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Pharmacological assessment of the relationship between cue properties and rewarding effects of electrical… Druhan, Jonathan Peter 1985

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PHARMACOLOGICAL ASSESSMENT OF THE RELATIONSHIP BETWEEN CUE PROPERTIES AND REWARDING EFFECTS OF ELECTRICAL STIMULATION OF THE VENTRAL TEGMENTAL AREA by JONATHAN PETER DRUHAN B . S c , M c G i l l U n i v e r s i t y , 1983 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS i n THE FACULTY OF GRADUATE STUDIES (Department of Psychology) We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE © UNIVERSITY OF BRITISH COLUMBIA September, 1985 Jonathan Peter Druhan, 1985 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. JONATHAN PETER DRUHAN Department of PSYCHOLOGY The University of British Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date OCTOBER 1 0 . 1 9 8 5 DE-6(3/81) i i ABSTRACT The present s e r i e s of experiments was designed to assess the u t i l i t y of a d i s c r i m i n a t i o n procedure f o r measuring the a f f e c t i v e p r o p e r t i e s of rewarding b r a i n - s t i m u l a t i o n . I f the rewarding and d i s c r i m i n a t i v e stimulus p r o p e r t i e s of e l e c t r i c a l b r a i n s t i m u l a t i o n were r e l a t e d , they may share a common s u b s t r a t e and be a f f e c t e d s i m i l a r l y by the same pharmacological manipulations. In Experiment 1, a d i s c r i m i n a t i o n procedure was developed to measure the cue p r o p e r t i e s of EBS d e l i v e r e d to the v e n t r a l tegmental area (VTA). Rats with VTA e l e c t r o d e s were t r a i n e d to ob t a i n food p e l l e t s by making a d i s c r i m i n a t e d operant response on one of two l e v e r s f o l l o w i n g pulses of high i n t e n s i t y s t i m u l a t i o n , or on the a l t e r n a t e l e v e r a f t e r low i n t e n s i t y p u l s e s . F o l l o w i n g t r a i n i n g , the r a t s were given t e s t s i n which g e n e r a l i z e d responding to in t e r m e d i a t e i n t e n s i t i e s was measured. These t e s t s were repeated e i t h e r with c o n d i t i o n s kept constant, or with the absolute i n t e n s i t i e s of the cues d e l i v e r e d w i t h i n a se s i o n i n c r e a s e d or decreased r e l a t i v e to b a s e l i n e . The t e s t s with higher or lower i n t e n s i t y ranges were intended to mimic the c o n d i t i o n s that might p r e v a i l i f the perceived i n t e n s i t i e s of the EBS were modified by drugs. The r e s u l t s of t h i s experiment i n d i c a t e d that g e n e r a l i z a t i o n g r a d i e n t s remained s t a b l e across three t e s t s with c o n d i t i o n s kept constant. When higher or lower c u r r e n t ranges were i i i d e l i v e r e d , the d i s c r i m i n a t e d responses were a p p r o p r i a t e l y biased towards one l e v e r or the other, r e s u l t i n g i n l a t e r a l s h i f t s i n the g e n e r a l i z a t i o n g r a d i e n t s . These r e s u l t s v e r i f i e d that the d i s c r i m i n a t i o n procedure provided a s t a b l e measure of the EBS stimulus p r o p e r t i e s , and that t h i s measure was s e n s i t i v e to changes i n the i n t e n s i t i e s of the cues. In Experiment 2, t e s t s f o r EBS g e n e r a l i z a t i o n and s e l f -s t i m u l a t i o n (ICSS) were given a f t e r i n j e c t i o n s of v e h i c l e , d-amphetamine (1.0 mg/kg and 2.0 mg/kg) and h a l o p e r i d o l (.075 mg/kg and .10 mg/kg). The r e s u l t s i n d i c a t e d that these doses of amphetamine and h a l o p e r i d o l d i d not a f f e c t the EBS g e n e r a l i z a t i o n . However, during ICSS s e s s i o n s , 2.0 mg/kg amphetamine decreased t h r e s h o l d and i n c r e a s e d r a t e s f o r ICSS whereas .10 mg/kg h a l o p e r i d o l r e s u l t e d i n an i n c r e a s e i n t h r e s h o l d . These r e s u l t s suggest a d i s s o c i a t i o n of the stimulus p r o p e r t i e s of EBS from the DA reward s u b s t r a t e . In Experiment 3, the r a t s were t e s t e d f o r g e n e r a l i z a t i o n a f t e r i n j e c t i o n s of physostigmine (.25 mg/kg and .50 mg/kg), scopolamine (.10 mg/kg and .25 mg/kg) and v e h i c l e . Only the high dose of physostigmine (.50 mg/kg) produced s i g n i f i c a n t d i f f e r e n c e s i n reponding i n t h i s experiment. A f t e r i n j e c t i o n of t h i s drug, lower i n t e n s i t y s t i m u l i e l i c i t e d responding on the l e v e r a p p r o p r i a t e f o r the high c u r r e n t i n t e n s i t y , i n d i c a t i n g a p o s s i b l e augmentation of the stimulus property of a f i x e d i n t e n s i t y of b r a i n i v s t i m u l a t i o n . The r e s u l t s of t h i s study i n d i c a t e that the cue p r o p e r t i e s of VTA b r a i n - s t i m u l a t i o n are d i s s o c i a b l e from EBS reward r e l a t e d to the a c t i v a t i o n of DA neurons. However, evidence i s provided which suggests that c h o l i n e r g i c neurons may be i n v o l v e d i n the mediation of the EBS cues. In as much as c h o l i n e r g i c neurons are a l s o i n v o l v e d i n the rewarding e f f e c t s of VTA b r a i n - s t i m u l a t i o n , these r e s u l t s may i n d i c a t e a r e l a t i o n s h i p between the cue p r o p e r t i e s of VTA EBS and an a c e t y l c h o l i n e reward system. Anthony G. P h i l l i p s V TABLE OF CONTENTS A b s t r a c t . . . i i Table of Contents v L i s t of F i g u r e s v i i Acknowledgements i x INTRODUCTION 1 D i s c r i m i n a t i o n of Food Reward 3 The R e i n f o r c i n g and Stimulus P r o p e r t i e s of Drugs .. 4 D i s c r i m i n a t i o n of Rewarding B r a i n S t i m u l a t i o n 8 O b j e c t i v e s of the Present I n v e s t i g a t i o n 14 GENERAL METHOD 18 Subjects 18 Surgery 18 Apparatus 18 Procedure 19 H i s t o l o g y 22 EXPERIMENT 1: D i s c r i m i n a t i o n and g e n e r a l i z a t i o n of d i f f e r e n t i n t e n s i t i e s of EBS: Changes i n the response g r a d i e n t a s s o c i a t e d with s h i f t s i n the absolute i n t e n s i t y range... 23 Method 25 Re s u l t s 26 D i s c u s s i o n 37 VI EXPERIMENT 2: Comparison of amphetamine and h a l o p e r i d o l e f f e c t s on ICSS and EBS d i s c r i m i n a t i o n .. 41 Method 43 R e s u l t s 45 D i s c u s s i o n 54 EXPERIMENT 3: Measurement of EBS d i s c r i m i n a t i o n a f t e r i n j e c t i o n s of physostigmine and scopolamine 60 Method 62 R e s u l t s 63 D i s c u s s i o n 71 GENERAL DISSCUSSION 74 REFERENCES 86 v i i LIST OF FIGURES Figure 1. E l e c t r o d e placements 28 Figure 2. B a s e l i n e g e n e r a l i z a t i o n g r a d i e n t s f o r r a t s d i s c r i m i n a t i n g i n t e n s i t i e s of EBS 31 Figure 3. G e n e r a l i z a t i o n g r a d i e n t s obtained during t e s t s with d i f f e r e n t i n t e n s i t y ranges 33 Figure 4. Changes i n d i s c r i m i n a t e d response b i a s e s to f i x e d i n t e n s i t i e s during t e s t s with d i f f e r e n t i n t e n s i t y ranges 36 Figu r e 5. G e n e r a l i z a t i o n g r a d i e n t s measured f o l l o w i n g i n j e c t i o n s of amphetamine and h a l o p e r i d o l ... 