i n the p r e s e n t experiment, up t o 3 hr a f t e r the shock (Blanchard & Blanchard, 1969a). However, i t should be noted t h a t the number of f r e e z i n g responses by s a l i n e - t r e a t e d r a t s d i d show a s m a l l i n c r e a s e , not s t a t i s t i c a l l y s i g n i f i c a n t , from the b a s e l i n e of zero responses. The i n c r e a s e i n f r e e z i n g produced by metoclopramide was not l i m i t e d t o the f i r s t shock. F r e e z i n g responses were s i g n i f i c a n t l y more frequent by drugged r a t s a f t e r the second shock as w e l l . A f t e r the seventh shock metoclopramide-t r e a t e d r a t s were f r e e z i n g i n a mean of 11.6 of 12 o b s e r v a t i o n p e r i o d s . I f t h i s group was e x p e r i e n c i n g a f a c i l i t a t i o n i n f r e e z i n g responses d u r i n g t h i s f i n a l Chapter I I I 126 o b s e r v a t i o n p e r i o d , t h i s would have been masked by c e i l i n g e f f e c t s . There are no grounds f o r a t t r i b u t i n g the enhancement of f r e e z i n g by metoclopramide t o changes i n p a i n t h r e s h o l d s or t o changes i n the a c t i v i t y o f p a i n systems. Metoclopramide d i d not d i s r u p t escape responses e l i c i t e d by shock p r e s e n t a t i o n i n Experiment 1.4 or i n the experiments o f Chapter I I . The r e s u l t of t h i s experiment i s important i n t h a t i t p r o v i d e s another i n s t a n c e of a s u b s t a n t i a l e f f e c t of a n e u r o l e p t i c compound on i t s f i r s t a d m i n i s t r a t i o n . As such, i t p r o v i d e s s t r o n g evidence a g a i n s t the p o s s i b i l i t y t h a t n e u r o l e p t i c e f f e c t s on a v e r s i v e l y motivated behaviours are mediated e x c l u s i v e l y by some form of l e a r n i n g d e f i c i t (Beninger, 1988). Experiment III.2 - C o n d i t i o n a l s t i m u l u s - i n d u c e d f r e e z i n g F r e e z i n g i s a response of r a t s not o n l y t o a v e r s i v e s t i m u l i such as shock and p r e d a t o r s , but a l s o t o c o n d i t i o n a l s t i m u l i t h a t have p r e v i o u s l y been p a i r e d w i t h a v e r s i v e events. For example, Blanchard and Blanchard (1969a), B o l l e s and C o l l i e r (1976), and Fanselow (1980) have a l l r e p o r t e d t h a t i f r a t s are shocked i n one shock chamber t h e i r f r e e z i n g responses are g r e a t e r i f they are subsequently observed i n the same chamber than i f they are observed i n a d i s c r i m i n a b l y d i f f e r e n t chamber. Apparently the Chapter I I I 127 environmental cues are a c t i n g as c o n d i t i o n e d s t i m u l i f o r shock p r e s e n t a t i o n . C o n d i t i o n e d f r e e z i n g may a l s o be observed when r a t s are pres e n t e d w i t h more d i s c r e t e c o n d i t i o n a l s t i m u l i . For example, Bouton and B o l l e s (1980) demonstrated c o n d i t i o n e d f r e e z i n g when r a t s were presented w i t h a tone t h a t had p r e v i o u s l y been p a i r e d w i t h shock: L e v e l s o f f r e e z i n g were much h i g h e r when the tone had been p a i r e d w i t h shock i n a f o r w a r d - c o n d i t i o n i n g procedure than when they had been p a i r e d i n a backward-conditioning procedure. S i m i l a r l y , Sigmundi, Bouton, and B o l l e s (1980) observed c o n d i t i o n e d f r e e z i n g when white n o i s e or a l i g h t was used as the c o n d i t i o n a l s t i m u l u s , r e l a t i v e t o a p s e u d o c o n d i t i o n i n g c o n t r o l . I n t e r e s t i n g l y , the amount of f r e e z i n g observed i n c r e a s e d w i t h u n c o n d i t i o n a l s t i m u l u s i n t e n s i t y o n l y i f the c o n d i t i o n a l s t i m u l u s was the white n o i s e . Subsequent t o these r e p o r t s f r e e z i n g has been used as a s e n s i t i v e index o f c o n d i t i o n e d f e a r i n a number of s t u d i e s (e.g., Cook e t a l . , 1987; Fanselow & H e l m s t e t t e r , 1988; Iwata, Ledoux, Meely, A r n e r i c , & R e i s , 1986; Ledoux, Iwata, P e a r l , & R e i s s , 1986; Mineka e t ' a l . , 1984). Having determined t h a t f r e e z i n g responses f o l l o w i n g shock p r e s e n t a t i o n are enhanced by metoclopramide i n Experiment I I . 1 , the prese n t experiment i n v e s t i g a t e s whether a s i m i l a r e f f e c t i s t o be found when r a t s a re presented with a c o n d i t i o n a l s t i m u l u s p r e v i o u s l y p a i r e d w i t h shock d e l i v e r y . In a d d i t i o n t o a group r e c e i v i n g s a l i n e p r i o r t o Chapter I I I 128 the t e s t f o r c o n d i t i o n e d f r e e z i n g , a d d i t i o n a l c o n t r o l groups i n c l u d e d a S e n s i t i z a t i o n group which r e c e i v e d o n l y p r e -exposure t o the c o n d i t i o n a l s t i m u l u s , and a P s e u d o c o n d i t i o n i n g group which r e c e i v e d exposure t o o n l y the u n c o n d i t i o n a l footshock. Method Su b j e c t s and apparatus: Rats s i m i l a r t o those of p r e v i o u s experiments were t e s t e d u s i n g the same P l e x i g l a s chamber, and v i d e o r e c o r d i n g equipment as i n Experiment I I I . l . The P s e u d o c o n d i t i o n i n g group r e c e i v e d shock p r e s e n t a t i o n s i n the shock s i d e of the one-way avoidance apparatus. Procedure: The experiment was conducted a c r o s s a two day p e r i o d , a C o n d i t i o n i n g Day and a T e s t Day. Rats were as s i g n e d randomly t o one of f o u r groups. On the c o n d i t i o n i n g day r a t s of the two c o n d i t i o n i n g groups (Groups Cond-Met and Cond-Sal, each n = 7) were p l a c e d i n the P l e x i g l a s chamber. A f t e r a 10-min a c c l i m a t i z a t i o n p e r i o d they were presented w i t h f i v e tone-shock p a i r i n g s . Each p a i r i n g c o n s i s t e d of a 10-s tone p e r i o d f o l l o w e d by a 0.5-s, 1.0 mA footshock d u r i n g which the tone remained on. (A p i l o t experiment i n d i c a t e d t h a t a l l shocked r a t s , even s a l i n e - t r e a t e d c o n t r o l s , would f r e e z e f o r v i r t u a l l y a l l of the o b s e r v a t i o n p e r i o d i f they had been g i v e n 10 p a i r i n g s of tone w i t h 1.0-s, 1.0-mA footshock) The i n t e r t r i a l i n t e r v a l was 2 min. F o l l o w i n g the f i n a l shock each r a t remained i n the chamber f o r an a d d i t i o n a l 10 min. Rats of the Chapter I I I 129 S e n s i t i z a t i o n group (n = 7) r e c e i v e d e x a c t l y the same p a t t e r n of tone p r e s e n t a t i o n s as the C o n d i t i o n i n g Groups, but d i d not r e c e i v e any footshocks. Rats o f the P s e u d o c o n d i t i o n i n g group (n = 6) r e c e i v e d f i v e shocks on the same schedule as the C o n d i t i o n i n g groups, but d i d not r e c e i v e any tone p r e s e n t a t i o n s . To minimize a s s o c i a t i o n s between the chamber and the shocks, shocks were presented t o the Ps e u d o c o n d i t i o n i n g group i n the shock s i d e o f the one-way avoidance apparatus. On the t e s t day, r a t s i n Group Cond-Met were ad m i n i s t e r e d 5.0 mg/kg metoclopramide, as were r a t s o f the S e n s i t i z a t i o n and P s e u d o c o n d i t i o n i n g groups. Rats i n Group Cond-Sal were ad m i n i s t e r e d s a l i n e . S i x t y t o n i n e t y minutes a f t e r i n j e c t i o n , a s i n g l e r a t was p l a c e d i n the P l e x i g l a s compartment. No scheduled events o c c u r r e d i n the f i r s t 10 min t h a t the r a t was i n the compartment. At the end of t h i s 10-min p e r i o d the r a t r e c e i v e d f i v e 10-s p r e s e n t a t i o n s of the tone, w i t h an i n t e r t r i a l i n t e r v a l of 2 min. A f t e r the f i f t h tone the r a t remained i n the chamber f o r an a d d i t i o n a l 10 min. R e a c t i o n s t o the f i v e tones were score d from the vi d e o t a p e u s i n g the same sampling technique used i n Experiment I I I . l . During the tones themselves, behaviour was sampled every 2 s, timed from tone onset (or from 2 min p r i o r t o the f i r s t tone f o r the b a s e l i n e s c o r e ) . F o l l o w i n g the tone, behaviour was sampled every 5 s f o r the next 2 min. Chapter I I I 130 Data a n a l y s i s : As i n Experiment I I I . l , an ANOVA was conducted on f r e e z i n g response o c c u r r i n g d u r i n g the 1 min p e r i o d b e g i n n i n g 3 0 s a f t e r the o f f s e t o f each tone, as w e l l as f o r a b a s e l i n e p e r i o d p r i o r t o the onset o f the f i r s t tone. In a d d i t i o n , a separate ANOVA was conducted on f r e e z i n g responses t h a t o c c u r r e d d u r i n g the 10-s CS p e r i o d , and d u r i n g a 10-s b a s e l i n e p e r i o d commencing 2 min p r i o r t o the onset o f the f i r s t tone. During these 10-s p e r i o d s , behaviours were scored every 2 s, f o r a t o t a l of f i v e o b s e r v a t i o n s . For both tone and post-tone i n t e r v a l s , data was analyzed u s i n g a two-way (Group x T r i a l ) ANOVA. In each case s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-K e u l 1 s p o s t hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . R e s u l t s The number of f r e e z i n g responses d u r i n g the tone p e r i o d s are i l l u s t r a t e d i n the top panel o f F i g u r e 14. Note t h a t i n the 10-s tone p e r i o d t h e r e were f i v e o b s e r v a t i o n s t h a t o c c u r r e d a t 2-s i n t e r v a l s . There was a s i g n i f i c a n t e f f e c t of T r i a l [F(5,115) = 3.22, p < .01], but t h e r e was no s i g n i f i c a n t e f f e c t of Group [F(3,23) = 1.80, p > .10], and no s i g n i f i c a n t Group x T r i a l i n t e r a c t i o n (F < 1). The post hoc t e s t i n d i c a t e d t h a t the onl y s i g n i f i c a n t comparison between t r i a l s was between the b a s e l i n e p e r i o d and T r i a l 4. F r e e z i n g responses d u r i n g the i n t e r v a l s from 30 t o 90 s f o l l o w i n g tone o f f s e t are i l l u s t r a t e d i n the bottom panel o f F i g u r e 14. Note t h a t i n t h i s 60-s p e r i o d t h e r e were 12 Chapter I I I 131 F i g u r e 14. F r e e z i n g induced by CS+ Top panel shows number of f r e e z i n g responses by r a t s d u r i n g the 10 s p e r i o d s i n which the c o n d i t i o n a l s t i m u l u s (tone) was b e i n g presented, as w e l l as d u r i n g the b a s e l i n e p e r i o d 2 min p r i o r t o the f i r s t tone. Behaviours were sc o r e d every 2 s from tone onset f o r a t o t a l of f i v e o b s e r v a t i o n s per p e r i o d . Bottom panel shows number of f r e e z i n g responses by r a t s i n the p e r i o d from 3 0 t o 90 s a f t e r tone p r e s e n t a t i o n , as w e l l as d u r i n g the b a s e l i n e p e r i o d 90 t o 30 s p r i o r t o the f i r s t CS+. Behaviours were scored every 5 s i n b a s e l i n e p e r i o d and a f t e r each CS+, f o r a t o t a l of 12 o b s e r v a t i o n s per p e r i o d . On the day p r i o r t o t e s t i n g r a t s of Group Cond-Sal and Cond-Met r e c e i v e d f i v e p a i r i n g s of CS+ and shock, Group S e n s i t i z a t i o n r e c e i v e d o n l y CS+ p r e s e n t a t i o n s , and Group P s e u d o c o n d i t i o n i n g was shocked f i v e times i n a s e p a r a t e compartment. On t e s t day Groups Cond-Met, S e n s i t i z a t i o n , and P s e u d o c o n d i t i o n i n g r e c e i v e d 5.0 mg/kg metoclopramide, Group Cond-Sal r e c e i v e d s a l i n e . Chapter I I I 132 FREEZING DURING CS+ PRESENTATION 5-FREEZING 30 - 90 s AFTER CS+ Chapter I I I 13 3 o b s e r v a t i o n s t h a t o c c u r r e d a t 5-s i n t e r v a l s . There was a s i g n i f i c a n t e f f e c t of T r i a l [F(5,115) = 11.12, p < .001], but t h e r e was no s i g n i f i c a n t e f f e c t of Group [F(3,23) = 1.52, p > .20], and no s i g n i f i c a n t Group x T r i a l i n t e r a c t i o n [F(15,115) = 1.38, p > .10]. Post hoc examination of the T r i a l e f f e c t i n d i c a t e d t h a t t h e r e were more f r e e z i n g responses a f t e r each c o n d i t i o n a l s t i m u l u s p r e s e n t a t i o n than d u r i n g the b a s e l i n e p e r i o d . There were no s i g n i f i c a n t d i f f e r e n c e s between the f i v e t r i a l s . D i s c u s s i o n The data from the p r e s e n t experiment do not support the h y p o t h e s i s t h a t metoclopramide i n c r e a s e s the amount of f r e e z i n g induced by a c o n d i t i o n a l s t i m u l u s t h a t has been p a i r e d w i t h shock. Such a c o n c l u s i o n would have r e q u i r e d a s i g n i f i c a n t d i f f e r e n c e between Groups Cond-Met and Cond-Sal, and f u r t h e r demonstration t h a t the magnitude of f r e e z i n g was h i g h e r i n Group