48 Figu r e 6. L a t e n c i e s f o r d i s c r i m i n a t e d responding during g e n e r a l i z a t i o n t e s t s with amphetamine and h a l o p e r i d o l 50 Figu r e 7. Current t h r e s h o l d s f o r ICSS on a VI-20 schedule of reinforcement a f t e r amphetamine and h a l o p e r i d o l 53 Figu r e 8. R a t e - i n t e n s i t y f u n c t i o n s f o r VI-20 ICSS a f t e r i n j e c t i o n s of amphetamine and h a l o p e r i d o l ... 56 Figure 9. G e n e r a l i z a t i o n i n j e c t i o n s of scopolamine .. v i i i g r a d i e n t s measured f o l l o w i n g physostigmine and 65 Figure 10. L a t e n c i e s f o r d i s c r i m i n a t e d responding during g e n e r a l i z a t i o n t e s t s with physostigmine and scopolamine 68 Fi g u r e 11. Percentage of d i s c r i m i n a t i o n t r i a l s on which a response occured during t e s t s with physostigmine and scopolamine 70 i x ACKNOWLEDGEMENTS I would l i k e to extend my deepest g r a t i t u d e to my a d v i s o r , Dr. Anthony P h i l l i p s , f o r h i s generous support and p e r s i s t e n t encouragement throughout the course of t h i s study. His c l o s e a t t e n t i o n and involvement i n t h i s study has made working on t h i s p r o j e c t a s t i m u l a t i n g and s a t i s f y i n g experience. I would l i k e to thank Dr. Donald W i l k i e f o r ta k i n g the time to answer the barrage of questions I approached him with over the past two years, and f o r h e l p i n g with s t a t i s t i c s and computer r e l a t e d problems. My g r a t i t u d e i s a l s o extended to Dr. Mathew Ma r t i n - I v e r s o n , who suggested many of the experimental parameters used i n t h i s study, and with whom I had many long d i s c u s s i o n s concerning p o s s i b l e c o n c e p t u a l i z a t i o n s of the data presented here. I would l i k e to thank Dr. C h r i s F i b i g e r f o r a d v i s i n g me on the ap p r o p r i a t e pharmacological procedures used i n experiment 3, and f o r t a k i n g the time to be on my t h e s i s committee. F i n a l l y , I am a p p r e c i a t i v e of the help that I r e c e i v e d from Fred LePiane, who wrote the o r i g i n a l computer programs f o r the running of the experiments and i n s t r u c t e d me i n the use of the l a b f a c i l i t i e s . 1 N e u r o b i o l o g i c a l s t u d i e s of animal m o t i v a t i o n t r a d i t i o n a l l y have i n v o l v e d o b s e r v a t i o n of approach or withdrawal responses to environmental s t i m u l i f o l l o w i n g manipulations of c e n t r a l nervous system (CNS) f u n c t i o n s . The i n d i c e s of motivated behavior have been d e r i v e d mainly from measurement of response r a t e , d u r a t i o n or l a t e n c y with the assumption that changes i n these measures r e f l e c t a l t e r a t i o n s i n the i n c e n t i v e value or r e i n f o r c i n g e f f i c a c y of the m o t i v a t i n g s t i m u l u s . However, these response v a r i a b l e s can a l s o be a f f e c t e d by manipulations that i n t e r f e r e with the c o n t r o l of motor performance. I n t e r p r e t a t i o n of b e h a v i o r a l data i n terms of e f f e c t s on m o t i v a t i o n a l processes i s thus l i m i t e d when the manipulation employed has demonstrable e f f e c t s on the response c a p a c i t y of an animal. To circumvent t h i s confound, attempts have been made to develop paradigms i n which the i n d i c e s of mo t i v a t i o n are unconfounded by performance v a r i a b l e s . Recently, d i s c r i m i n a t i o n procedures have been employed to measure the m o t i v a t i o n a l p r o p e r t i e s of rewarding s t i m u l i . The r a t i o n a l f o r using d i s c r i m i n a t i o n measures f o r t h i s purpose extends from the c o n t e n t i o n that the d e l i v e r y of a reward i s a s s o c i a t e d with changes i n the a f f e c t i v e s t a t e of an animal. T h i s s t a t e change, which has been d e s c r i b e d as an a f f e c t i v e or hedonic a r o u s a l (Young, 1961), may c o n s t i t u t e a h i g h l y s a l i e n t f e a t u r e of a rewarding event. I f animals attend to a f f e c t i v e consequences of a rewarding event, then 2 d i s c r i m i n a t i o n procedures may provide a s e n s i t i v e measure of the hedonic r e a c t i o n s a s s o c i a t e d with such s t i m u l i . The primary advantage of employing a d i s c r i m i n a t i o n procedure to measure the hedonic p r o p e r t i e s of reward s t i m u l i i s that the e f f e c t s of motor or c o g n i t i v e impairments on the dependent measure are d i s s o c i a b l e from s e l e c t i v e e f f e c t s of a p h y s i o l o g i c a l m anipulation on s t i m u l u s p e r c e p t i o n . In most d i s c r i m i n a t i o n procedures an animal may s e l e c t one of two d i s c r e t e response a l t e r n a t i v e s f o l l o w i n g cue d e l i v e r y , with the a p p r o p r i a t e response being s i g n a l l e d by d i s t i n c t a t t r i b u t e s of the two d i s c r i m i n a t i v e s t i m u l i . M a n i p u l a t i o n s that s e l e c t i v e l y a l t e r p e r c e p t i o n of a stimulus should r e s u l t i n a b i a s i n g of responses toward one of the two p o s s i b l e c h o i c e s . By c o n t r a s t , i n t e r f e r e n c e with motor or c o g n i t i v e c a p a c i t i e s would be manifest as r e d u c t i o n s i n the o v e r a l l accuracy of the d i s c r i m i n a t i o n , and the behavior would resemble random response s e l e c t i o n . A disadvantage of d i s c r i m i n a t i o n measures of hedonic processes i s that animals may attend to non-hedonic p r o p e r t i e s of a r e i n f o r c i n g s t i m u l u s . Most rewards have stimulus a t t r i b u t e s that provide sensory i n f o r m a t i o n with no i n h e r e n t m o t i v a t i o n a l v a l u e . Conceivably, these s t i m u l i could be more s a l i e n t than i n t e r n a l a f f e c t i v e r e a c t i o n s and thus overshadow hedonic p r o p e r t i e s of a rewarding stimulus when i t i s used as a d i s c r i m i n a t i v e cue. Thus, i t i s not p o s s i b l e to assume c a t e g o r i c a l l y that d i s c r i m i n a t i o n 3 paradigms are s e n s i t i v e measures of m o t i v a t i o n a l processes. P r i o r e m p i r i c a l determinations are r e q u i r e d to i d e n t i f y the r e l e v e n t f e a t u r e s of a reward cue that maintain