Cond-Met than i n the S e n s i t i z a t i o n and P s e u d o c o n d i t i o n i n g c o n t r o l s . In the absence of s a l i n e -t r e a t e d s e n s i t i z a t i o n and p s e u d o c o n d i t i o n i n g c o n t r o l s i t i s not even p o s s i b l e t o determine i f the f r e e z i n g seen i n a l l groups f o l l o w i n g tone p r e s e n t a t i o n s i s due t o P a v l o v i a n a s s o c i a t i o n s , as p r e v i o u s l y r e p o r t e d (Blanchard & Blanchard, 1969a; B o l l e s & C o l l i e r , 1976; Bouton & B o l l e s 1980; Cook e t a l . , 1987; Fanselow 1980; Mineka e t a l . , 1984; Sigmundi e t a l . , 1980) . Examination of F i g u r e 14 suggests t h a t i t would be i n a p p r o p r i a t e t o d i s m i s s the n o t i o n t h a t metoclopramide Chapter I I I 134 enhances c o n d i t i o n e d f r e e z i n g out of hand. In the 1-min o b s e r v a t i o n i n t e r v a l s f o l l o w i n g the f i r s t t h r e e tone p r e s e n t a t i o n s the r a t s of Group Conditioned-Met were f r o z e n d u r i n g 86% of the b e h a v i o u r a l samples observed, compared t o 40% f o r Group C o n d i t i o n e d - S a l , 49% f o r the S e n s i t i z a t i o n group and 62% f o r the P s e u d o c o n d i t i o n i n g group. These data suggest t h a t w i t h a more s e n s i t i v e measuring technique s u b s t a n t i a l d i f f e r e n c e s might have been found between the groups. A s u r p r i s i n g outcome of t h i s experiment was the h i g h l e v e l of f r e e z i n g observed i n the r a t s of the S e n s i t i z a t i o n and P s e u d o c o n d i t i o n i n g groups. That t h i s f r e e z i n g was not a primary e f f e c t of metoclopramide treatment i s a t t e s t e d t o by the low l e v e l of f r e e z i n g by these groups d u r i n g the b a s e l i n e p e r i o d and by the absence of f r e e z i n g by Group Met i n the b a s e l i n e p e r i o d of Experiment I I I . l . Instead, such f r e e z i n g might be a t t r i b u t e d t o the g e n e r a l i z a t i o n of apparatus cues on the p a r t of the P s e u d o c o n d i t i o n i n g group. In the case of the S e n s i t i z a t i o n group i t appears t h a t f e a r must have been e l i c i t e d d i r e c t l y by the tone, or p o s s i b l y by a combination of the cue and u n c o n d i t i o n e d f e a r - e l i c i t i n g p r o p e r t i e s of the t e s t box ( b r i g h t overhead l i g h t , probable presence of f e a r pheromones). In t h i s context, i t i s i n t e r e s t i n g t o note t h a t v a r i o u s experimenters have r e p o r t e d o c c a s i o n a l l y t h a t avoidance responses can be p o t e n t i a t e d by p r e s e n t a t i o n of a supposedly n e u t r a l s i g n a l (e.g., Jacobs & LoLordo, 1980; Myers, 1962; Smith, McFarland & T a y l o r , 1961). Chapter I I I 13 5 D i s c u s s i o n of Chapter I I I The f i r s t experiment i n t h i s chapter c l e a r l y i n d i c a t e d t h a t metoclopramide enhances f r e e z i n g responses f o l l o w i n g shock p r e s e n t a t i o n . I t i s l e s s obvious t h a t metoclopramide i n c r e a s e s f r e e z i n g responses e l i c i t e d by c o n d i t i o n a l s t i m u l i . The r e s u l t s of Experiment III.2 f a i l t o support such a c o n c l u s i o n . However, the r e s u l t s of Experiment I I I . l may be i n t e r p r e t e d i n j u s t t h i s way. I t may seem s u r p r i s i n g t h a t the f r e e z i n g responses observed i n the i n t e r v a l f o l l o w i n g shock p r e s e n t a t i o n should be regarded as a c o n d i t i o n e d response t o s h o c k - r e l a t e d cues. However, c o n s i d e r the a l t e r n a t i v e s . Is f r e e z i n g an i n s t r u m e n t a l response t h a t i s r e i n f o r c e d by somehow modifying the shock's d e l i v e r y or impact? Arguing a g a i n s t t h i s p r o p o s a l i s the f a c t t h a t the p r o b a b i l i t y of f r e e z i n g decreases, r a t h e r than i n c r e a s e s , through the d u r a t i o n of an extended footshock (Blanchard & Blanchard, 1969a). There i s another argument a g a i n s t v i e w i n g f r e e z i n g as an i n s t r u m e n t a l response. Indeed, f r e e z i n g as an avoidance response has been r e p o r t e d t o be a c q u i r e d r a p i d l y by r a t s (Bindra & Anchel, 1963; Brener & G o e s l i n g , 1970). But c o n s i d e r an important paper i n which B o l l e s and R i l e y (1973) examined f r e e z i n g responses r e i n f o r c e d by shock avoidance on a Sidman schedule. In t h i s experiment the animals were shocked every 5 s as long as they were a c t i v e , but shock was w i t h h e l d as soon as f r e e z i n g o c c u r r e d . The shock s e r i e s was r e i n s t a t e d i f the animals q u i t f r e e z i n g and were a c t i v e f o r a Chapter I I I 13 6 p e r i o d of 15 s. A complementary group was punished f o r f r e e z i n g . That i s , the s e r i e s of shocks o c c u r r e d a f t e r the r a t s f r o z e f o r 15 s and continued as l o n g as the f r e e z i n g c o n t i n u e d . F r e e z i n g was a p p a r e n t l y a c q u i r e d r a p i d l y as an i n s t r u m e n t a l response, whereas the punishment contingency r e s u l t e d i n lower l e v e l s of f r e e z i n g . However, comparison of the experimental r a t s w i t h yoked c o n t r o l s , w i t h r a t s i n e x t i n c t i o n , and with r a t punished f o r f r e e z i n g f o r even 1 s a l l showed t h a t the avoidance and punishment c o n t i n g e n c i e s a f f e c t e d f r e e z i n g o n l y to the extent t h a t they produced d i f f e r e n t f r e q u e n c i e s of shock. B o l l e s and R i l e y concluded t h a t f r e e z i n g was n e i t h e r strengthened by the avoidance procedure nor weakened by the punishment procedure, and on the s t r e n g t h of t h i s f i n d i n g B o l l e s (1975) argued t h a t f r e e z i n g must always be a respondent, not s u b j e c t t o l e a r n i n g as an operant response. The o t h e r obvious i n t e r p r e t a t i o n of f r e e z i n g f o l l o w i n g shock a d m i n i s t r a t i o n i s t h a t i t i s an u n c o n d i t i o n a l response t o shock. However, as Fanselow (1980) p o i n t s out T h i s i d e a would r e q u i r e some adjustment of the u s u a l view of the UR [ u n c o n d i t i o n a l response] as an immediate, s h o r t - l i v e d r e f l e x , because f r e e z i n g i s not l i k e the u s u a l sudden j e r k UR t h a t i s i n v a r i a b l y e l i c i t e d by shock. The occurrence of f r e e z i n g i s p r o b a b i l i s t i c , f r e e z i n g has a d e l a y e d onset, and i t occurs i n prolonged bouts l a s t i n g s e v e r a l minutes... These p r o b a b i l i s t i c and temporal p r o p e r t i e s s e t the f r e e z i n g response somewhat a p a r t from the u s u a l UR. (p. 177). Beyond these c o n s i d e r a t i o n s , e m p i r i c a l evidence argues t h a t f r e e z i n g f o l l o w i n g shock i s a c o n d i t i o n e d , r a t h e r than an u n c o n d i t i o n a l , response. Blanchard and Blanchard (1969a) Chapter I I I 137 and B o l l e s and C o l l i e r (1976) found much l e s s f r e e z i n g f o l l o w i n g shock treatment i f they moved r a t s i n t o a novel compartment than i f they handled them and r e t u r n e d them t o the shock compartment. In the study by Blanchard and Blanchard f r e e z i n g (or "crouching") was reduced t o the l e v e l of nonshocked c o n t r o l s , but i n t e r p r e t a t i o n o f t h e i r f i n d i n g s i s c o m p l i c a t e d by t h e i r f a i l u r e t o counterbalance compartments. In the study by B o l l e s and C o l l i e r f r e e z i n g was reduced t o an i n t e r m e d i a t e l e v e l , h i g h e r than t h a t of nonshocked c o n t r o l s . To determine i f post-shock f r e e z i n g c o n s t i t u t e d a c o n d i t i o n e d response or an u n c o n d i t i o n a l response Fanselow (1980) not onl y changed compartments f o r h a l f of h i s r a t s , he a l s o delayed t e s t i n g of h a l f the r a t s by 24 h r i n a f a c t o r i a l d e s i g n . G r e a t e r f r e e z i n g was observed i f the r a t s were t e s t e d i n the same compartment t h a t they were shocked i n , and the magnitude of t h i s e f f e c t was j u s t as g r e a t i f a 24-hr d e l a y was imposed between shock and t e s t . I f t h e r e was an u n c o n d i t i o n a l component t o the f r e e z i n g , i t i s o n l y reasonable t o expect t h a t i t would a t l e a s t have d i m i n i s h e d a f t e r t h i s d e l a y . As i t d i d not, i t was concluded t h a t a l l f r e e z i n g observed i n the compartment i n which the shocked r a t s had not been shocked was due t o g e n e r a l i z a t i o n w i t h the shock apparatus. T h i s c o n c l u s i o n r e c e i v e s f u r t h e r support from r e p o r t s t h a t no f r e e z i n g i s observed i n the f i v e minutes f o l l o w i n g shock i f r a t s are shocked immediately upon being p l a c e d i n the compartment (Blanchard e t a l . , 1976; Fanselow 1986). Chapter I I I 138 T h i s demonstrates t h a t f r e e z i n g i s not simply a r e a c t i o n t o shock, but r a t h e r a response c o n d i t i o n e d t o cues i n the environment. I f the r a t does not have s u f f i c i e n t exposure t o the envirionment p r i o r t o shock onset, no c r o u c h i n g o c c u r s . Together, these c o n s i d e r a t i o n s l e a d t o the c o n c l u s i o n t h a t f r e e z i n g responses observed a f t e r shock a d m i n i s t r a t i o n are c o n d i t i o n e d responses e l i c i t e d by environmental s t i m u l i t h a t the r a t has come t o a s s o c i a t e w i t h shock a f t e r as few as a s i n g l e u n c o n d i t i o n a l shock p r e s e n t a t i o n . A c c o r d i n g l y , i t i s concluded from Experiment I I I . l t h a t metoclopramide does indeed i n c r e a s e c o n d i t i o n e d f r e e z i n g responses of r a t s t o s h o c k - r e l a t e d s t i m u l i . In l i g h t of t h i s demonstration, we must r e - e v a l u a t e the avoidance a c q u i s i t i o n d e f i c i t produced by metoclopramide. Chapter IV 139 IV CAN FEAR DISRUPT AVOIDANCE RESPONDING? I f an animal f r e e z e s , i t cannot perform an avoidance response. I t f o l l o w s t h a t m a n i p u l a t i o n s t h a t enhance f r e e z i n g can d i s r u p t avoidance responding. For example, Weiss e t a l . (19 68) found t h a t when they gave r a t s e i g h t p a i r i n g s of a tone c o n d i t i o n a l s t i m u l u s w i t h 10-s footshock, a c q u i s i t i o n of avoidance, u s i n g the tone as the WS, was subsequently i n h i b i t e d . T h i s f i n d i n g , i n c o n t r a s t t o those of Experiment II.2 and those of s e v e r a l o t h e r i n v e s t i g a t o r s (Anisman e t a l . , 1982; G a l l o n , 1972; Overmier & Leaf, 1965), appears t o be the r e s u l t of the ve r y long shocks a d m i n i s t e r e d by Weiss e t a l . Such severe shock experience would be expected t o l e a d t o i n t e n s e f r e e z i n g , and, indeed, a n a l y s i s of the r a t s 1 behaviour d u r i n g avoidance t r i a l s i n d i c a t e d t h a t they were f r e e z i n g , r a t h e r than a v o i d i n g . In f a c t , avoidance responding was improved i f f e a r l e v e l s (and hence, f r e e z i n g ) were reduced by g i v i n g f e a r e x t i n c t i o n . These r e s u l t s are c o n s i s t e n t w i t h o t h e r r e p o r t s t h a t responding may d e c l i n e i f e x c e s s i v e l y s t r o n g shocks are used as the AS (e.g., Moyer & Korn, 19 64). An i n v e r s e r e l a t i o n s h i p between f r e e z i n g and avoidance has a l s o been demonstrated i n s i t u a t i o n s not i n v o l v i n g i n t e n s e shock l e v e l s . Blanchard & Blanchard (1969b) found a ne g a t i v e c o r r e l a t i o n between d i s c r i m i n a t e d avoidance of a moving prod and f r e e z i n g f o l l o w i n g a s i n g l e shock. Chapter IV 140 Lenard and Beer (1975) proposed t h a t i n a p p r o p r i a t e r e a c t i o n s t o shock l e a d t o impaired avoidance response maintenance f o l l o w i n g c e n t r a l a p p l i c a t i o n of 6-OHDA. Ac c o r d i n g t o them, d u r i n g the f i r s t few s e s s i o n s a f t e r treatment w i t h [6-OHDA] t h e r e was an i n c r e a s e i n the frequency of a new s e r i e s of responses, i n c l u d i n g f r e e z i n g , t h a t was i n c o m p a t i b l e w i t h the avoidance response and was c o r r e l a t e d w i t h the d e c l i n e i n the frequency of avoidance behaviour. I t i s p o s s i b l e t h a t the r a t s had l e a r n e d t o suppress avoidance responses (p. 177) . Although no q u a n t i t a t i v e data on these i n c o m p a t i b l e responses were p r o v i d e d , Beer and Lenard (1975) supported t h i s h y p o t h e s i s by demonstrating t h a t a d m i n i s t r a t i o n of diazepam, which a p p a r e n t l y a t t e n u a t e d f r e e z i n g d u r i n g avoidance s e s s i o n s , a l l e v i a t e d the 6-OHDA-induced d e f i c i t , even though t h i s a n x i o l y t i c had no e f f e c t on avoidance by i t s e l f . T h i s h y p o t h e s i s gains credence by v i r t u e of the f a c t t h a t p a r a l l e l arguments have been advanced t o account f o r avoidance d e f i c i t s observed f o l l o w i n g l e s i o n s of the amygdala or the dorsomedial nucleus of the thalamus (DMN). For example, Robinson (1963) found e l e v a t e d l e v e l s of c r o u c h i n g i n amygdala-lesioned r a t s , and a s t r o n g c o r r e l a t i o n (r = 0.83) between c r o u c h i n g and l o g response l a t e n c y f o r amygdalectomized r a t s , but not f o r c o n t r o l s . Robinson (1963) suggested t h a t the amygdalectomized r a t s were o v e r - r e s p o n s i v e t o a v e r s i v e s t i m u l i . S i m i l a r l y , Campenot (1969) proposed " t h a t amygdaloid l e s i o n s i n c r e a s e an animal's tendency t o suppress responding as a r e a c t i o n t o b e i n g shocked" (p. 496). Chapter IV 141 D i s r u p t i o n of avoidance responding by i n a p p r o p r i a t e r e a c t i o n s t o shock c o u l d a l s o account f o r the c u r i o u s f i n d i n g s of O l t o n and Isaacson (1967) concerning the e f f e c t s of DMN l e s i o n s . D e f i c i t s were observed i n the r e t e n t i o n of avoidance responding o n l y i f r a t s were t e s t e d i n r e a c q u i s i t i o n , when the r a t s r e c e i v e d footshock as a r e s u l t of f a i l u r e s t o respond. The r a t s were p e r f e c t l y capable of performing avoidance responses, as demonstrated by t h e i r undiminished c a p a c i t y t o execute responses i f they were t e s t e d i n e x t i n c t i o n , y e t somehow the presence of shock d i s r u p t e d performance. T h i s i n t e r p r e t a t i o n i s supported by the o b s e r v a t i o n t h a t the d e f i c i t was not so pronounced i n one-way as i n two-way avoidance, i n which both c o n t r o l and l e s i o n e d r a t s r e c e i v e d more shocks. Can a s i m i l a r a n a l y s i s be a p p l i e d t o the avoidance d e f i c i t s observed a f t e r a d m i n i s t r a t i o n of n e u r o l e p t i c drugs? As reviewed i n Chapter I I , i t i s c l e a r t h a t such drugs do not d i s r u p t l e a r n i n g about the a v e r s i v e nature of shock. On the o t h e r hand, i t was demonstrated i n Chapter I I I t h a t n e u r o l e p t i c s do i n f a c t a l t e r f r e e z i n g responses i n a f e a r f u l environment. Thus, i t i s reasonable t o h y p o t h e s i z e t h a t the enhanced f r e e z i n g observed i n Chapter I I I should i n t e r f e r e w i t h avoidance responding. The experiments of the p r e s e n t chapter t e s t t h i s h y p o t h e s i s . Chapter IV 142 Experiment IV.1 - E f f e c t o f non-contingent shock I f shock-induced f r e e z i n g f o l l o w i n g metoclopramide treatment c o n t r i b u t e s t o the avoidance d e f i c i t observed i n Experiment 1.4 and throughout Chapter I I , then p r e s e n t i n g the r a t s w i t h a d d i t i o n a l u n c o n t r o l l a b l e footshocks throughout the avoidance s e s s i o n should a c t s y n e r g i s t i c a l l y w i t h a dose of metoclopramide t o d i s r u p t avoidance responding. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of the experiments of Chapters I t o I I I were used. A l l t e s t i n g was conducted i n the one-way avoidance apparatus used i n Chapter I, and p r e l i m i n a r y tone-shock p a i r i n g s were d e l i v e r e d i n the P l e x i g l a s compartment d e s c r i b e d i n Experiment I I . 2 . Procedure: Rats were a s s i g n e d randomly t o one of f o u r groups (n = 6 per group). Each r a t r e c e i v e d 10 non-c o n t i n g e n t WS-AS p a i r i n g s i n the shock s i d e o f the avoidance apparatus. On the next day r a t s o f a l l groups r e c e i v e d an i n i t i a l avoidance t r a i n i n g s e s s i o n c o n s i s t i n g o f f i v e s t andard avoidance t r i a l s . T h i s amount of t r a i n i n g was s e l e c t e d t o p r o v i d e the r a t s w i t h a moderate amount of p r o t e c t i o n from the e f f e c t s of metoclopramide (see Experiment I I . 2 ) . There were no s i g n i f i c a n t d i f f e r e n c e s between groups on the t r a i n i n g day ( a l l Fs < 1). On the f o l l o w i n g day, the t e s t day, r a t s o f each group were t e s t e d on 10 avoidance t r i a l s . Two groups of r a t s , the Chapter IV 14 3 non-contingent footshock (NCF) groups, r e c e i v e d a 3.0-s footshock i n the shock s i d e of the avoidance apparatus p r i o r t o the f i r s t t r i a l . In a d d i t i o n , these r a t s r e c e i v e d a 1.0-s footshock on each t r i a l a f t e r b e i n g p l a c e d i n the shock s i d e of the compartment, p r i o r t o the onset of the WS. Rats of the two C o n t r o l groups d i d not r e c e i v e the non-contingent footshock. One NCF group (NCF-Met) and one c o n t r o l group (Control-Met) r e c e i v e d 5.0 mg/kg metoclopramide p r i o r t o t e s t i n g , w h i l e the other two groups (NCF-Sal and C o n t r o l - S a l ) r e c e i v e d s a l i n e i n j e c t i o n s . S t a t i s t i c a l a n a l y s i s : The number of avoidances were analyzed u s i n g a two-way (Drug treatment x Shock treatment) ANOVA. Latency s c o r e s were analyzed w i t h a three-way (Drug x Shock x T r i a l ) ANOVA. In each case s i g n i f i c a n t e f f e c t s were f u r t h e r analyzed u s i n g Newman-Keul 1s post hoc t e s t a t a .05 l e v e l of s i g n i f i c a n c e . R e s u l t s The number of avoidances are i l l u s t r a t e d i n the top panel of F i g u r e 15. As can be seen i n the f i g u r e , non-c o n t i n g e n t footshock d i s r u p t e d the performance of the r a t s t h a t had r e c e i v e d metoclopramide, but i t d i d not d i s r u p t the performance of the r a t s t h a t had r e c e i v e d s a l i n e . Drug a d m i n i s t r a t i o n alone produced a minor d e f i c i t (6.9/10 c o r r e c t responses v s . 9.0/10 f o r C o n t r o l r a t s ) . T h i s d e f i c i t was markedly exacerbated by a d m i n i s t e r i n g non-contingent shocks t o the d r u g - t r e a t e d r a t s p r i o r t o each Chapter IV 14 4 F i g u r e 15. E f f e c t o f p r e t r i a l shock Top panel i n d i c a t e s mean number of avoidances executed on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . A l l r a t s r e c e i v e d 10 tone-shock p a i r i n g s on Day 1 and 5 avoidance t r a i n i n g t r i a l s on Day 2. On the t e s t day NCF Groups r e c e i v e d non-contingent shock p r i o r t o each t r i a l , C o n t r o l Groups d i d not. S a l Groups r e c e i v e d s a l i n e on the t e s t day, Met Groups r e c e i v e d 5.0 mg/kg metoclopramide. Chapter IV 145 NON-CONTINGENT FOOTSHOCK 10 - i Control NCF Chapter IV 14 6 t r i a l ( r e d u c i n g Group NCF-Met t o 3.8/10), a procedure t h a t had no e f f e c t on undrugged r a t s (9.2/10 f o r Group NCF-Sal). T h i s impression i s confirmed by the ANOVA. There was a s i g n i f i c a n t e f f e c t of Drug [F(l,20) = 43.83, p < .001], a s i g n i f i c a n t e f f e c t of Shock [F(l,20) = 6.26, p < .05], and a s i g n i f i c a n t Drug x Shock i n t e r a c t i o n [F(l,20) = 7.81, p < .05]. Post hoc t e s t i n g i n d i c a t e d t h a t of the two groups t h a t r e c e i v e d metoclopramide, the one t h a t r e c e i v e d non-contingent shocks (NCF-Met) performed worse than the group t h a t d i d not r e c e i v e shock (Control-Met). In c o n t r a s t , the performance of the two groups t h a t r e c e i v e d s a l i n e d i d not d i f f e r . Thus, t h e r e was a s y n e r g i s t i c e f f e c t of metoclopramide and non-c o n t i n g e n t shock. Examination of the l a t e n c y s c o r e s (bottom panel of F i g u r e 15) suggests a s i m i l a r p a t t e r n of r e s u l t s . However, because of g r e a t e r within-group v a r i a b i l i t y , the i n t e r a c t i o n was not s i g n i f i c a n t . There was a s i g n i f i c a n t e f f e c t of drug [ F ( l , 2 0 ) = 19.74, p < .001], but not a s i g n i f i c a n t e f f e c t of Shock [F(l,20) = 1.49, p > .20], nor a s i g n i f i c a n t Drug x Shock i n t e r a c t i o n [F(l,20) = 1.73, p > .20]. D i s c u s s i o n The r e s u l t s of t h i s experiment support the h y p o t h e s i s t h a t r a t s t r e a t e d with n e u r o l e p t i c drugs f r e e z e i n response t o shock, thereby s u p p r e s s i n g avoidance responding. However, an a l t e r n a t i v e i n t e r p r e t a t i o n of these r e s u l t s i s p o s s i b l e . Rather than d i s r u p t i n g the performance of metoclopramide-t r e a t e d r a t s by i n t e r f e r i n g with t h e i r Chapter IV 147 response c a p a b i l i t i e s , the non-contingent footshocks may have i n t e r f e r e d w i t h t h e i r avoidance performance by d i s r u p t i n g t h e i r r e p r e s e n t a t i o n s of response-outcome c o n t i n g e n c i e s . T h i s i s a v a r i a n t of the " l e a r n e d h e l p l e s s n e s s " h y p o t h e s i s of Overmier and Seligman (1967), i n which they suggest t h a t s u b j e c t s may l e a r n t h a t t h e i r responses are independent of shock t e r m i n a t i o n . There i s no obvious reason why the drug should have produced such a c o n f u s i o n i n metoclopramide-t r e a t e d r a t s when the undrugged r a t s were not d i s r u p t e d . Nonetheless, Experiment IV.2 was conducted t o exclude t h i s p o s s i b i l i t y . Experiment IV.2 - E f f e c t of shock i n a d i f f e r e n t c ontext I t i s p o s s i b l e t h a t r a t h e r than e l i c i t i n g i n a p p r o p r i a t e , i n c o m p a t i b l e responses, the noncontingent shocks a d m i n i s t e r e d t o the r a t s i n Experiment IV.1 i n t e r f e r e d w i t h avoidance performance by d i s r u p t i n g t h e i r r e p r e s e n t a t i o n s of response-outcome c o n t i n g e n c i e s . T h i s i n t e r p r e t a t i o n c o u l d be d i s c o u n t e d by showing t h a t shock a d m i n i s t e r e d i n a separate compartment, p r i o r t o t e s t i n g , has a s i m i l a r d e l e t e r i o u s e f f e c t . Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of the experiments of Chapters I t o I I I were used. Avoidance t e s t i n g was conducted i n the one-way avoidance apparatus d e s c r i b e d i n Chapter I, and a d d i t i o n a l tone and shock Chapter IV 148 p r e s e n t a t i o n s were d e l i v e r e d i n the P l e x i g l a s compartment d e s c r i b e d i n Experiment I I . 2 . Procedure: The de s i g n o f the experiment was i d e n t i c a l t o t h a t of Experiment IV.1 except f o r the manner i n which non-contingent footshocks were ad m i n i s t e r e d . Rats were as s i g n e d randomly t o one of f o u r groups (n = 8 per group). On the f i r s t day of the experiment each r a t r e c e i v e d 10 WS-AS p a i r i n g s i n the P l e x i g l a s compartment. On the next day r a t s of a l l groups r e c e i v e d an i n i t i a l avoidance t r a i n i n g s e s s i o n c o n s i s t i n g of f i v e standard avoidance t r i a l s . T h i s amount of t r a i n i n g was s e l e c t e d t o p r o v i d e r a t s w i t h a moderate amount of p r o t e c t i o n from the e f f e c t s o f metoclopramide, as i n Experiment IV.1. There were no d i f f e r e n c e s between groups i n number of avoidances o r response l a t e n c i e s on t h i s t r a i n i n g day (Fs < 1). On the f o l l o w i n g day, the t e s t day, r a t s of each group r e c e i v e d 10 avoidance t r i a l s . Immediately p r i o r t o the commencement of these t e s t t r i a l s the r a t s o f two groups, the Shock groups, r e c e i v e d t h r e e non-contingent, 1.5-s, 1.0-mA footshocks i n the P l e x i g l a s apparatus, w i t h an i n t e r s h o c k i n t e r v a l of 3 0 s. Rats o f the two C o n t r o l groups d i d not r e c e i v e such non-contingent footshock. Rats o f one Shock group (Shock-Met) and one C o n t r o l group (Control-Met) r e c e i v e d i n j e c t i o n s of 5.0 mg/kg metoclopramide p r i o r t o t e s t i n g , w h i l e the oth e r two groups (Shock-Sal and C o n t r o l -Sal) r e c e i v e d s a l i n e i n j e c t i o n s . Chapter IV 149 S t a t i s t i c a l A n a l y s i s : The data were analyzed u s i n g the ANOVA and Newman-Keul 1s post hoc t e s t , as d e s c r i b e d i n Experiment IV.1. R e s u l t s The number of avoidances are i l l u s t r a t e d i n the top panel o f F i g u r e 16. As can be seen i n t h i s f i g u r e , footshock d i s r u p t e d the