stimulus c o n t r o l over responding. The u t i l i t y of d i s c r i m i n a t i o n procedures f o r measuring hedonic p r o p e r t i e s of reward s t i m u l i has been i n v e s t i g a t e d i n only a few s t u d i e s . The r e s u l t s of these s t u d i e s , however, suggest that r a t s may d i s c r i m i n a t e the i n c e n t i v e p r o p e r t i e s of both food ( M a r t i n - I v e r s o n , 1985) and rewarding b r a i n - s t i m u l a t i o n ( S t u t z , 1968) when these rewards are used as d i s c r i m i n a t i v e s t i m u l i . In a d d i t i o n , although the r e l a t i o n s h i p between cue and r e i n f o r c i n g e f f e c t s of drugs has not been researched d i r e c t l y , there i s converging evidence which suggests that these two p r o p e r t i e s of psycho-motor s t i m u l a n t drugs may be mediated by the same ne u r a l p rocesses. Thus, i t appears that d i s c r i m i n a t i o n procedures may i n f a c t measure hedonic p r o p e r t i e s of d i f f e r e n t reward s t i m u l i . The a v a i l a b l e evidence p e r t i n e n t to t h i s i s s u e w i l l be reviewed below. D i s c r i m i n a t i o n of food reward. M a r t i n - I v e r s o n (1985) r e c e n t l y has employed a d i s c r i m i n a t i o n procedure to determine the f e a t u r e s used by r a t s to d i s t i n g u i s h between d i f f e r e n t q u a n t i t i e s of food. Rats were t r a i n e d to d i s c r i m i n a t e between one and four sweetened food p e l l e t s , and respond f o r food reinforcement 4 on one of two s e p a r a t e l e v e r s a f t e r p r e s e n t a t i o n of each cue. The r a t s were then g i v e n g e n e r a l i z a t i o n t e s t s w i t h two and t h r e e p e l l e t s b e i n g d e l i v e r e d on some of the t r i a l s . To determine whether the d i s c r i m i n a t i o n was based on hedonic p r o p e r t i e s of the reward s t i m u l u s , the same g e n e r a l i z a t i o n t e s t s were g i v e n e i t h e r w i t h unsweetened p e l l e t s , or w h i l e the r a t s were m a i n t a i n e d a t d i f f e r e n t l e v e l s of food d e p r i v a t i o n . These m a n i p u l a t i o n s produced r e l i a b l e changes i n p r e f e r e n c e measures of approach b e h a v i o r , i n d i c a t i n g t h a t they can a l t e r the i n c e n t i v e v a l u e of food reward. The r e s u l t s of t h i s s tudy i n d i c a t e d t h a t d e c r e a s i n g the p a l a t a b i l i t y of the food and r e d u c i n g the l e v e l of food d e p r i v a t i o n r e s u l t e d i n an i n c r e a s e i n the r a t s ' tendancy t o respond on the f o u r - p e l l e t l e v e r r e l a t i v e t o b a s e l i n e . Thus, pro c e d u r e s which d e c r e a s e d the r a t s ' m o t i v a t i o n f o r the food appears to have caused them to p e r c e i v e q u a n t i t i e s of food as b e i n g g r e a t e r than the same amounts g i v e n d u r i n g b a s e l i n e t e s t s . T h i s r e s u l t i s c o n t r a r y to what might be expected i f the r a t s were d i s c r i m i n a t i n g on the b a s i s of t h e i r a f f e c t i v e r e a c t i o n t o the f o o d . Reducing d e p r i v a t i o n l e v e l and p a l a t a b i l i t y d e c r e a s e s approach r e s p o n s e s t o the food and, by i n f e r e n c e , i t s hedonic v a l u e . I f the d i s c r i m i n a t i o n of food was based on the r e l a t i v e hedonic responses t o the d i f f e r e n t q u a n t i t i e s of f o o d , then the i n c e n t i v e r e d u c t i o n s h o u l d have made each q u a n t i t y more s i m i l a r t o the l e s s r e w a r d i n g s i n g l e - p e l l e t cue. 5 The d i s c r i m i n a t i o n of food q u a n t i t i e s i n t h i s experiment i n v o l v e d mechanisms that could not be a t t r i b u t e d simply to d i s t i n c t i o n s between the hedonic impact of the cues. However, i t appears t h a t m o t i v a t i o n a l v a r i a b l e s d i d i n f l u e n c e the p e r c e p t i o n of food q u a n t i t y . M a r t i n - I v e r s o n (1985) has argued that the d i s c r i m i n a t i o n may have been based p a r t l y on the a b i l i t y of the d i f f e r e n t q u a n t i t i e s to s a t i s f y the r a t s ' a p p e t i t e f o r the food. Under c o n d i t i o n s of reduced d e p r i v a t i o n or decreased p a l a t a b i l i t y the r a t s had l e s s of an a p p e t i t e f o r the p e l l e t s , and a given q u a n t i t y was thus p e r c i e v e d as being more s a t i s f y i n g than during b a s e l i n e t e s t s . The R e i n f o r c i n g and Stimulus P r o p e r t i e s of Drugs. C e r t a i n drugs may a l s o have stimulus p r o p e r t i e s that are r e l a t e d to t h e i r rewarding e f f e c t s . In humans, drugs of abuse c h a r a c t e r i s t i c a l l y induce s a l i e n t changes i n emotional s t a t e s concomittant with t h e i r CNS a c t i o n s . These s u b j e c t i v e e f f e c t s are thought to c o n s t i t u t e a major i n c e n t i v e f o r repeated drug use ( L a i , 1977). I f the a b i l i t y of euphorogenic drugs to r e i n f o r c e behavior i s d i r e c t l y r e l a t e d to the a f f e c t i v e s e n s a t i o n s e l l i c i t e d by these compounds, then d i s c r i m i n a t i o n procedures may provide a means of studying the n e u r a l mechanisms of drug reinforcement. Although the r e l a t i o n s h i p between the stimulus and r e i n f o r c i n g p r o p e r t i e s of euphorogenic drugs has not been 6 s t u d i e d thoroughly, there are i n d i c a t i o n s that with c e r t a i n compounds these two e f f e c t s may be mediated by a common neu r a l s u b s t r a t e . For i n s t a n c e , the a b i l i t y of psychomotor s t i m u l a n t s such as amphetamine and cocaine to serve as both a cue and a reward appears to depend to a l a r g e extent on t h e i r a c t i o n s on mesolimbic dopamine (DA) neurons. The major a c t i o n of these drugs on DA neurons i s to block DA reuptake i n t o the p r e s y n a p t i c t e r m i n a l s , with the secondary e f f e c t being an i n c r e a s e of DA c o n c e n t r a t i o n s at p o s t - s y n a p t i c r e c e p t o r s (Iversen & Iversen, 1981). I t i s presumably the p o s t - s y n a p t i c p h y s i o l o g i c a l changes r e s u l t i n g from the i n c r e a s e s i n DA l e v e l s which produce both the drug s t i m u l i and t h e i r r e i n f o r c i n g e f f e c t s . There i s abundant evidence suggesting that DA r e c e p t o r s mediate the r e i n f o r c i n g e f f e c t s of psychomotor s t i m u l a n t s . Intravenous s e l f - a d m i n i s t r a t i o n of s t i m u l a n t s by r a t s i s attenuated i n an e x t i n c t i o n - l i k e manner by n e u r o l e p t i c drugs, which block DA r e c e p t o r s (see Wise, 1978 f o r a r e v i e w ) . Importantly, low doses of n e u r o l e p t i c s produce what appears to be a compensatory f a c i l i t a t i o n of responding f o r the s t i m u l a n t s . P a r t i a l r e c e p t o r blockade presumably causes r a t s to i n c r e a s e t h e i r drug i n t a k e i n order to maintain an optimal l e v e l of r e c e p t o r a c t i v a t i o n . These r e s u l t s a l s o have been obtained with b i l a t e r a l i n j e c t i o n s of the n e u r o l e p t i c s p i r o p e r i d o l i n t o the nucleus accumbens (NAS), a b r a i n r e g i o n i n n e r v a t e d by mesolimbic DA p r o j e c t i o n s 7 ( P h i l l i p s , Broekkamp & F i b i g e r , 1983). D e s t r u c t i o n of DA neurons with b i l a t e r a l i n j e c t i o n s of the n e u r o t o x i n 6-hydroxydopamine (6-OHDA) i n t o the NAS a l s o produces e x t i n c t i o n - l i k e responding f o r cocaine (Roberts, Koob, K l o n o f f & F i b i g e r , 1980). Moreover, i n j e c t i o n s of 6-OHDA i n t o the NAS prevent the a q u i s i t i o n of amphetamine s e l f - a d m i n i s t r a t i o n (Lyness, F r i e d l e & Moore, 1979). These r e s u l t s , together with the e f f e c t s of n e u r o l e p t i c s on drug s e l f - a d m i n i s t r a t i o n , i n d i c a t e that i n t e r f e r e n c e with DA f u n c t i o n i n g at both pre- and p o s t - s y n a p t i c l e v e l s w i t h i n the NAS r e s u l t s i n an a t t e n u a t i o n of s t i m u l a n t reinforcement. T h i s i m p l i e s that DA p r o j e c t i o n s to the NAS represent a c r i t i c a l s u b s t r a t e f o r the rewarding e f f e c t s of psychomotor s t i m u l a n t s . The stimulus p r o p e r t i e s of s t i m u l a n t drugs a l s o appear to be mediated by a dopaminergic s u b s t r a t e . Rats t r a i n e d to d i s c r i m i n a t e a p a r t i c u l a r s t i m u l a n t from i t s v e h i c l e w i l l emit responses a p p r o p r i a t e f o r the drug s t a t e when t e s t e d f o r g e n e r a l i z a t i o n with other s t i m u l a n t compounds or d i r e c t DA r e c e p t o r a g o n i s t s ( C o l p a e r t , Niemegeers & Jansen, 1979; Schecter, 1980). T h i s g e n e r a l i z a t i o n does not occur, however, i f one ad m i n i s t e r s compounds which do not i n t e r a c t with DA systems ( C o l p a e r t et a l , 1979; see Silverman & Ho, 1977 and Ho and Silverman, 1978 f o r re v i e w s ) . When a DA ant a g o n i s t i s i n j e c t e d along with the s t i m u l a n t the animals tend to make responses a p p r o p r i a t e f o r the non-drugged 8 c o n d i t i o n (Ho & Huang, 1975; Ho & McKenna, 1978; Schecter & Cook, 1975). Thus, s t i m u l a n t cues are blocked by pharmacological i n t e r f e r e n c e with DA r e c e p t o r s . Recently, N i e l s e n and Scheel-Kruger (1984) demonstrated that cues produced by i n t r a p e r i t o n e a l i n j e c t i o n s of amphetamine are mediated, i n p a r t , by DA p r o j e c t i o n s to the NAS. Rats t r a i n e d to d i s c r i m i n a t e p e r i p h e r a l l y administered amphetamine from s a l i n e responded on the drug a p p r o p r i a t e l e v e r when the amphetamine was i n j e c t e d d i r e c t l y i n t o the NAS. T h i s g e n e r a l i z a t i o n was found to be dose dependent, and was blocked when - s u l p i r i d e was c o - i n j e c t e d i n t o the NAS with the amphetamine. NAS i n j e c t i o n of - s u l p i r i d e alone, however, only p a r t i a l l y blocked the drug a p p r o p r i a t e responding when amphetamine was administered p e r i p h e r a l l y . Although DA r e c e p t o r s i n the NAS appear to play a r o l e i n the mediation of the amphetamine cues, other n e u r a l processes e v i d e n t l y are i n v o l v e d as w e l l . The mimicking of cues of one psychomotor s t i m u l a n t by other s t i m u l a n t s , coupled with n e u r o l e p t i c blockade of these cues, p r o v i d e s strong support f o r dopaminergic mediation of the cue p r o p e r t i e s of psychomotor s t i m u l a n t drugs. Furthermore, the involvement of DA p r o j e c t i o n s to the NAS i n the mediation of these cues suggests that the stimulus p r o p e r t i e s of st i m u l a n t drugs may share a common n e u r a l s u b s t r a t e with the r e i n f o r c i n g e f f e c t s of these compounds. I f t h i s i s the case, then the drug d i s c r i m i n a t i o n procedure 9 may serve as a u s e f u l t o o l f o r a n a l y s i s of the ne u r a l mechanisms u n d e r l y i n g drug re i n f o r c e m e n t . D i s c r i m i n a t i o n of Rewarding B r a i n S t i m u l a t i o n . E l e c t r i c a l b r a i n s t i m u l a t i o n (EBS) repr e s e n t s a t h i r d type of reward stimulus which can be d i s c r i m i n a t e d by r a t s . For example, l a t e r a l hypothalamic (LH) and s e p t a l EBS may serve as a d i s c r i m i n a t i v e stimulus f o r both avoidance ( C o l p a e r t , Meert & M a r o l i , 1982; Stutz & Asdourian, 1965) and a p p e t a t i v e responding (Bass, 1974; Butcher & S t u t z , 1969), or as a c o n d i t i o n a l stimulus (CS) f o r both e x c i t a t o r y and i n h i b i t o r y c o n d i t i o n i n g of the n i c t i t a t i n g membrane response i n r a b b i t s (Hupka, 1970; Moore, Marchant, Norman & Kwaterski, 1973). S e p t a l and hippocampal EBS can a l s o be used as a CS f o r c l a s s i c a l c o n d i t i o n i n g of a c o n d i t i o n e d emotional response ( S t u t z , 1968). F i n a l l y , l i t h i u m - i n d u c e d a v e r s i o n s may be c o n d i t i o n e d to amygdaloid EBS, r e s u l t i n g i n an a t t e n u a t i o n of i t s rewarding e f f e c t s ( P h i l l i p s & McDonald, 1979) and suppresion of a d r i n k i n g response a s s o c i a t e d with the d e l i v e r y of the s t i m u l a t i o n ( P h i l l i p s & LePiane, 1978). Taken together, these r e s u l t s i n d i c a t e that rewarding EBS provides s t i m u l i which can f u n c t i o n as d i s c r i m i n a t i v e cues i n the same way. as e x t e r n a l s t i m u l a t i o n of p e r i p h e r a l sensory r e c e p t o r s . The r e l a t i o n s h i p between the stimulus and rewarding p r o p e r t i e s of EBS was i n v e s t i g a t e d f i r s t by Stutz and h i s 10 coworkers. In an e a r l y study, Stutz (1968) implanted e l e c t r o d e s i n both the septum and hippocampus of r a t s and employed the EBS d e l i v e r e d to one of these s i t e s as a CS f o r e l e c t r i c shock i n a c o n d i t i o n e d s u p p r e s s i o n paradigm. In a l l r a t s , the s e p t a l placement was capable of supporting i n t r a - c r a n i a l s e l f - s t i m u l a t i o n (ICSS), whereas the hippocampal EBS was r e i n f o r c i n g i n only h a l f of the r a t s . Subjects t r a i n e d with s e p t a l s t i m u l a t i o n as a cue g e n e r a l i z e d the CS to