performance of the r a t s t h a t had r e c e i v e d metoclopramide, but d i d not d i s r u p t the performance o f the r a t s t h a t had r e c e i v e d s a l i n e . T h i s i mpression i s confirmed by the ANOVA. There was a s i g n i f i c a n t e f f e c t o f Drug [F(l,28) = 14.24 p < .001], a s i g n i f i c a n t e f f e c t o f Shock treatment [F(l,28) = 6.33, p < .05], and a s i g n i f i c a n t Drug x Shock treatment i n t e r a c t i o n [F(l,28) = 14.24, p < .001]. Post hoc t e s t s i n d i c a t e d t h a t Group Shock-Met avoided l e s s o f t e n than any other group on the t e s t day. Examination of the l a t e n c y s c o r e s (bottom panel o f F i g u r e 16) r e v e a l e d a s i m i l a r p a t t e r n o f r e s u l t s . There was a s i g n i f i c a n t e f f e c t of Drug [F(l,28) = 8.15 p < .01], a s i g n i f i c a n t e f f e c t of Shock treatment [F( 1,2.8) = 4.37, p < .05], and a s i g n i f i c a n t Drug x Shock treatment i n t e r a c t i o n [ F ( l ,28) = 8.81, p < .01]. Post hoc t e s t s i n d i c a t e d t h a t the response l a t e n c i e s of Group Shock-Met were l o n g e r than those of any oth e r group on the t e s t day. D i s c u s s i o n In c o n j u n c t i o n w i t h Experiment IV.1, the pr e s e n t r e s u l t s i n d i c a t e unambiguously t h a t a d d i t i o n a l p r e s e n t a t i o n s o f shock d i s r u p t the avoidance responding behaviour o f Chapter IV 150 F i g u r e 16. Out of context p r e t r i a l shock Top panel i n d i c a t e s mean number of avoidances executed on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . A l l r a t s r e c e i v e d 10 tone-shock p a i r i n g s on Day 1 and 5 avoidance t r a i n i n g t r i a l s on Day 2. On the t e s t day the Shock Groups r e c e i v e d t h r e e 1.5 s footshocks i n a separate compartment p r i o r t o the f i r s t avoidance t r i a l . S a l Groups r e c e i v e d s a l i n e and Met Groups r e c e i v e d 5.0 mg/kg metoclopramide p r i o r t o t e s t i n g . Chapter IV 151 OUT-OF-CONTEXT PRETRIAL SHOCK 10 - i Control Shock Chapter IV 152 metoclopramide-treated r a t s . U n l i k e Experiment IV. 1, where shock p r e s e n t a t i o n s o c c u r r e d on each t r i a l and i n the same compartment i n which the r a t was about t o r e c e i v e an avoidance t r i a l , circumstances t h a t c o u l d have d i s r u p t e d avoidance responding by d i s t o r t i n g the r a t ' s r e p r e s e n t a t i o n s of the stimulus-environment-response c o n t i n g e n c i e s , the shocks i n the pr e s e n t experiment were a l l a d m i n i s t e r e d p r i o r t o the onset of the t r i a l and i n a separate compartment. In n e i t h e r the p r e v i o u s experiment nor t h i s was t h e r e any i n d i c a t i o n t h a t the a d d i t i o n a l shocks had a d i s r u p t i v e e f f e c t on the avoidance responding of undrugged r a t s . But i n each case shocks c l e a r l y d i s r u p t e d avoidance responding by r a t s t h a t had been a d m i n i s t e r e d 5.0 mg/kg metoclopramide. The observed d i s r u p t i o n of avoidance responding by shock treatment i n drugged r a t s i s c o n s i s t e n t w i t h the f i n d i n g of Experiment I I I . l t h a t metoclopramide-treated r a t s have an exaggerated f r e e z i n g response t o shock. I t i s a l s o c o n s i s t e n t with the p r o p o s a l o f Lenard and Beer (1975) t h a t dopamine d i s r u p t i o n causes i n a p p r o p r i a t e r e a c t i o n s t o shock t h a t l e a d t o impaired avoidance responding and w i t h Robinson's (1963) f i n d i n g t h a t t h e r e i s a s t r o n g c o r r e l a t i o n between avoidance d i s r u p t i o n and f r e e z i n g f o l l o w i n g a v o i d a n c e - d i s r u p t i n g b r a i n l e s i o n s . Together, these f i n d i n g s suggest t h a t a t l e a s t some p o r t i o n of the d i s r u p t i v e e f f e c t of n e u r o l e p t i c drugs on avoidance can be a t t r i b u t e d t o the enhancement of incompatible f r e e z i n g responses f o l l o w i n g shock. Chapter IV 153 As d e s c r i b e d i n the d i s c u s s i o n of Chapter I I I , p o s t -shock f r e e z i n g may b e s t be i n t e r p r e t e d as a c o n d i t i o n a l response t o environmental cues. In t h i s p e r s p e c t i v e the r e s u l t s of the p r e s e n t experiment may seem somewhat s u r p r i s i n g : T r a n s f e r r i n g the r a t s t o a new environment should have decreased the magnitude of such c o n d i t i o n e d f r e e z i n g . However, B o l l e s and C o l l i e r (1976) and Faneslow (1980) r e p o r t e d c o n s i d e r a b l e f r e e z i n g when r a t s were moved t o a n o v el compartment f o l l o w i n g shock, f r e e z i n g t h a t Faneslow (1980) a t t r i b u t e d to inter-compartment g e n e r a l i z a t i o n . That such g e n e r a l i z a t i o n was e v i d e n t i n the p r e s e n t experiment i s not s u r p r i s i n g , g i v e n t h a t the P l e x i g l a s box i n which the noncontingent shocks were ad m i n i s t e r e d had a g r i d f l o o r l i k e t h a t of the avoidance apparatus, the two boxes were i n the same room, and both had high, f l a t w a l l s . F u r t h e r , the r a t s had r e c e i v e d shock i n both the P l e x i g l a s compartment and i n the avoidance apparatus b e f o r e the t e s t day. Experiment IV.3 - E f f e c t of a c o n d i t i o n a l s t i m u l u s The p r e v i o u s experiments demonstrated t h a t shock can d i s r u p t the avoidance behaviour of n e u r o l e p t i c - t r e a t e d r a t s , a p p a r e n t l y by i n c r e a s i n g i n c o m p a t i b l e f r e e z i n g responses. Evidence d e s c r i b e d above i n d i c a t e s t h a t f r e e z i n g responses f o l l o w i n g non-contingent shock are c o n d i t i o n e d responses (Fanselow, 1980, 1986). Thus, i t appears t h a t c o n d i t i o n e d responses t o s h o c k - r e l a t e d s t i m u l i d i s r u p t avoidance Chapter IV 154 responding by metoclopramide-treated r a t s . The p r e s e n t experiment was designed t o e s t a b l i s h t h i s p o i n t u n e q u i v o c a l l y by demonstrating t h a t a s t i m u l u s p r e v i o u s l y p a i r e d w i t h shock c o u l d i n t e r f e r e w i t h avoidance responding. In o r d e r t h a t a tone c o u l d be used as the a d d i t i o n a l c o n d i t i o n a l s t i m u l u s , the u s u a l tone WS was r e p l a c e d by i l l u m i n a t i o n of a cue l i g h t f o r t h i s experiment. Method S u b j e c t s and apparatus: S u b j e c t s s i m i l a r t o those of the o t h e r experiments were used. The one-way avoidance apparatus was d e s c r i b e d i n Chapter I, and a d d i t i o n a l s t i m u l i were presented i n the P l e x i g l a s compartment d e s c r i b e d i n Experiment I I . 2 . Procedure; Rats were a s s i g n e d randomly t o one of f o u r groups. Two groups of r a t s (CS+ groups) r e c e i v e d 10 non-c o n t i n g e n t tone-shock p a i r i n g s i n the P l e x i g l a s compartment on each of the f i r s t two days of the experiment. Rats of the o t h e r groups ( C o n t r o l groups) were simply p l a c e d i n the P l e x i g l a s compartment and then removed, without having experienced any programmed events i n the box. On the f o l l o w i n g day r a t s of a l l groups r e c e i v e d an i n i t i a l avoidance t r a i n i n g s e s s i o n c o n s i s t i n g of f i v e avoidance t r i a l s . In t h i s t r a i n i n g . s e s s i o n the WS c o n s i s t e d of i l l u m i n a t i o n of the cue l i g h t mounted on the end w a l l of the shock s i d e of the box. The c e i l i n g l i g h t s i n the t e s t room were not i l l u m i n a t e d on t h i s day, the o n l y ambient l i g h t i n g Chapter IV 155 being p r o v i d e d by two dim red incandescent b u l b s . P r i o r t e s t i n g i n d i c a t e d t h a t t h i s amount of t r a i n i n g would p r o v i d e r a t s w i t h a moderate amount of p r o t e c t i o n from the e f f e c t s of metoclopramide, as i n Experiments IV.1 and IV.2. There were no d i f f e r e n c e s between groups on number of avoidances or response l a t e n c i e s on t h i s t r a i n i n g day (Fs < 1). On the f o l l o w i n g day r a t s of each group were t e s t e d on 10 avoidance t r i a l s . On the t e s t day the two C o n t r o l groups were t e s t e d u s i n g o n l y the cue l i g h t WS. However, f o r the two CS+ groups the tone was a c t i v a t e d a t the same time as the l i g h t WS. One CS+ group (CS+-Met, n = 9) and one C o n t r o l group ( C o n t r o l -Met, n = 9) r e c e i v e d 5.0 mg/kg metoclopramide p r i o r t o t e s t i n g , w h i l e Groups CS+-Sal (n = 10) and C o n t r o l - S a l (n = 10) r e c e i v e d s a l i n e i n j e c t i o n s . S t a t i s t i c a l A n a l y s i s : The data were analyzed u s i n g the ANOVA and Newman-Keul 1s post hoc t e s t , as d e s c r i b e d i n Experiment IV.1. R e s u l t s The number of avoidances are i l l u s t r a t e d i n the top panel o f F i g u r e 17. I t i s apparent t h a t the c o n d i t i o n a l s t i m u l u s d i s r u p t e d the performance o f the metoclopramide-t r e a t e d r a t s . T h i s impression i s confirmed by the ANOVA. There was a s i g n i f i c a n t e f f e c t of Drug [F(l,34) = 23.33 p < .001], and a s i g n i f i c a n t Drug x C o n d i t i o n i n g i n t e r a c t i o n [F(l,34) = 11.46, p < .005], but t h e r e was no s i g n i f i c a n t e f f e c t o f C o n d i t i o n i n g (F < 1). Post hoc t e s t s i n d i c a t e d Chapter IV 156 F i g u r e 17. E f f e c t o f a d d i t i o n a l shock CS+ Top panel i n d i c a t e s mean number of avoidances executed on the t e s t day. Bottom panel i n d i c a t e s mean response l a t e n c i e s . CS+ r a t s r e c e i v e d 10 tone-shock p a i r i n g s on Days 1 and 2. A l l r a t s r e c e i v e d 5 avoidance t r a i n i n g t r i a l s w i t h a l i g h t WS on Day 3. On the t e s t day the WS was a t o n e - l i g h t compound f o r the CS+ Groups and was a l i g h t f o r the C o n t r o l Groups. S a l Groups r e c e i v e d s a l i n e on the t e s t day, w h i l e Met Groups r e c e i v e d 5.0 mg/kg metoclopramide. Chapter IV . 157 Chapter IV 158 t h a t Group C o n t r o l - S a l d i d not d i f f e r from e i t h e r Group Control-Met or Group CS+-Met, but t h a t Group CS+-Met performed s i g n i f i c a n t l y worse than any o t h e r group. Thus, the presence of the a d d i t i o n a l tone CS+ d i d not have an adverse e f f e c t on the performance of the s a l i n e t r e a t e d r a t s ( i n f a c t Group CS+-Sal performed n o n - s i g n i f i c a n t l y b e t t e r than Group C o n t r o l - S a l ) , but the c o n d i t i o n a l s t i m u l u s had an adverse impact on the performance of metoclopramide-treated r a t s . Examination of the l a t e n c y s c o r e s (bottom panel of F i g u r e 17) suggests a s i m i l a r p a t t e r n of r e s u l t s . However, the s t a t i s t i c a l a n a l y s i s i n d i c a t e d a s l i g h t l y d i f f e r e n t p a t t e r n of e f f e c t s . There was a s i g n i f i c a n t e f f e c t of Drug [F(l,34) = 20.12 p_ < .001], and a s i g n i f i c a n t Drug x C o n d i t i o n i n g i n t e r a c t i o n [F(l,34) = 9.47, p_ < .005], but t h e r e was no s i g n i f i c a n t e f f e c t of C o n d i t i o n i n g (F < 1). The p o s t hoc t e s t s again i n d i c a t e d t h a t t h e r e was no d i f f e r e n c e between the performance of the s a l i n e - and metoclopramide-t r e a t e d r a t s t h a t were not exposed t o the tone. However, Group CS+-Met d i d not have s i g n i f i c a n t l y l o n g e r l a t e n c i e s than d i d Group Control-Met. Instead, i n t e r e s t i n g l y , Group CS+-Sal had s i g n i f i c a n t l y lower l a t e n c i e s than d i d Group C o n t r o l - S a l . Thus, the a d d i t i o n a l c o n d i t i o n a l s t i m u l u s p o t e n t i a t e d performance f o r undrugged r a t s , as indexed by the l a t e n c y s c o r e s , whereas f o r drugged r a t s t h e r e was a non-s i g n i f i c a n t d i s r u p t i o n of performance. Chapter IV 159 D i s c u s s i o n The presence of an a d d i t i o n a l tone c o n d i t i o n a l s t i m u l u s d i d not have an adverse e f f e c t on the performance of s a l i n e -t r e a t e d r a t s (compare Group CS+-Sal w i t h Group C o n t r o l - S a l ) . In f a c t , the response l a t e n c i e s of the r a t s t h a t were pr e s e n t e d w i t h the c o n d i t i o n a l s t i m u l u s were a c t u a l l y lower w i t h than those of c o n t r o l r a t s . T h i s f i n d i n g i s c o n s i s t e n t w i t h numerous r e p o r t s t h a t p r e s e n t a t i o n of a c l a s s i c a l l y c o n d i t i o n e d s t i m u l u s a s s o c i a t e d w i t h shock can l e a d t o enhanced avoidance responding (e.g., Jacobs & LoLordo, 1980; Overmier & Leaf, 1965; R e s c o r l a & LoLordo, 1965; Scobie, 1972; Solomon & Turner, 1962; Weisman & L i t n e r , 1969, 1972; Z i e l i n s k i & Cotton, 1982). Yet the c o n d i t i o n a l s t i m u l u s decreased, r a t h e r than i n c r e a s e d , the number of avoidances s u c c e s s f u l l y executed by the metoclopramide-treated r a t s . Metoclopramide by i t s e l f had o n l y a minor e f f e c t on the performance of c o n t r o l r a t s , but i n combination with the c o n d i t i o n a l s t i m u l u s i t produced a s u b s t a n t i a l d i s r u p t i o n i n performance. Thus, the d i s r u p t i v e e f f e c t s of shock and metoclopramide i n combination t h a t were observed i n Experiments IV.1 and IV.2 were a l s o observed u s i n g a c o n d i t i o n a l s t i m u l u s i n p l a c e o f footshock. These o b s e r v a t i o n s lend support t o the p r o p o s a l t h a t , f o r p r e s e n t purposes, f r e e z i n g responses f o l l o w i n g shock are c o n d i t i o n e d responses t o f e a r - e l i c i t i n g s t i m u l i . Chapter IV 160 D i s c u s s i o n of Chapter IV Together, the experiments of t h i s c h apter c l e a r l y i n d i c a t e t h a t the avoidance performance of metoclopramide-t r e a t e d r a t s i s a d v e r s e l y i n f l u e n c e d by the non-contingent p r e s e n t a t i o n of a v e r s i v e footshock or c o n d i t i o n e d s t i m u l i a s s o c i a t e d w i t h footshock. In combination w i t h the f i n d i n g s of Chapter I I I , and the o b s e r v a t i o n s of Weiss e t a l . (1968) and Blanchard & Blanchard (1969b) t h a t f r e e z i n g e l i c i t e d by f e a r can d i s r u p t avoidance responding, i t appears t h a t i n c r e a s e d f r e e z i n g by metoclopramide-treated r a t s can account f o r t h i s d e f i c i t . These f i n d i n g s are extremely important f o r the e v a l u a t i o n of d e f i c i t s i n avoidance a c q u i s i t i o n observed f o l l o w i n g n e u r o l e p t i c treatment. During a c q u i s i t i o n a l l r a t s w i l l n o rmally experience s e v e r a l shocks b e f o r e becoming p r o f i c i e n t one-way a v o i d e r s . However, whereas these shocks w i l l p o t e n t i a t e the subsequent avoidance responding of undrugged r a t s , they w i l l d i s r u p t the responding of metoclopramide t r e a t e d r a t s . In subsequent s e s s i o n s , back i n the s h o c k - r e l a t e d environment, the n e u r o l e p t i c - t r e a t e d r a t s w i l l f r e e z e more and a v o i d l e s s than c o n t r o l s . T h i s l i n e of r e a s o n i n g may a l s o account i n p a r t f o r the gr a d u a l onset of d i s r u p t i o n of avoidance responding seen a f t e r n e u r o l e p t i c treatment i n r a t s who have p r e v i o u s l y a c q u i r e d the response. Although a drugged r a t may respond w e l l a t f i r s t , - environmental cues may e v e n t u a l l y l e a d t o an i n c r e a s e i n f r e e z i n g and consequent response i n h i b i t i o n , or Chapter IV 161 e l s e the r a t may e v e n t u a l l y get a shock, and i s more l i k e l y t o f r e e z e i n response t o t h a t shock than a non-drugged r a t . Thus, i t i s not s u r p r i s i n g t h a t doses o f n e u r o l e p t i c drugs r e q u i r e d t o impair performance on bar p r e s s or s h u t t l e avoidance are lower than those r e q u i r e d t o d i s r u p t performance of a s i m p l e r response (Latz e t a l . , 1969). Although these c o n s i d e r a t i o n s support the s u g g e s t i o n t h a t metoclopramide enhances f r e e z i n g i n the avoidance s i t u a t i o n , thereby d i s r u p t i n g avoidance responding, c o n f i d e n c e i n t h i s c o n c l u s i o n must be tempered by two f a c t o r s . F i r s t , t h e r e i s no independent evidence t h a t n e u r o l e p t i c - t r e a t e d r a t s a c t u a l l y f r e e z e i n the avoidance s i t u a t i o n . However Posluns (1962), examining the e f f e c t s of chlorpromazine on one-way avoidance, made j u s t such an o b s e r v a t i o n . He found t h a t under chlorpromazine t h e r e was a h i g h l y s i g n i f i c a n t c o r r e l a t i o n between the time i t took a drugged r a t t o i n i t i a t e locomotion and the number of shocks i t r e c e i v e d i n the s e s s i o n (r = .94). From P o s l u n s 1 s y s t e m a t i c o b s e r v a t i o n and d e s c r i p t i o n of the response p a t t e r n of h i s r a t s , i t i s apparent t h a t the r a t s ' f a i l u r e t o i n i t i a t e locomotion was e q u i v a l e n t t o f r e e z i n g . Thus, f r e e z i n g was a s s o c i a t e d w i t h f a i l u r e t o a v o i d on the p a r t of the n e u r o l e p t i c - t r e a t e d r a t s . I t should be noted, however, t h a t not a l l avoidance response f a i l u r e s can be a t t r i b u t e d t o f r e e z i n g a t the commencement of the t r i a l . Posluns observed t h a t r a t s f r e q u e n t l y paused j u s t b e f o r e e n t e r i n g the s a f e compartment. In the p r e s e n t s e r i e s of experiments Chapter IV 162 metoclopramide-treated r a t s were f r e q u e n t l y observed running t o the d i v i d e r s e p a r a t i n g the two p o r t i o n s of the avoidance apparatus, o f t e n f r e e z i n g i n f r o n t of the d i v i d e r or r e a r i n g and f r e e z i n g w h i l e l e a n i n g a g a i n s t i t , but f a i l i n g t o pass though the open g u i l l o t i n e door. A second, more s u b t l e c o n s i d e r a t i o n i s the problem of i n f e r r i n g a c a u s a l r e l a t i o n s h i p i n the c o r r e l a t i o n between f r e e z i n g and impairment i n avoidance responding. Such a c o r r e l a t i o n has been noted i n the case of r a t s ' f a i l u r e t o a c q u i r e a bar p r e s s avoidance. But, as B o l l e s (1975) has p o i n t e d out, r a t h e r than f a i l i n g t o a v o i d because i t i s f r e e z i n g , a r a t may f r e e z e because i t i s unable t o a v o i d . C e r t a i n l y , the r a t s of Experiment I I I . l were unable t o a v o i d , so f r e e z i n g was an a p p r o p r i a t e response. How can we be c e r t a i n t h a t the metoclopramide-treated r a t s of the experiments presented i n t h i s chapter were not r e a c t i n g s i m i l a r l y ? I f t h i s i s the case we must ask y e t a g a i n why n e u r o l e p t i c - t r e a t e d r a t s are unable t o a v o i d . T h i s q u e s t i o n w i l l be addressed, y e t again, i n the g e n e r a l d i s c u s s i o n . D i s c u s s i o n 163 GENERAL DISCUSSION The p r e c e d i n g s e c t i o n s have presented a v a r i e t y of data t h a t r e p l i c a t e and extend e a r l i e r f i n d i n g s c o n c e r n i n g the e f f e c t s of n e u r o l e p t i c drugs on the d e f e n s i v e behaviours of r a t s . T h i s f i n a l s e c t i o n begins by summarizing the major f i n d i n g s of the r e s e a r c h and the c o n c l u s i o n s t h a t may be drawn from them. The numbers i n parentheses r e f e r t o s p e c i f i c experiments. F i r s t , the a c q u i s i t i o n of one-way avoidance behaviour by n a i v e r a t s i s a b o l i s h e d by a d m i n i s t r a t i o n of a moderate dose o f h a l o p e r i d o l (1.1). T h i s e f f e c t of h a l o p e r i d o l i s a l s o observed w i t h metoclopramide (1.4, I I . 1 ) . Second, h a l o p e r i d o l does not i n i t i a l l y have a s t r o n g e f f e c t on the performance of a p r e v i o u s l y a c q u i r e d response, but the e f f e c t i n c r e a s e s over repeated drug t e s t s (1.1). T h i s i s a l s o observed f o l l o w i n g metoclopramide a d m i n i s t r a t i o n (1.4, I I . 1 ) . T h i r d , complete and s e l e c t i v e d i s r u p t i o n of avoidance a c q u i s i t i o n was not observed w i t h t h i o r i d a z i n e (I.2a, I.2b) or c l o z a p i n e (1.3). T h i o r i d a z i n e and c l o z a p i n e are a t y p i c a l n e u r o l e p t i c s , potent a n t i p s y c h o t i c agents i n f r e q u e n t l y a s s o c i a t e d w i t h e x t r a p y r a m i d a l s i d e e f f e c t s (EPSEs), whereas metoclopramide i s not w e l l e s t a b l i s h e d as an a n t i p s y c h o t i c agent, but i t i s s t r o n g l y a s s o c i a t e d w i t h EPSEs. A c c o r d i n g l y , these f i n d i n g s suggest t h a t d i s r u p t i o n of avoidance a c q u i s i t i o n i s more c l o s e l y r e l a t e d t o the EPSE-i n d u c i n g p r o p e r t i e s of n e u r o l e p t i c s than t o t h e i r D i s c u s s i o n 164 a n t i p s y c h o t i c e f f e c t s . T h i s i n t u r n suggests t h a t d i s r u p t i o n of avoidance a c q u i s i t i o n may not be an a p p r o p r i a t e model f o r d e t e c t i n g drugs t h a t w i l l a l l e v i a t e psychoses. Because EPSEs are a s s o c i a t e d with n i g r o s t r i a t a l dopamine d y s f u n c t i o n , and i n l i g h t of the evidence reviewed on pp. 64, these p h a r m a c o l o g i c a l s t u d i e s are c o n s i s t e n t w i t h the s u g g e s t i o n t h a t avoidance a c q u i s i t i o n i s p r i m a r i l y dependent on n i g r o s t r i a t a l dopamine a c t i v i t y . Fourth, i n order t o be p r o t e c t e d from the e f f e c t of metoclopramide treatment, the one-way avoidance response need onl y have been performed a few times ( I I . 1 , I I . 2 ) . In f a c t , the r a t need never have a c t u a l l y avoided the shock: Escape t r a i n i n g was as e f f e c t i v e as avoidance t r a i n i n g ( I I . 5 ) . T h i s i s c o n s i s t e n t with the n o t i o n t h a t the development of r e s i s t a n c e t o n e u r o l e p t i c e f f e c t s i s more a matter of " p r o b l e m - s o l v i n g " than a case of " h a b i t - f o r m a t i o n " . F i f t h , exposing r a t s t o p r i o r p a i r i n g s of the tone WS and footshock f a c i l i t a t e d the development of r e s i s t a n c e t o metoclopramide e f f e c t s (II.2) but was not s u f f i c i e n t f o r t h i s purpose ( I I . 5 ) . S i x t h , g i v i n g r a t s p r i o r " s a f e t y " c o n d i t i o n i n g w h i l e they were undrugged d i d not a t t e n u a t e metoclopramide 1s e f f e c t s on avoidance a c q u i s i t i o n ( I I . 3 , I I . 4 ) . T h i s argues a g a i n s t the p o s s i b i l i t y t h a t n e u r o l e p t i c drugs s p e c i f i c a l l y d i s r u p t l e a r n i n g about the i n c e n t i v e v a l u e of s a f e t y s i g n a l s . Seventh, a s t r i c t performance d e f i c i t i n t e r p r e t a t i o n i s r u l e d out by the f i n d i n g t h a t i f metoclopramide was D i s c u s s i o n 165 a d m i n i s t e r e d d u r i n g escape t r a i n i n g the p r o p h y l a c t i c e f f e c t o f such t r a i n i n g was e l i m i n a t e d , even though both drugged and undrugged r a t s escaped the shocks ( I I . 5 , I I . 6 , I I . 7 ) . E i g h t h , metoclopramide enhanced f r e e z i n g responses f o l l o w i n g shock a d m i n i s t r a t i o n ( I I I . l ) . Even though no c o n c l u s i v e evidence of enhanced f r e e z i n g t o a tone c o n d i t i o n a l s t i m u l u s was found ( I I I . 