hippocampal EBS only when the l a t t e r was rewarding i n a f r e e operant s i t u a t i o n . S i m i l a r l y , when hippocampal s t i m u l a t i o n was the CS, g e n e r a l i z a t i o n to s e p t a l EBS occurred only i f the hippocampal s t i m u l a t i o n was capable of su p p o r t i n g ICSS. Thus, g e n e r a l i z a t i o n occurred when EBS to both e l e c t r o d e s i t e s was rewarding i n an operant context, but not when the EBS to the two s i t e s d i f f e r e d i n rewarding e f f i c a c y . One e x p l a n a t i o n f o r these r e s u l t s , i s that the rewarding p r o p e r t i e s of b r a i n s t i m u l a t i o n represent the most s a l i e n t f e a t u r e of an EBS cue. When rewarding EBS i s d e l i v e r e d to d i f f e r e n t n e u r a l s i t e s , the s i m i l a r i t i e s with r e s p e c t to the rewarding e f f i c a c i e s of the s t i m u l i causes g e n e r a l i z a t i o n to occur r e g a r d l e s s of the d i f f e r e n c e s r e s u l t i n g from a c t i v a t i o n of separate anatomical systems. I f the i n c e n t i v e p r o p e r t i e s of the s t i m u l a t i o n d i f f e r , t h i s d i s t i n c t i o n p rovides the b a s i s f o r the d i s c r i m i n a t i o n of the EBS. In a r e l a t e d study ( S t u t z , Butcher & R o s s i , 1969), r a t s 11 were t r a i n e d over a s i x day p e r i o d to d i s c r i m i n a t e s e p t a l EBS from s t i m u l a t i o n of e i t h e r the LH, the v e n t r a l tegmental area (VTA) or the hippocampus. In some r a t s s t i m u l a t i o n of both l o c i was rewarding. In others the s t i m u l a t i o n was rewarding at only one of the placements. For a t h i r d group, the EBS was not rewarding at e i t h e r s i t e . A n a l y s i s of the a c q u i s i t i o n r a t e s f o r the three groups i n d i c a t e d that EBS d i s c r i m i n a t i o n s were acq u i r e d only when s t i m u l a t i o n of the separate regions d i f f e r e d i n rewarding e f f i c a c i y . When the EBS was e i t h e r non-rewarding at each s i t e , or rewarding at both l o c i , the r a t s d i d not d i s c r i m i n a t e the s t i m u l a t i o n w i t h i n the 6 day t r a i n i n g p e r i o d . The most simple e x p l a n a t i o n f o r these r e s u l t s i s that the d i f f e r e n c e s i n the rewarding e f f i c a c y of the EBS provided a b a s i s f o r d i f f e r e n t i a t i n g the cues i n the group with b i v a l e n t s t i m u l a t i o n cues. T h i s d i s t i n c t i o n between the cues f a c i l i t a t e d the a c q u i s i t i o n of the d i s c r i m i n a t i o n task r e l a t i v e to the groups wherein d i f f e r e n c e s i n the rewarding e f f i c a c y were smal l e r or n o n - e x i s t a n t . The data obtained by Stutz (1968) and Stutz et a l (1969) suggest that the rewarding p r o p e r t i e s of b r a i n s t i m u l a t i o n represent a h i g h l y s a l i e n t f e a t u r e of an EBS cue. I f t h i s i s the case, manipulation of EBS reward s u b s t r a t e s should r e s u l t i n changes i n d i s c r i m i n a t e d responding to EBS cues. For example, pharmacological treatments which s h i f t reward t h r e s h o l d s might a l s o a l t e r 12 cue d e t e c t i o n t h r e s h o l d s . R e s u l t s of t h i s s o r t would provide strong evidence f o r a commonality of the processes mediating these two p r o p e r t i e s of EBS. At present, there i s only l i m i t e d understanding of the neu r a l processes u n d e r l y i n g b r a i n - s t i m u l a t i o n reward. I t i s apperent, however, that mesolimbic DA neurons play an important r o l e i n mediating the r e i n f o r c i n g e f f e c t s of EBS d e l i v e r e d to a v a r i e t y of b r a i n regions ( F i b i g e r , 1978; Wise, 1978). Drugs which a l t e r DA f u n c t i o n produce r e l i a b l e s h i f t s i n ICSS t h r e s h o l d s (Schaefer & Holtzman, 1979; Z a r e v i c s & S e t l e r , 1979) and a l t e r response r a t e s f o r f i x e d i n t e n s i t i e s of EBS ( P h i l l i p s , Brooke & F i b i g e r , 1975). Recent attempts to modulate EBS cues with dopaminergic a g o n i s t s and a n t a g o n i s t s , however, have y i e l d e d c o n f l i c t i n g r e s u l t s . Schaefer and Michael (1985) repo r t e d that the d e t e c t i o n t h r e s h o l d s f o r LH EBS were not a l t e r e d a f t e r subcutaneous i n j e c t i o n s of .10 to 1.0 mg/kg amphetamine or .01 to .056 mg/kg h a l o p e r i d o l . Kornetsky and E s p o s i t o (1981) found that d e t e c t i o n t h r e s h o l d s f o r LH EBS were i n c r e a s e d a f t e r cocaine i n j e c t i o n s . These t h r e s h o l d s h i f t s were, however, opposite i n d i r e c t i o n from what might be p r e d i c t e d i f the cues were r e l a t e d to the r e l e a s e of DA. Cocaine i n c r e a s e s the presence of DA i n the s y n a p t i c c l e f t ( Iverson & Iverson, 1981) and t h e r e f o r e would be expected to enhance any p r o p e r t i e s of the EBS r e l a t e d to DA a c t i v i t y . In f a c t , Kornetsky and E s p o s i t o (1981) demonstrated that EBS 13 t h r e s h o l d s f o r ICSS were decreased i n the same r a t s f o l l o w i n g cocaine a d m i n i s t r a t i o n . Wheeling and Kornetsky (1984) r e c e n t l y have examined the e f f e c t s of the n e u r o l e p t i c s h a l o p e r i d o l and c l o z a p i n e on EBS d e t e c t i o n t h r e s h o l d s i n r a t s with e l e c t r o d e s i n medial and l a t e r a l p r e - f r o n t a l c o r t e x , the neostriatum, the l a t e r a l p r e o p t i c area, the r e t i c u l a r formation, the p e r i a q u e d u c t a l gray and the brachium of the i n f e r i o r c o l l i c u l u s . They found that low doses of h a l o p e r i d o l (.0125 to .05 mg/kg) e l e v a t e d d e t e c t i o n t h r e s h o l d s i n a l l f o r e b r a i n areas, with the exception of the l a t e r a l f r o n t a l c o r t e x . Higher doses (.075 mg/kg) were r e q u i r e d to produce comparable e f f e c t s with p e r i a q u e d u c t a l gray s t i m u l a t i o n and no changes were observed f o r d e t e c t i o n of r e t i c u l a r or c o l l i c u l a r s t i m u l a t i o n . Clozapine produced the opposite p a t t e r n of r e s u l t s , with lower doses being e f f e c t i v e on brainstem s t i m u l a t i o n , while higher doses were r e q u i r e d to a l t e r t h r e s h o l d s f o r f o r e b r a i n EBS. The mechanisms u n d e r l y i n g the e f f e c t s of c l o z a p i n e on EBS d e t e c t i o n appear to i n v o l v e non-dopaminergic processes, as the s t r o n g e s t e f f e c t s are produced when EBS i s d e l i v e r e d to r e g i o n s c o n t a i n i n g l i t t l e DA i n n e r v a t i o n . In c o n t r a s t , the t h r e s h o l d e l e v a t i n g a c t i o n s of h a l o p e r i d o l appear to i n v o l v e the blockade of DA r e c e p t o r s at the e l e c t r o d e s i t e s . The authors r e p o r t that the time courses f o r the h a l o p e r i d o l e f f e c t s p a r a l l e l those observed with s i n g l e u n i t r e c o r d i n g s from the same r e g i o n s . 14 C o l p a e r t et a l (1977) a l s o have repo r t e d that the cues a s s o c i a t e d with LH EBS are blocked by h a l o p e r i d o l . In t h i s study, r a t s could respond on the a p p r o p r i a t e one of two l e v e r s to o b t a i n water during the l a s t 15 min of d a i l y , 20 min s e s s i o n s . The a p p r o p r i a t e l e v e r was s i g n a l l e d by the presence or absence of EBS throughout the t r i a l . For one group of r a t s , the EBS was d e l i v e r e d at a r a t e of one t r a i n every 10 s. These animals were subsequently t e s t e d f o l l o w i n g subcutaneous i n j e c t i o n s of .02 mg/kg of h a l o p e r i d o l . The second group r e c e i v e d the s t i m u l a t i o n at a r a t e of one t r a i n every 2.5 s, and .04 mg/kg of h a l o p e r i d o l was administered on the t e s t day. A f t e r r e c e i v i n g h a l o p e r i d o l , a l l r a t s i n the f i r s t group responded on the l e v e r a p p r o p r i a t e f o r the n o - s t i m u l a t i o n c o n d i t i o n i n the presence of the EBS. In these r a t s , the EBS cues were presumably blocked by the h a l o p e r i d o l , causing them to respond as i f the s t i m u l a t i o n was absent. In the high frequency group however, only one out of four r a t s responded on the n o - s t i m u l a t i o n l e v e r , d e s p i t e the higher dose of h a l o p e r i d o l . Thus, h a l o p e r i d o l was not as e f f e c t i v e i n b l o c k i n g EBS cues d e l i v e r e d at a higher frequency. In a separate study, C o l p a e r t r e p l i c a t e d the h a l o p e r i d o l e f f e c t using a s i m i l a r procedure. In t h i s experiment, .04 mg/kg of h a l o p e r i d o l i n c r e a s e d the c u r r e n t t h r e s h o l d at which r a t s made responses a p p r o p r i a t e f o r the presence of LH EBS. In a d d i t i o n , and i n c o n t r a s t to Kornetsky and E s p o s i t o (1981), C o l p a e r t a l s o demonstrated a 15 decrease i n d e t e c t i o n t h r e s h o l d s f o l l o w i n g the a d m i n i s t r a -t i o n of 5 mg/kg of co c a i n e . O b j e c t i v e s of the Present Experiment. The r e s u l t s of the s t u d i e s reviewed above suggest that r a t s may respond to m o t i v a t i o n a l l y s i g n i f i c a n t p r o p e r t i e s of a reward stimulus when i t i s d e l i v e r e d as a d i s c r i m i n a t i v e cue. The evidence f o r t h i s i s perhaps s t r o n g e s t i n the case of food d i s c r i m i n a t i o n s ( M a r t i n - I v e r s o n , 1985), where manipulations a f f e c t i n g the i n c e n t i v e value of food r e s u l t i n d i f f e r e n t i a l d i s c r i m i n a t e d responses to the same q u a n t i t y of p e l l e t s . The r e l a t i o n s h i p between the cue and rewarding p r o p e r t i e s of drugs i s l e s s c l e a r . There i s no standard method of manipulating the i n c e n t i v e value of drugs, thus i t i s not p o s s i b l e to compare the e f f e c t s of m o t i v a t i o n a l changes on drug d i s c r i m i n a t i o n and s e l f - a d m i n i s t r a t i o n . However, the evidence f o r anatomical and pharmacological overlap of the s u b s t r a t e s f o r r e i n f o r c i n g and cue p r o p e r t i e s of s t i m u l a n t s , suggests that these c h a r a c t e r i s t i c s of drugs may be a t t r i b u t e d to common n e u r a l and b e h a v i o r a l p r o c e s s e s . At present, there i s only l i m i t e d evidence to suggest that the stimulus p r o p e r t i e s of EBS are r e l a t e d to i t s r e i n f o r c i n g e f f e c t s . A r e l a t i o n s h i p may be i m p l i e d from demonstrations that EBS s t i m u l i are more e a s i l y d i s c r i m i n a t e d when they d i f f e r i n hedonic valence than when they are equated i n t h i s r e s p e c t ( S t u t z , 1968; Stutz et a l , 16 1969). These r e s u l t s i n d i c a t e that rewarding a t t r i b u t e s can provide a b a s i s f o r d i s t i n g u i s h i n g between separate b r a i n -s t i m u l a t i o n cues. Attempts to a l t e r EBS cues with drugs that a f f e c t ICSS, however, have y i e l d e d c o n f l i c t i n g and i n c o n c l u s i v e r e s u l t s . As noted, psychomotor s t i m u l a n t s have been re p o r t e d to i n c r e a s e (Kornetsky & E s p o s i t o , 1981), decrease ( C o l p a e r t , 1977) or have no e f f e c t s (Schaefer & M i c h a e l , 1985) on d e t e c t i o n t h r e s h o l d s f o r LH EBS. In a d d i t i o n , e q u i v a l e n t doses of h a l o p e r i d o l have been shown both to i n c r e a s e t h r e s h o l d s ( C o l p a e r t , 1977; C o l p a e r t et a l , 1977) or have no e f f e c t s (Schaefer & M i c h a e l , 1985) on the d e t e c t i o n of LH EBS. The v a r i a b i l i t y i n the e f f e c t i v e n e s s of s t i m u l a n t and n e u r o l e p t i c drugs on EBS d e t e c t i o n may r e f l e c t h e t e r o g e n e i t y i n the cues e l i c i t e d by LH s t i m u l a t i o n . In the LH, f u n c t i o n a l l y d i v e r s e axonal p r o j e c t i o n s converge to form a c i r c u m s c r i b e d pathway, the medial f o r e b r a i n bundle (MFB), which courses through the b a s a l f o r e b r a i n . S t i m u l a t i o n of t h i s area a c t i v a t e s a v a r i e t y of n e u r a l systems which p o t e n t i a l l y might serve as mediators of b r a i n s t i m u l a t i o n cues. The r e s u l t i n g cue might be a composite of both rewarding and non-rewarding s t i m u l i , with the r e l a t i v e c o n t r i b u t i o n s of each being a f u n c t i o n of the e l e c t r o d e placement. Furthermore, both dopaminergic and non-dopaminergic reward processes are contained w i t h i n the MFB. In f a c t , the reward pathways that are most r e a d i l y a c t i v a t e d 17 by EBS appear to be those o r i g i n a t i n g i n the d i a g o n a l band of Broca and p r o j e c t i n g c a u d a l l y towards the VTA ( G a l l i s t e l , S h i z g a l & Yeomans, 1981; Yeoraans, 1982). Thus, the cue p r o p e r t i e s of EBS i n the LH may be r e l a t e d to the a c t i v a t i o n of reward processes that are independent of the DA neurons. The present study was designed to i n v e s t i g a t e f u r t h e r the e f f e c t s of pharmacological treatments on the d i s c r i m i n a t i o n of EBS e l i c i t e d s t i m u l i to determine whether these cues might be r e l a t e d to the a c t i v a t i o n of reward systems. An attempt was made to l i m i t the h e t e r o g e n e i t y of the cues by i m p l a n t i n g the s t