2 ) , p r e v i o u s s t u d i e s i n d i c a t e t h a t f r e e z i n g observed f o l l o w i n g shock a d m i n i s t r a t i o n i s a c o n d i t i o n e d response t o the presence of s h o c k - r e l a t e d environmenatl s t i m u l i (Fanselow, 1980, 1986). F i n a l l y , shock (IV.1, IV.2) and cues f o r shock (IV.3) d i s r u p t e d the avoidance responding of metoclopramide-treated r a t s , whereas the performance of s a l i n e - t r e a t e d r a t s was not d i s r u p t e d (IV.1, IV.2). In f a c t , performance of c o n t r o l r a t s was a c t u a l l y enhanced by p r e s e n t a t i o n of a s h o c k - r e l a t e d c o n d i t i o n a l s t i m u l u s (IV.3). These f i n d i n g s , p l u s the many p r e v i o u s l y r e p o r t e d phenomena concerning dopamine systems and avoidance behaviour, must be addressed by any t h e o r e t i c a l account of the e f f e c t s of n e u r o l e p t i c drugs and of the r o l e of dopamine i n behaviour. T h e o r e t i c a l i n t e r p r e t a t i o n of dopamine involvement i n avoidance behaviour In the 35 years s i n c e C o u r v o i s i e r e t a l . (1953) found t h a t a n e u r o l e p t i c drug (chlorpromazine) would a t t e n u a t e avoidance responding, v a r i o u s t h e o r e t i c a l i n t e r p r e t a t i o n s of D i s c u s s i o n 166 the e f f e c t have been put forward. At the same time, s e v e r a l hypotheses of dopamine f u n c t i o n have a r i s e n from a n a l y s i s of dopaminergic involvement i n a p p e t i t i v e behaviour. The f o l l o w i n g s e c t i o n s w i l l examine the c a p a c i t y of these v a r i o u s hypotheses t o account f o r the data a t hand. N e u r o l e p t i c drugs as major t r a n q u i l i z e r s One e a r l y h y p o t h e s i s developed t o account f o r n e u r o l e p t i c e f f e c t s on avoidance behaviour suggested t h a t they a c t e d by d e c r e a s i n g f e a r or a n x i e t y (Ader & C l i n k , 1957; M i l l e r , Murphy, & Mirsky, 1957). T h i s h y p o t h e s i s ran i n t o t r o u b l e when i t was shown t h a t n e u r o l e p t i c - t r e a t e d r a t s c o u l d a c q u i r e a c o n d i t i o n e d emotional response (Hunt, 1956; see a l s o Beninger e t a l . , 1980b), and even more s e r i o u s l y , t h a t n e u r o l e p t i c - t r e a t e d r a t s which had f a i l e d t o a c q u i r e an avoidance response w h i l e drugged nonetheless showed c o n s i d e r a b l e savings when l a t e r t e s t e d i n an undrugged s t a t e (Posluns, 1962; see a l s o Beninger e t a l . , 1980b; Davidson & Weidley, 1976; F i b i g e r e t a l . , 1975). The a b i l i t y of r a t s t o a c q u i r e , or manifest, o t h e r s h o c k - r e l a t e d l e a r n i n g w h i l e drugged a l s o c h a l l e n g e d t h i s n o t i o n (Beninger e t a l . , 1980c; C o r r a d i n i e t a l . , 1984). In the p r e s e n t experiments, the i n c r e a s e d amount of f r e e z i n g observed i n metoclopramide-t r e a t e d r a t s p r o v i d e s f u r t h e r evidence a g a i n s t the p o s s i b i l i t y t h a t f e a r i s decreased by n e u r o l e p t i c s . Motor impairment or response b i a s I t has o f t e n been suggested t h a t n e u r o l e p t i c e f f e c t s on behaviour p r i m a r i l y r e f l e c t a motor d e f i c i t . In the case of D i s c u s s i o n 167 the avoidance d e f i c i t t h i s c o u l d be i n t e r p r e t e d as an i n a b i l i t y t o execute an a c t i v e avoidance response. T h i s p o s s i b i l i t y i s excluded by the h i g h l e v e l of performance seen i n p r e v i o u s l y t r a i n e d r a t s on t h e i r i n i t i a l treatment w i t h n e u r o l e p t i c s . An a l t e r n a t i v e h y p o t h e s i s c o u l d be t h a t n e u r o l e p t i c s p r e d i s p o s e r a t s t o f r e e z e , r a t h e r than t o perform a c t i v e responses. Such an a n a l y s i s would l e a d t o the p r e d i c t i o n t h a t i m m o b i l i t y as an avoidance response would be enhanced u n i v e r s a l l y by n e u r o l e p t i c s . T h i s i s not the case. In f a c t , s e v e r a l s t u d i e s have r e p o r t e d n e u r o l e p t i c - t r e a t e d r a t s d i s p l a y e d reduced response l a t e n c i e s i n p a s s i v e avoidance s i t u a t i o n s , w hile others have r e p o r t e d no changes (see Bammer, 1982, f o r r e v i e w ) . These c o n f l i c t i n g r e s u l t s are d i f f i c u l t t o i n t e r p r e t , g i v e n g r e a t d i v e r g e n c e s i n t e s t procedure and drug a d m i n i s t r a t i o n between the t e s t s . Step through p a s s i v e avoidance was d i s r u p t e d by chlorpromazine (Iwahara, Iwaski, & Hasegawa, 1968; Johnson, 1970), and by v e r y low doses of h a l o p e r i d o l (Kovacs & De Weid, 1978). No e f f e c t s were seen u s i n g doses of h a l o p e r i d o l or pimozide t h a t t y p i c a l l y d i s r u p t a c t i v e avoidance (Bammer, 1982). The r e s u l t s of the p a s s i v e avoidance study of Iwahara e t a l . (1968) are i n t e r e s t i n g i n t h a t examination of t h e i r data i n d i c a t e s t h a t c h l o r p r o m a z i n e - t r e a t e d r a t s spent a m a j o r i t y of the t e s t time i n the to-be-avoided s m a l l compartment, where shocks had been administered, r a t h e r than i n an a d j a c e n t l a r g e compartment. I t i s c o n c e i v a b l e t h a t the r a t s were indeed f r e e z i n g , but i n t h e i r f r i g h t f i r s t r an i n t o the D i s c u s s i o n 168 s m a l l e r compartment, which might have served as an u n c o n d i t i o n a l s a f e t y s i g n a l . Whatever the reason f o r the s h o r t e r l a t e n c i e s sometimes r e p o r t e d i n p a s s i v e avoidance, the c r i t i c a l p o i n t i s t h a t n e u r o l e p t i c - t r e a t e d r a t s do not simply become immobile, c a t a l e p t i c , or slower t o i n i t i a t e movements as a r e s u l t of drug treatment. T h e r e f o r e the i n c r e a s e d f r e e z i n g observed f o l l o w i n g metoclopramide treatment i n Experiment I I I . l must be dependent upon environmental s t i m u l i . Anhedonia One i n f l u e n t i a l account of n e u r o l e p t i c e f f e c t s , developed i n the context of a p p e t i t i v e behaviour, i s the "anhedonia" h y p o t h e s i s of Wise (1982, 1985). I t o r i g i n a t e d from the o b s e r v a t i o n t h a t the operant responding of n e u r o l e p t i c - t r e a t e d animals d e c l i n e s over the course of a t e s t s e s s i o n when any of a v a r i e t y of r e i n f o r c e r s are used (e.g., E t t e n b e r g & C a r l i s l e , 1985; F o u r i e z o s & Wise, 1976; Wise e t a l . , 1978). In i t s o r i g i n a l form the anhedonia h y p o t h e s i s a t t r i b u t e d these d e f i c i t s t o an a b i l i t y o f n e u r o l e p t i c s t o b l u n t the hedonic impact of p o s i t i v e r e i n f o r c e r s , thereby l e a d i n g t o e x t i n c t i o n of the response. L a t e r the h y p o t h e s i s was extended t o r e c o g n i z e the a b i l i t y of n e u r o l e p t i c s t o b l u n t the m o t i v a t i o n a l impact of i n c e n t i v e s t i m u l i (Gray & Wise, 1980; Wise, 1985). I f the anhedonia h y p o t h e s i s were t o be extended t o the case of avoidance behaviour, i t might contend t h a t the reward v a l u e of s a f e t y s t i m u l i are b l u n t e d by n e u r o l e p t i c treatment. D i s c u s s i o n 169 Although such an approach c o u l d account f o r the g r a d u a l d e t e r i o r a t i o n i n performance seen w i t h s u c c e s s i v e metoclopramide treatments, i t does not account f o r the a b i l i t y o f drugged r a t s t o l e a r n an escape response, nor the i n e f f e c t i v e n e s s of e x p l i c i t s a f e t y c o n d i t i o n i n g t o overcome n e u r o l e p t i c - i n d u c e d d e f i c i t s . Nor, more c r i t i c a l l y , can any apparent v a r i a t i o n on the h y p o t h e s i s account f o r i n c r e a s e d f r e e z i n g responses or the n e g a t i v e impact of shock and shock cues on avoidance performance observed f o l l o w i n g metoclopramide treatment. The anhedonia h y p o t h e s i s i s s i l e n t w i t h r e s p e c t t o performance, t h e r e f o r e i t cannot account f o r these a l t e r a t i o n s i n performance. I n c e n t i v e m o t i v a t i o n a l learning; Beninger (1988, 1989) has r e c e n t l y developed a p r o p o s a l t h a t i n c o r p o r a t e s elements of the anhedonia h y p o t h e s i s but which focuses on the involvement of dopamine systems i n l e a r n i n g . He proposes t h a t d i s r u p t i o n of dopaminergic f u n c t i o n does not i n t e r f e r e w i t h l e a r n i n g a s s o c i a t i o n s between shock o f f s e t and s a f e t y - r e l a t e d s t i m u l i . However, he suggests t h a t f o l l o w i n g n e u r o l e p t i c treatment the i n c e n t i v e m o t i v a t i o n a l p r o p e r t i e s of the reward (shock o f f s e t ) may not be t r a n s f e r r e d t o the s a f e t y - r e l a t e d s t i m u l i , and hence the animals can l e a r n where s a f e t y i s but cannot l e a r n t o go t h e r e . T h i s f o r m u l a t i o n can account f o r the f i n d i n g s of Experiments II.3 and I I . 4 : Even though the r a t s l e a r n the s i g n i f i c a n c e of the s a f e t y cues on the c o n d i t i o n i n g day they are unable, when drugged, t o l e a r n t o d i r e c t t h e i r responses D i s c u s s i o n 170 towards them. T h i s a n a l y s i s i s c o n s i s t e n t w i t h o t h e r r e p o r t s t h a t dopamine a c t i v i t y , i f not necessary f o r l e a r n i n g , can p l a y a f a c i l i t a t o r y r o l e i n the a c q u i s i t i o n of s t i m u l u s -s t i m u l u s l e a r n i n g (Carr & White, 1984; White & Major, 1978). However, Beninger's h y p o t h e s i s runs i n t o s e r i o u s t r o u b l e i n a c c o u n t i n g f o r the data of Chapters I I I and IV. In the case of Experiment I I I . l , t h e r e are no i n c e n t i v e s t i m u l i p r e s e n t towards which drugged or undrugged r a t s can d i r e c t t h e i r responses. Why should the metoclopramide-treated r a t s f r e e z e more i n response t o the shock? Nor can the h y p o t h e s i s account f o r the outcome of Experiment IV.2. Why should the r a t s 1 avoidance responses be a l t e r e d by the p r e s e n t a t i o n of shock b e f o r e the s e s s i o n ? A l e a r n i n g - b a s e d h y p o t h e s i s cannot account f o r a l t e r a t i o n s i n responding t h a t occur o u t s i d e of the c o n t e x t of the avoidance c o n t i n g e n c i e s . Drugged and undrugged, shocked and unshocked, the r a t s of a l l groups i n Experiment IV.2 had i d e n t i c a l t r a i n i n g i n the avoidance apparatus p r i o r t o the t e s t . Nor i s any a n a l y s i s based e n t i r e l y on l e a r n i n g a b l e t o account f o r the a b i l i t y of n e u r o l e p t i c s t o suppress a p r e v i o u s l y c o n d i t i o n e d a p p e t i t i v e response (Blackburn e t a l . , 1987; 1989b). Response i n i t i a t i o n d e f i c i t Posluns (1962) and F i b i g e r e t a l . (1975) have proposed t h a t n e u r o l e p t i c s impair avoidance responding by s e l e c t i v e l y b l o c k i n g the i n i t i a t i o n of v o l u n t a r y or operant motor responses. Posluns (1962) observed t h a t d u r i n g i n i t i a l t r a i n i n g the avoidance responses of n a i v e r a t s c o n s i s t e d of a D i s c u s s i o n 171 number of d i s c r e t e component a c t s and h y p o t h e s i z e d t h a t each component was under v o l u n t a r y c o n t r o l . With a d d i t i o n a l t r a i n i n g the i n i t i a t i o n l a t e n c i e s of the components were hy p o t h e s i z e d t o decrease u n t i l avoidance became a smooth i n t e g r a t e d response. N e u r o l e p t i c s were h e l d t o d i s r u p t the dopamine-mediated process by which the WS t r i g g e r e d the i n i t i a l components of the avoidance response. F i b i g e r e t a l . (1975) proposed t h a t the i n e f f e c t i v e n e s s of n e u r o l e p t i c s a t d i s r u p t i n g the behaviour of " w e l l - t r a i n e d animals c o u l d r e f l e c t a p r o g r e s s i o n of the [avoidance] response from a s e r i e s of v o l u n t a r i l y i n i t i a t e d component b e h a v i o r s i n n a i v e r a t s t o a more r e f l e x i v e , automatic, s y n t h e s i z e d type of b e h a v i o r i n t r a i n e d animals" (p. 313). By a s c r i b i n g the a t t e n u a t e d impact of the drugs on p r e v i o u s l y a c q u i r e d responses t o the p r o g r e s s i v e a u t o m a t i z a t i o n of avoidance responding, the response i n i t i a t i o n d e f i c i t h y p o t h e s i s i s now c h a l l e n g e d by the f i n d i n g t h a t a r a t may be p r o t e c t e d from n e u r o l e p t i c e f f e c t s a f t e r having s u c c e s s f u l l y executed o n l y a s i n g l e avoidance response (Experiment I I . 2 ) , or having been t r a i n e d o n l y with escape c o n t i n g e n c i e s .(Experiments I I . 5 , I I . 6 , I I . 7 ) . F u r t h e r , although t h i s f o r m u l a t i o n , l i k e t h a t of Beninger (1989), can account f o r some of the phenomena c o n c e r n i n g n e u r o l e p t i c e f f e c t s on avoidance behaviour, i t i s unable to account f o r the e f f e c t s of n e u r o l e p t i c drugs t h a t are observed f o l l o w i n g the p r e s e n t a t i o n of shock (Experiment I I I . l ) , or the i n t e r a c t i o n of shock and n e u r o l e p t i c D i s c u s s i o n 172 treatments i n the d i s r u p t i o n of an a c q u i r e d avoidance response (Chapter I V ) . Sensorimotor d e f i c i t Ungerstedt (1971), i n the paper f i r s t d e s c r i b i n g the b e h a v i o u r a l e f f e c t s of 6-OHDA l e s i o n s of the n i g r o s t r i a t a l bundle, r e p o r t e d t h a t r a t s w i t h u n i l a t e r a l l e s i o n s show a c h r o n i c tendency t o t u r n i n the d i r e c t i o n of the l e s i o n e d s i d e of the b r a i n . M a r s h a l l , Richardson, and Teitelbaum (1974) observed t h a t such r a t s d i s p l a y d i f f i c u l t y u s i n g the limbs c o n t r a l a t e r a l t o the l e s i o n f o r r i g h t i n g , c l i m b i n g and r e s i s t i n g g r a v i t a t i o n a l p u l l . E x t r a p o l a t i n g from e a r l i e r work they had conducted on r a t s w i t h u n i l a t e r a l l e s i o n s of the l a t e r a l hypothalamus ( M a r s h a l l , Turner, & Teitelbaum, 1971) they proposed t h a t t h i s p o s t u r a l asymmetry r e f l e c t s a s t a t e of "sensory n e g l e c t " . That such l e s i o n s do not r e f l e c t a motor d e f i c i t was shown by the f i n d i n g t h a t l e s i o n e d r a t s have i n c r e a s e d l a t e n c i e s t o remove s m a l l p i e c e s o f adhesive paper t h a t are a p p l i e d t o v a r i o u s p a r t s o f the limbs or the snout, i f those o b j e c t s are a p p l i e d c o n t r a l a t e r a l l y t o the l e s i o n . T h i s d e f i c i t was observed even though removal of the adhesive paper d i d not r e q u i r e body movements or p o s t u r a l adjustments ( S c h a l l e r t , Upchurch, Lobaugh, F a r r a r , Spirduso, G i l l i a m , Vaughn, & Wilcox, 1982). That t h i s a f f l i c t i o n does not r e f l e c t a primary sensory d e f i c i t was shown by the c a p a c i t y of s t i m u l i t o evoke r e l a t i v e l y normal responses on f i r s t p r e s e n t a t i o n . For example, i f the whiskers of a l e s i o n e d r a t are touched i t may t u r n toward the s t i m u l u s , but D i s c u s s i o n 173 i f they are brushed again soon a f t e r w a r d the r a t w i l l not o r i e n t ( M a r s h a l l e t a l . , 1974). Thus, i t appears t h a t d e f i c i t s observed f o l l o w i n g n i g r o s t r i a t a l bundle damage are n e i t h e r w holly m o t o r i c nor wholly sensory, but r a t h e r appear t o r e f l e c t d i s r u p t i o n of a h i g h e r l e v e l of sensorimotor i n t e g r a t i o n . White (1986) has developed the sensorimotor h y p o t h e s i s f u r t h e r t o account f o r the aphagia observed a f t e r damage t o the n i g r o s t r i a t a l bundle. White (1986) proposed t h a t i n t e n s e environmental s t i m u l i can e l i c i t responses d e s p i t e s e v e r e l y reduced l e v e l s o f dopamine a c t i v i t y , but t h a t h i g h l e v e l s of neuronal a c t i v i t y are r e q u i r e d f o r responses t o weak s t i m u l i . Thus, he proposed t h a t the aphagia of l e s i o n e d animals r e s u l t s l a r g e l y from an i n a b i l i t y of f o o d - r e l a t e d cues t o e l i c i t approach responses t h a t would b r i n g them i n t o c o n t a c t w i t h the food. In a s i m i l a r v e i n Dews and Morse (1961) and Clody and C a r l t o n (1980) have suggested t h a t n e u r o l e p t i c s p r e f e r e n t i a l l y d i s r u p t responses e l i c i t e d by l e s s e f f i c a c i o u s s t i m u l i , but s t i l l permit responses immediately r e l a t e d t o primary reinforcement. Although many data are compatible w i t h t h i s i n t e r p r e t a t i o n of dopamine f u n c t i o n i n i n g e s t i v e behaviour, Blackburn e t a l . (1989a) have p o i n t e d out t h a t i t i s incomplete i n t h a t i t f a i l s t o acknowledge the a b i l i t y of f o o d - r e l a t e d s t i m u l i t o i n f l u e n c e the a c t i v i t y of dopaminergic neurons, which i n t u r n c o u l d i n f l u e n c e the i n i t i a t i o n and v i g o u r o f approach behaviours. D i s c u s s i o n 174 No attempt has been made t o account f o r avoidance d e f i c i t s i n terms of the sensorimotor h y p o t h e s i s . However, the o u t l i n e o f such an approach can r e a d i l y be sketched. When a n a i v e r a t i s t r e a t e d w i t h a n e u r o l e p t i c drug, shock i s capable o f e l i c i t i n g responses from i t , but the weaker, l e s s e f f i c a c i o u s WS i s not. Thus, the r a t i s unable t o a c q u i r e the avoidance response. A p r e v i o u s l y t r a i n e d r a t may experie n c e a c o n d i t i o n e d r e l e a s e of dopamine f o l l o w i n g p r e s e n t a t i o n of shock or s h o c k - r e l a t e d s t i m u l i (Herman e t a l . , 1982) which i s a b l e , i n p a r t , t o compensate f o r p o s t -s y n a p t i c r e c e p t o r b l o c k a d e 1 . Nonetheless, t h i s i n t e r p r e t a t i o n i s unable t o account f o r enhanced f r e e z i n g observed f o l l o w i n g metoclopramide treatment, and f o r the adverse e f f e c t s of shock on the avoidance performance o f metoclopramide-treated r a t s . As p o i n t e d out by C a r l i e t a l . , (1985) the n o t i o n of a sensorimotor d e f i c i t can be i n t e r p r e t e d i n terms of e i t h e r an a t t e n t i o n a l f a i l u r e , where the a p p r o p r i a t e s t i m u l i are not a v a i l a b l e c e n t r a l l y f o r t r i g g e r i n g responses, o r an a c t i v a t i o n a l f a i l u r e , i n which a c t i o n s may be s e l e c t e d but cannot be i n i t i a t e d . The experiments of C a r l i e t a l . (1985) p r o v i d e d evidence f a v o u r i n g an a c t i v a t i o n a l d e f i c i t : Animals were capable of responding t o a s t i m u l u s p r e s e n t e d c o n t r a l a t e r a l t o t h e i r l e s i o n e d s i d e so long as the response 1. In a s i m i l a r v e i n Fowler (1989; S k j o l d a g e r & Fowler, 1988) has suggested t h a t the r e l a t i v e l y m i l d impact of n e u r o l e p t i c s a t the be g i n n i n g o f a t e s t s e s s i o n may be due t o e l e v a t e d dopamine r e l e a s e as a r e s u l t of n e u r o l e p t i c a c t i o n s a t p r e s y n a p t i c a u t o r e c e p t o r s . D i s c u s s i o n 175 was t o be d i r e c t e d i p s i l a t e r a l l y , but were d e f i c i e n t i n responding c o n t r a l a t e r a l l y r e g a r d l e s s o f the p o s i t i o n of the cue. The data of C a r l i e t a l . l e d them t o support a v e r s i o n of the sensorimotor d e f i c i t h y p o t h e s i s t h a t was s i m i l a r t o the response i n i t i a t i o n d e f i c i t h y p o t h e s i s d e s c r i b e d above, namely t h a t dopamine-depleted r a t s have no d e f i c i t i n knowing which'environmental s t i m u l i t o respond t o , but cannot respond t o them (see Salmone, 1988, f o r a s i m i l a r a c t i v a t i o n a l h y p o t h e s i s of dopamine f u n c t i o n ) . A t t e n t i o n a l d e f i c i t I t may be unwise t o d i s m i s s out of hand the p o s s i b i l i t y t h a t dopaminergic d i s r u p t i o n i n t e r f e r e s w i t h a t t e n t i o n a l mechanisms. The term " a t t e n t i o n " i s used by d i f f e r e n t r e s e a r c h e r s t o denote d i f f e r e n t concepts, and i t i s u n l i k e l y t hese w i l l ever be reduced t o a s i n g l e c o n s t r u c t . Thus, the r e l a t i o n s h i p of a t t e n t i o n t o dopamine f u n c t i o n cannot be determined w i t h a s i n g l e experiment. The d e f i n i t i o n of a t t e n t i o n used i n the experiment of C a r l i e t a l . (1985) i s e q u i v a l e n t t o enhancement of s i g n a l d e t e c t i o n . T h e i r evidence i n d i c a t e s t h a t t h i s i s not a f u n c t i o n mediated by dopamine. However, other s t u d i e s i n d i c a t e t h a t dopamine may p l a y a r o l e i n d i s t i n c t a t t e n t i o n a l phenomena. One l i n e of evidence i m p l i c a t i n g dopamine i n a t t e n t i o n comes from a r e c e n t study by Brown (1988). Rats were p l a c e d i n a r e s t r a i n i n g harness and t h e i r f o r e l i m b s were s t i m u l a t e d w i t h a n ylon b r i s t l e . M o n i t o r i n g of m e t a b o l i c a c t i v i t y , indexed by 1 4 C - d e o x y g l u c o s e a n a l y s i s , i n d i c a t e d t h a t such D i s c u s s i o n 176 s t i m u l a t i o n produced a minor focus of a c t i v a t i o n i n the p o r t i o n of the s t r i a t u m t o p o g r a p h i c a l l y r e l a t e d t o the f o r e l i m b , and t h a t t h i s focus was r i n g e d by an i n h i b i t o r y surround. 6-OHDA treatment, d e p l e t i n g the dopamine i n p u t t o the s t r i a t u m , removed the i n h i b i t o r y surround. These data were i n t e r p r e t e d as i n d i c a t i n g t h a t dopamine se r v e s t o enhance the s i g n a l - t o - n o i s e r a t i o of sensory s t i m u l i , which i s o f t e n c o n s i d e r e d t o be a f u n c t i o n of a t t e n t i o n a l mechanisms. I t i s important t o note t h a t such changes were independent of l e a r n i n g or any o p p o r t u n i t y t o respond on the p a r t of the animals. There i s an a d d i t i o n a l experimental l i t e r a t u r e , s t i l l i n i t s i n f a n c y , i n d i c a t i n g t h a t dopamine systems may be i n v o l v e d i n s e l e c t i v e a t t e n t i o n mechanisms. T h i s work has r e l i e d p r i m a r i l y upon the phenomenon of l a t e n t i n h i b i t i o n . In the l a t e n t i n h i b i t i o n paradigm, s u b j e c t s g i v e n n o n r e i n f o r c e d preexposures t o a s t i m u l u s are much slower t o l e a r n , subsequently, when t h a t s t i m u l u s i s p a i r e d w i t h a r e i n f o r c e r . For example, r a t s w i l l e x h i b i t a g r e a t l y a t t e n u a t e d c o n d i t i o n e d response t o a tone f o l l o w i n g tone-shock p a i r i n g s i f they r e c e i v e d 10 or 100 tone p r e s e n t a t i o n s p r i o r t o the b e g i n n i n g of c o n d i t i o n i n g . L a t e n t i n h i b i t i o n i s d i s r u p t e d i n r a t s g i v e n c h r o n i c amphetamine treatment (Hellman, C r i d e r , & Solomon, 1983; Solomon & Staton, 1982; Solomon e t a l . , 1981; Weiner, Lubow, & Feldon, 1984) and i n r a t s t h a t have had dopamine r e c e p t o r s u p e r s e n s i t i v i t y induced by c h r o n i c h a l o p e r i d o l treatment (Solomon e t a l . , 1981), but i s enhanced D i s c u s s i o n 177 when t e s t i n g i s conducted w i t h n e u r o l e p t i c - t r e a t e d r a t s ( C h r i s t i s o n , Atwater, Dunn, & K i l t s , 1988; Weiner & Feldon, 1987; Weiner, Feldon, & Katz, 1987). A r e c e n t study by Baruch, Hemsley and Gray (1988) examined l a t e n t i n h i b i t i o n i n s c h i z o p h r e n i c s . S c h i z o p h r e n i a i s b e l i e v e d t o be r e l a t e d t o a h y p e r a c t i v i t y o f dopamine systems i n v o l v i n g an i n c r e a s e i n p o s t s y n a p t i c dopamine r e c e p t o r s (Swerdelow & Koob, 1987). I t has been suggested t h a t a d i m i n i s h e d a b i l i t y t o screen out i r r e l e v a n t s t i m u l i may u n d e r l i e p s y c h o t i c symptoms (see C l a r k , G e f f e n , & Geffen, 1987; N u e c h t e r l e i n & Dawson, 1984, f o r r e v i e w s ) . C o n s i s t e n t w i t h t h i s n o t i o n i s the f i n d i n g t h a t a n t i p s y c h o t i c drugs improve the a b i l i t y of p s y c h o t i c p a t i e n t s t o a t t e n d t o r e l e v a n t s t i m u l i (Spohn, 1977). In t h e i r study Baruch e t a l . (1988) found t h a t acute s c h i z o p h r e n i c s , but not c h r o n i c s c h i z o p h r e n i c s , showed impairment i n a l a t e n t i n h i b i t i o n t a s k , r e l a t i v e t o normal c o n t r o l s . Another b e h a v i o u r a l t e s t p urported t o t e s t f o r s e l e c t i v e a t t e n t i o n i s the b l o c k i n g paradigm (Mackintosh, 1975). " B l o c k i n g " r e f e r s t o the phenomenon by which the amount of c o n d i t i o n i n g a c c r u i n g t o one element of a compound c o n d i t i o n a l s t i m u l u s i s attenuated by p r i o r c o n d i t i o n i n g of the o t h e r element alone. For example, i f r a t s are c o n d i t i o n e d t o asymptotic l e v e l s of responding u s i n g a tone as the c o n d i t i o n a l s t i m u l u s , and then r e c e i v e as many r e i n f o r c e d t o n e - l i g h t p r e s e n t a t i o n s as are normally r e q u i r e d f o r r o b ust c o n d i t i o n i n g , they w i l l subsequently f a i l t o D i s c u s s i o n 178 e x h i b i t a c o n d i t i o n e d response t o the l i g h t i f i t i s p r e s e n t e d alone. The second s t i m u l u s (e.g., l i g h t ) i s t r e a t e d as i r r e l e v a n t by an i n t a c t animal. B l o c k i n g , l i k e l a t e n t i n h i b i t i o n , was found t o be a t t e n u a t e d by c h r o n i c amphetamine treatment ( C r i d e r , Solomon, & McMahon, 1982) or by dopamine r e c e p t o r s u p e r s e n s i t i v i t y ( C r i d e r , B l o c k e l , & Solomon, 1986). I t i s tempting t o view the a l t e r a t i o n s i n l a t e n t i n h i b i t i o n and b l o c k i n g as a l t e r a t i o n s i n the animals' a b i l i t y t o l e a r n t h a t a g i v e n s t i m u l u s i s i r r e l e v a n t . However, t h i n g s are not so simple. The e f f e c t s on l a t e n t i n h i b i t i o n are not seen i f the drugs are o n l y a d m i n i s t e r e d d u r i n g pre-exposure t o the s t i m u l u s , they must a l s o be a p p l i e d d u r i n g the c o n d i t i o n i n g phase (Weiner e t a l . , 1984, 1987). I n t e r e s t i