i m u l a t i n g e l e c t r o d e s p o s t e r i o r to the LH, i n the VTA. T h i s e l e c t r o d e placement might allow reward pathways to be e x c i t e d without simultaneous a c t i v a t i o n of processes w i t h i n the MFB. In a d d i t i o n , t h i s r e g i o n c o n t a i n s the c e l l bodies of mesolimbic DA neurons (Fal o n & Moore, 1978), and the rewarding e f f e c t s produced by EBS i n t h i s area are l a r g e l y dependent on the i n t e g r i t y of these c e l l s ( P h i l l i p s & F i b i g e r , 1978). Together, these f a c t o r s might be expected to maximize the l i k e l i h o o d of the stimulus p r o p e r t i e s of the EBS being mediated by reward systems, and i n p a r t i c u l l a r , the DA reward s u b s t r a t e . The c o n t r i b u t i o n of DA reward processes to the EBS cues was assessed by a d m i n i s t e r i n g drugs which i n f l u e n c e the b i n d i n g a c t i v i t y of DA, to r a t s t r a i n e d to d i s c r i m i n a t e d i f f e r e n t i n t e n s i t i e s of VTA s t i m u l a t i o n . In a d d i t i o n , a p o s s i b l e r o l e of non-dopaminergic reward processes was 18 examined. Drugs which a f f e c t a c e t y l c h o l i n e (ACH) t r a n s m i s s i o n were i n j e c t e d f o r t h i s purpose, as recent evidence suggests that ACH neurons may a l s o be i n v o l v e d i n mediating LH and VTA b r a i n s t i m u l a t i o n reward (Gratton & Wise, 1985; Yeomans, Kofman & McFarlane, 1985). I f the EBS cues were mediated by e i t h e r DA or ACH neurons, drugs which i n c r e a s e the r e c e p t o r b i n d i n g of these t r a n s m i t t e r s might p o t e n t i a t e the pe r c e i v e d i n t e n s i t i e s of the s t i m u l a t i o n and thereby cause lower c u r r e n t l e v e l s to be responded to as though they were higher v a l u e s . In c o n t r a s t , a n t a g o n i s t compounds which i n t e r f e r e with t r a n s m i t t e r b i n d i n g might block the EBS cues and cause the animals to respond to high i n t e n s i t i e s as though they were lower. Evidence f o r modulation of stimulus p r o p e r t i e s of EBS by compounds i n f l u e n c i n g DA and/or ACH t r a n s m i s s i o n would suggest a p o s s i b l e c o n t r i b u t i o n of reward processes to the complex of ne u r a l events c o n s t i t u t i n g the VTA EBS cue. A c c o r d i n g l y , the d i s c r i m i n a t i o n procedure may provide a measure f o r a s s e s s i n g the e f f e c t s of d i f f e r e n t compounds on b r a i n s t i m u l a t i o n reward obtained from the VTA. 19 GENERAL METHODS Subjects The s u b j e c t s were male hooded r a t s ( C h a r l e s R i v e r , Long Evans s t r a i n ) weighing 300 to 350 gms at the time of surgery. Throughout the experiment, the animals were housed i n d i v i d u a l l y i n s t a i n l e s s s t e e l cages with tap water a v a i l a b l e a_d l i b i t u m . A l i m i t e d amount of food was given at the end of each day (at approximately the s t a r t of the dark c y c l e ) to maintain the animals at 90% of t h e i r pre-experimental body weights. A 12 hr l i g h t / d a r k c y c l e was maintained i n the animal colony. Surgery The r a t s were a n e s t h e t i z e d with 65 mg/kg sodium p e n t o b a r b i t a l , and b i p o l a r e l e c t r o d e s ( P l a s t i c Products MS303/2) were implanted s t e r e o t a x i c a l l y i n the VTA. With the nose-bar set at -3.2 mm below the i n t e r - a u r a l l i n e , the co o r d i n a t e s from s t e r e o t a x i c zero were: A.P. = +2.8 mm; L. = -0.6 mm; D.V. = +2.1 mm. The e l e c t r o d e s were anchored to the s k u l l with jewelers screws and d e n t a l cement. Apparatus The animals were t e s t e d i n s i x separate chambers (24 X 29 X 30 cm), each having P l e x i g l a s w a l l s and c e i l i n g , and a wire g r i d f l o o r . S l o t s were cut i n each of the end w a l l s so 20 that a l e v e r (4.5 x 7 cm) could be mounted 3.5 cm above the f l o o r on opposite s i d e s of every chamber. A 28 v o l t h o u s e - l i g h t was s t a t i o n e d e x t e r n a l to each chamber at the center of a t h i r d w a l l , with a food-hopper p o s i t i o n e d d i r e c t l y below i t (3 cm above the f l o o r ) . Each chamber was contained w i t h i n a sound a t t e n u a t i n g enclosure (55 X 55 X 60 cm), and fans were turned on to block extraneous n o i s e . During a l l s e l f - s t i m u l a t i o n s e s i o n s i l l u m i n a t i o n was provided by f l o r e s c e n t l i g h t s attached to the c e i l i n g s of the outer e n c l o s u r e s . Otherwise, the i l l u m i n a t i o n was c o n t r o l e d by the 28 V h o u s e l i g h t s as i n d i c a t e d below. The e l e c t r o d e leads ( P l a s t i c Products 303-302) hung through an opening i n the c e i l i n g of each chamber, suspended from Mercotac commutators which were s t a t i o n e d above. Constant c u r r e n t s t i m u l a t i o n was d e l i v e r e d to the r a t s by a 10 channel, programmable sine-wave s t i m u l a t o r . A Data General Nova 3 computer was used to c o n t r o l the experimental events and r e c o r d responses by the r a t s . S t i m u l a t i o n c u r r e n t s were monitered c o n t i n u o u s l y on a Telequipment D54R o s c i l l o s c o p e . Procedure A f t e r one week recovery from surgery, the animals were t r a i n e d to l e v e r - p r e s s to r e c e i v e 200 ms t r a i n s of 60 Hz sine wave EBS on a continuous reinforcement (CRF) schedule. F i v e d a i l y 1/2 hr s e s s i o n s of CRF responding were given with the c u r r e n t i n t e n s i t y set at 20 uA to determine the 21 r e i n f o r c i n g e f f i c a c y of the EBS. F o l l o w i n g t h i s phase of the experiment the animals were food deprived to 90 % of t h e i r f r e e - f e e d i n g weight and then given 7 to 11 ICSS s e s s i o n s wherein t h e i r response r a t e s were measured over a range of i n t e n s i t i e s . The c u r r e n t i n t e n s i t y was set at 6 uA at the s t a r t of each s e s s i o n , and subsequently i n c r e a s e d by 2uA every 5 min. When an i n t e n s i t y of 26 uA was reached, the same range of c u r r e n t s was again d e l i v e r e d i n a decreasing order of p r e s e n t a t i o n , with the i n t e n s i t y being lowered by 2uA every 5 min down to a l e v e l of 6 uA. Each change i n the c u r r e n t l e v e l was s i g n a l l e d by the f r e e d e l i v e r y of 10 s t i m u l a t i o n t r a i n s (2 t r a i n s / s) at the new i n t e n s i t y . The ascending and descending r a t e - i n t e n s i t y f u n c t i o n s measured over the f i n a l 4 days of t h i s phase were averaged to o b t a i n a s i n g l e f u n c t i o n r e l a t i n g response r a t e to c u r r e n t i n t e n s i t y . From t h i s f u n c t i o n , one low c u r r e n t i