n g l y , b l o c k i n g e f f e c t s are d i m i n i s h e d i f amphetamine i s o n l y a d m i n i s t e r e d d u r i n g i n i t i a l c o n d i t i o n i n g or compound c o n d i t i o n i n g , not i f i t i s a d m i n i s t e r e d d u r i n g both (Ohad, Lubow, Weiner, & Feldon, 1987). These f i n d i n g s were i n t e r p r e t e d as i n d i c a t i n g t h a t the drug does not d i s r u p t animals' a b i l i t y t o l e a r n t h a t a g i v e n s t i m u l u s i s i r r e l e v a n t , but, i n s t e a d , d i s r u p t s t h e i r a b i l i t y t o respond t o a s t i m u l u s as i r r e l e v a n t under changed c o n t i n g e n c i e s of r e i n f o r c e m e n t . . . I t p o i n t s i n a l l cases t o a f a i l u r e i n a p p l y i n g p r e v i o u s experience under changed environmental c o n d i t i o n s and t o an exaggerated c o n t r o l of the p r e v a i l i n g s i t u a t i o n a l demands (Ohad e t a l . , 1987, p. 141). I t i s d i f f i c u l t t o i n c o r p o r a t e these f i n d i n g s w i t h i n the e s t a b l i s h e d bounds of l e a r n i n g theory, and more d i f f i c u l t t o e x t r a p o l a t e from them t o make s t r o n g p r e d i c t i o n s concerning D i s c u s s i o n 179 e f f e c t s i n b e h a v i o u r a l paradigms not e x p l i c i t l y i n c o r p o r a t i n g i r r e l e v a n t s t i m u l i . Nonetheless, these data are of g r e a t importance. What the f i n d i n g s c o n c e r n i n g l a t e n t i n h i b i t i o n and b l o c k i n g t e l l us i s t h a t animals w i t h a l t e r e d dopamine f u n c t i o n may l e a r n d i f f e r e n t t h i n g s about environmental s t i m u l i than do c o n t r o l animals. What i s more, t h i s a l t e r a t i o n can occur i n a context i n which the animals need not a c t u a l l y respond t o those s t i m u l i . These data exclude any i n t e r p r e t a t i o n of dopamine f u n c t i o n based e x c l u s i v e l y on hedonic, m o t i v a t i o n a l , or responses i n i t i a t i o n p r o c e s s e s . Instead, a n a l y s i s must r e f e r t o changes i n which s t i m u l i c o n t r o l responses, and t o the c r i t e r i a by which those s t i m u l i g a i n or l o s e c o n t r o l . U s i n g a stimulus-based approach, we might t r y t o c o n s i d e r enhancement of f r e e z i n g observed a f t e r metoclopramide treatment i n the l i g h t of a d d i t i o n a l s t u d i e s conducted by Blanchard and Blanchard (1969b; 1970a,b). They found t h a t r a t s were more l i k e l y t o perform an a c t i v e avoidance response i f the e l i c i t i n g s t i m u l u s was s a l i e n t and d i s c r e t e (such as a moving prod or an aluminum box), but were more l i k e l y t o f r e e z e i f the e l i c i t i n g s t i m u l u s was l e s s d i s t i n c t (such as an unmarked p o r t i o n of an otherwise s a f e g r i d f l o o r ) . Might a n e u r o l e p t i c - t r e a t e d r a t respond t o d i f f e r e n t s t i m u l i i n the box than an undrugged r a t ? The data from the s e l e c t i v e a t t e n t i o n s t u d i e s p r o v i d e l i t t l e guidance on t h i s p o i n t . I f anything, the l a t e n t i n h i b i t i o n s t u d i e s D i s c u s s i o n 180 suggest t h a t n e u r o l e p t i c s should h e i g h t e n r a t s ' a b i l i t y t o igno r e i r r e l e v a n t background s t i m u l i . Nonetheless, the s t u d i e s of Blanchard and Blanchard remind us t h a t changes i n d e f e n s i v e response s t r a t e g i e s need not r e l y on concepts such as feedback cues or i n c e n t i v e l e a r n i n g . Instead we can f a l l back on B o l l e s ' a n a l y s i s , t h a t "when the t e s t s i t u a t i o n l o o k s l i k e a good p l a c e t o f r e e z e , the animal w i l l f r e e z e i f i t expects shock; when the s i t u a t i o n l o o k s l i k e a good p l a c e t o run, the animal w i l l run i n i t " ( B o l l e s , 1975, p. 365). The n e u r o l e p t i c s o n l y need t o change what makes a s i t u a t i o n look l i k e a good p l a c e t o f r e e z e . P r e p a r a t o r y Responding Examination of p r e p a r a t o r y a p p e t i t i v e behaviours l e d to the s u g g e s t i o n t h a t dopamine-dependent systems i n the f o r e b r a i n may be i n v o l v e d i n the p o t e n t i a t i o n o f non-r e f l e x i v e , t o p o g r a p h i c a l l y f l e x i b l e , p r e p a r a t o r y responses t o d i s t a l , e x t e r o c e p t i v e s t i m u l i (Blackburn, 1985; Blackburn e t a l . , 1989a). S i m i l a r l y , we may hyp o t h e s i z e t h a t t h e r e are c e r t a i n f o r e b r a i n systems t h a t mediate the e l i c i t a t i o n of a c t i v e avoidance behaviours by d i s t a l cues t h a t s i g n a l a v e r s i v e events. These are f l i g h t systems. There are oth e r n e u r a l systems r e s p o n s i b l e f o r autonomic responses and f r e e z i n g t o shock and s h o c k - r e l a t e d s t i m u l i . We would 2. LeDoux, Iwata, C i c c h e t t i , and R e i s (1988) have r e c e n t l y demonstrated t h a t c o n d i t i o n e d changes i n bl o o d p r e s s u r e and f r e e z i n g i n v o l v e p r o j e c t i o n s o f the c e n t r a l amygdaloid nucleus t o , r e s p e c t i v e l y , the l a t e r a l hypothalamus and the caudal p o r t i o n of the c e n t r a l gray r e g i o n . D i s c u s s i o n 181 expect a well-adapted nervous system t o e s t a b l i s h mutual i n h i b i t i o n between such i n c o m p a t i b l e responses (Konorski, 1967). Thus, f l i g h t systems should i n h i b i t f r e e z i n g responses, and i t seems reasonable t o expect t h a t f r e e z i n g s hould i n h i b i t f l i g h t systems, perhaps a t a c e n t r a l l e v e l as w e l l as i n terms of b e h a v i o u r a l c o m p e t i t i o n . W i t h i n t h i s framework we can s p e c u l a t e t h a t dopamine a c t i v i t y f a c i l i t a t e s o r primes f l i g h t systems i n the presence of a p p r o p r i a t e environmental s t i m u l i , but does not p o t e n t i a t e f r e e z i n g . In the absence of r e g u l a r l e v e l s of e f f e c t i v e dopamine n e u r o t r a n s m i s s i o n , f l i g h t systems are s t i l l capable of f u n c t i o n i n g , but they have l o s t a f a c i l i t a t o r y i n p u t . The dopamine systems t h a t promote p r e p a r a t o r y behaviours i n response t o d i s t a l s t i m u l i are d i s a b l e d . T h i s l e a d s t o h i g h l e v e l s of f r e e z i n g i n a n t i c i p a t i o n of shock. As a r e s u l t , the animal experiences a d d i t i o n a l shock which f u r t h e r enhances the p r o b a b i l i t y of f r e e z i n g a t the expense of f l i g h t responses. Once they have e s t a b l i s h e d an e x p e c t a t i o n t h a t f l i g h t , o r approach toward c e r t a i n s t i m u l i , w i l l l e a d t o s a f e t y , r a t s are capable of performing avoidance responses d e s p i t e n e u r o l e p t i c treatment. That i s , p o t e n t i a t i o n by dopamine i s not r e q u i r e d f o r the f l i g h t systems t o operate. In the case of one-way avoidance t h i s e x p e c t a t i o n can be e s t a b l i s h e d extremely r a p i d l y , perhaps i n the course of a s i n g l e s u c c e s s f u l avoidance response. N e u r o l e p t i c s e v i d e n t l y d i s r u p t the e s t a b l i s h m e n t of t h i s e x p e c t a t i o n . There may be D i s c u s s i o n 182 two mechanisms by which t h i s happens. F i r s t , because of treatment w i t h the n e u r o l e p t i c drug, p r e v i o u s l y u n t r a i n e d r a t s are i n c a p a b l e of i n i t i a t i n g a f i r s t s u c c e s s f u l response t h a t would p r o v i d e them w i t h the i n f o r m a t i o n t h a t c e r t a i n responses or s t i m u l i are r e l a t e d t o the absence of shock. However, an e x p e c t a t i o n s u f f i c i e n t t o permit avoidance t o occur i n drugged r a t s can a l s o be e s t a b l i s h e d i n the context of escape t r a i n i n g . The f i n d i n g t h a t such t r a i n i n g does not have a p r o p h y l a c t i c e f f e c t i f i t i s conducted w h i l e the r a t i s t r e a t e d w i t h metoclopramide i n d i c a t e s t h a t the n e u r o l e p t i c i s d i s r u p t i n g the formation o f the e x p e c t a t i o n through an a d d i t i o n a l mechanism. That i s , i n a d d i t i o n t o d i s r u p t i n g p r e p a r a t o r y responding w h i l e the animal i s drugged, n e u r o l e p t i c drugs a l s o appear t o d i s r u p t some l e a r n i n g p r o c e s s . Conceivably, dopamine p l a y s a r o l e i n l e a r n i n g about those s t i m u l i t h a t come t o evoke p r e p a r a t o r y responses, or i n a s s o c i a t i n g responses w i t h those s t i m u l i . I t i s important t o note t h a t i n the absence of e f f e c t i v e dopaminergic n e u r o t r a n s m i s s i o n , animals may s t i l l r e c o g n i z e s t i m u l i i n t h e i r c a p a c i t y as cues s i g n a l l i n g important events. Thus even though a r a t ' s a b i l i t y t o d i r e c t a p r e p a r a t o r y s k e l e t a l responses towards a p p r o p r i a t e s t i m u l i may be d i m i n i s h e d by n e u r o l e p t i c s , i t w i l l s t i l l r e c o g n i z e a tone as a s i g n a l f o r shock, and w i l l t h e r e f o r e f r e e z e . T h i s a n a l y s i s i s c o n s i s t e n t w i t h the observed e f f e c t of n e u r o l e p t i c drugs on a p p e t i t i v e behaviours. N e u r o l e p t i c -t r e a t e d r a t s were observed t o o r i e n t t o c o n d i t i o n e d meal D i s c u s s i o n 183 cues, but d i d not engage i n vigourous approach responses. Nonetheless, food was s t i l l capable o f e l i c i t i n g a p p r o p r i a t e consummatory responses from n e u r o l e p t i c - t r e a t e d r a t s (Blackburn e t a l . , 1987, 1989b). S i m i l a r l y , the f r e e z i n g of f r i g h t e n e d r a t s may be viewed as a l o c a l l y - d i r e c t e d consummatory response c o n t r o l l e d by the f e a r - e l i c i t i n g p r o p e r t i e s of the WS and the s h o c k - r e l a t e d environment. I f we grant t h a t f l i g h t and f r e e z i n g systems are l i k e l y t o be mut u a l l y i n h i b i t o r y we can account r e a d i l y f o r the f i n d i n g s of Chapter IV. By exposing a r a t t o shock, o r t o a cue f o r a p r e v i o u s l y i n e s c a p a b l e shock, a t the same time as we damp i t s f l i g h t system by a d m i n i s t e r i n g metoclopramide, we may expect an i n c r e a s e i n f r e e z i n g and a decrease i n avoidance. Summary and c o n c l u s i o n s The a n a l y s i s o f f e r e d here r e c o g n i z e s t h a t f r i g h t e n e d r a t s u s u a l l y have a b e h a v i o u r a l r e p e r t o i r e t h a t i s l i m i t e d t o a few s p e c i e s - t y p i c a l defence r e a c t i o n s , some of which are compatible with one-way avoidance responding, some of which are i n c o m p a t i b l e . The c u r r e n t h y p o t h e s i s contends t h a t n e u r o l e p t i c s b i a s the s e l e c t i o n of which SSDR i s e l i c i t e d towards f r e e z i n g by i m p a i r i n g the a b i l i t y o f drugged r a t s t o respond t o d i s t a l cues by f l e e i n g . To t h i s e x t e n t the a n a l y s i s i s c o n s i s t e n t w i t h the a s s e r t i o n of Jacobs and LoLordo (1980) t h a t the c r i t i c a l f e a t u r e i n de t e r m i n i n g avoidance responding i s the presence o f a p p r o p r i a t e D i s c u s s i o n 184 s u p p o r t i n g s t i m u l i , and w i t h a sensorimotor a n a l y s i s t h a t views dopamine as p o t e n t i a t i n g the a b i l i t y of s t i m u l i t o e l i c i t responses (Clody & C a r l t o n , 1980; M a r s h a l l e t a l . , 1974; White, 1986). That the e f f e c t of the drugs i s not p r i m a r i l y on l e a r n i n g i s i n d i c a t e d by the a b i l i t y o f n e u r o l e p t i c s t o a l t e r f r e e z i n g responses t o a s i n g l e shock. That the e f f e c t i s not d i r e c t l y on response mechanisms i s i n d i c a t e d by the d i f f e r e n t i a l e f f e c t s of drugged and undrugged escape p r e t r a i n i n g , as w e l l as by the o b s e r v a t i o n t h a t n e u r o l e p t i c s do not enhance p a s s i v e avoidance responding. T h i s a n a l y s i s has emerged from the j o i n t c o n s i d e r a t i o n of how a p p e t i t i v e and d e f e n s i v e behaviours are i n f l u e n c e d by n e u r o l e p t i c drugs. The data reviewed above i n d i c a t e t h a t these drugs a l t e r fundamental p s y c h o l o g i c a l p r o c e s s e s by which environmental s t i m u l i come t o e x e r t c o n t r o l over p r e p a r a t o r y behaviours. 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