n t e n s i t y (8 to 12 uA) and one high i n t e n s i t y (10 uA higher than the low i n t e n s i t y ) were chosen f o r use as d i s c r i m i n a t i v e s t i m u l i . Both i n t e n s i t i e s were s e l e c t e d from w i t h i n the range of c u r r e n t s over which the r a t s showed changes i n b a r - p r e s s i n g r a t e s with changes i n the EBS i n t e n s i t y . S e l e c t i o n of the d i s c r i m i n a t i v e s t i m u l i i n t h i s manner ensured that the i n t e n s i t i e s could be d i f f e r e n t i a t e d , at l e a s t with r e s p e c t to t h e i r rewarding p r o p e r t i e s . A f t e r the s e l f - s t i m u l a t i o n phase, a l l r a t s were t r a i n e d to bar-press to r e c e i v e a 45 mg Noyes food p e l l e t a f t e r each 22 response. T h i s t r a i n i n g occurred during 30 min s e s s i o n s conducted on two c o n s e c u t i v e days. During l e v e r - p r e s s t r a i n i n g f o r both food and b r a i n s t i m u l a t i o n , only one l e v e r was i n s e r t e d i n t o the chamber. The s i d e on which i t was placed was a l t e r n a t e d d a i l y to prevent development of a s i d e p r e f e r e n c e . During i n i t i a l d i s c r i m i n a t i o n t r a i n i n g , a l l r a t s r e c e i v e d d a i l y s e s s i o n s c o n s i s t i n g of 90 d i s c r i m i n a t i o n t r i a l s given 15 to 25 s apart ( v a r i a b l e i n t e r - t r i a l i n t e r v a l with an average of 20 s ) . Each t r i a l was s i g n a l l e d by a b r i e f (.05 s) f l a s h of the house l i g h t f o l l o wed 1 s l a t e r by d e l i v e r y of four 200 ms t r a i n s of e i t h e r high or low i n t e n s i t y EBS. The i n t e r - t r a i n i n t e r v a l f o r the EBS was 200 ms and the t o t a l d u r a t i o n of cue p r e s e n t a t i o n was 1400 ms. A f t e r a f u r t h e r 1 s delay, the house l i g h t was turned on and the next response made w i t h i n a 10 s p e r i o d was recorded and r e s u l t e d i n one of two p o s s i b l e consequences: responses on the l e v e r a p p r o p r i a t e f o r the cue on that t r i a l r e s u l t e d i n the d e l i v e r y of one 45 mg Noyes food p e l l e t and t e r m i n a t i o n of the t r i a l (the house l i g h t was turned o f f and the l e v e r i n a c t i v a t e d ) , whereas responses on the i n a p p r o r i a t e l e v e r r e s u l t e d i n non-rewarded c e s s a t i o n of the t r i a l . The l e v e r a p p r o p r i a t e f o r each c u r r e n t i n t e n s i t y was counterbalanced among r a t s . I f a r a t d i d not respond w i t h i n 10 s on any t r i a l , the house l i g h t was turned o f f and the i n t e r - t r i a l i n t e r v a l was s t a r t e d . During the f i r s t f i v e 23 t r a i n i n g s e s s i o n s , a l l c o r r e c t responses were rewarded. I n c o r r e c t responses i n i t i a t e d a f u r t h e r 10 s p e r i o d i n which the r a t s could respond a p p r o p r i a t e l y and r e c e i v e the food reward. In subsequent s e s s i o n s , i n c o r r e c t responses r e s u l t e d i n t e r m i n a t i o n of the t r i a l without reward. When the r a t s were responding with a high r a t e of accuracy, only 75% of c o r r e c t responses were r e i n f o r c e d . Responses during the i n t e r t r i a l i n t e r v a l were recorded s e p a r a t e l y f o r each l e v e r , but had no programmed consequence. H i s t o l o g y Upon completion of the experiment, a l l animals were k i l l e d with an overdose of sodium p e n t o b a r b i t a l and perfused t r a n s c a r d i a l l y with 0.9 % s a l i n e followed by 10 % f o r m o l -s a l i n e . The b r a i n s were removed and s t o r e d f o r at l e a s t one week i n 10 % f o r m o l - s a l i n e before being f r o z e n and s l i c e d i n 30 um s e c t i o n s and s t a i n e d with c r e s y l - v i o l e t f o r v e r i f i c a t i o n of e l e c t r o d e placements. 24 EXPERIMENT 1 D i s c r i m i n a t i o n and g e n e r a l i z a t i o n of d i f f e r e n t i n t e n s i t i e s of EBS: Changes i n the response g r a d i e n t a s s o c i a t e d with s h i f t s i n the a b s o l u t e i n t e n s i t y range Previous attempts to evaluate the e f f e c t s of drugs on the cue p r o p e r t i e s of EBS have i n v o l v e d measurements of the c u r r e n t t h r e s h o l d f o r EBS d e t e c t i o n i n r a t s t r a i n e d to d i s c r i m i n a t e the presence of an EBS cue from i t s absence. (Colpaert,1977; C o l p a e r t et a l , 1977; Kornetsky & E s p o s i t o , 1981; Schaefer & M i c h a e l , 1985; Wheeling & Kornetsky, 1984). T h i s t h r e s h o l d measure i s presumably an index of the e x c i t a b i l i t y of the n e u r a l processes mediating the s t i m u l a t i o n cues (Wheeling & Kornetsky, 1977). I t i s u n c e r t a i n , however, whether the t h r e s h o l d s being measured are those of the more s a l i e n t a t t r i b u t e s of the EBS, such as reward, or of the l o w e s t - t h r e s h o l d component of the cues. With regard to the l a t t e r p o s s i b i l i t y , i t i s noteworthy that c u r r e n t t h r e s h o l d s f o r cue d e t e c t i o n of LH EBS have been re p o r t e d to be s u b s t a n t i a l l y lower than those measured f o r ICSS through the same e l e c t r o d e (Kornetsky and E s p o s i t o , 1981). I f d e t e c t i o n procedures were s e l e c t i v e l y measuring only the most e x c i t a b l e of the processes mediating EBS cues, then they may not be a p p r o p r i a t e f o r i n v e s t i g a t i n g reward s t i m u l i . Reward s t i m u l i might only be measurable when they c o n s t i t u t e d the most e x c i t a b l e sensory processes i n the area 25 surrounding the e l e c t r o d e t i p . T h i s problem was circumvented i n the present study, by t r a i n i n g r a t s to d i s c r i m i n a t e between two EBS i n t e n s i t i e s that supported d i f f e r e n t ICSS r a t e s . F o l l o w i n g the d e l i v e r y of each i n t e n s i t y the r a t s were r e q u i r e d to perform the a p p r o p r i a t e one of two p o s s i b l e responses to o b t a i n food r e i n f o r c e m e n t . The processes mediating the d i s c r i m i n a t i v e s t i m u l i e l l i c i t e d by the EBS would n e c e s s a r i l y be those that were a c t i v a t e d to d i f f e r e n t degrees by the t r a i n i n g i n t e n s i t i e s . Reward processes would meet t h i s c r i t e r i o n , as the t r a i n i n g i n t e n s i t i e s were s e l e c t e d f o r t h e i r a b i l i t y to be d i f f e r e n t i a t e d with res p e c t to t h e i r rewarding p r o p e r t i e s . As an a l t e r n a t i v e to measuring the EBS d e t e c t i o n t h r e s h o l d s , d i s c r i m i n a t e d responding to i n t e r m e d i a t e i n t e n s i t i e s was assessed during g e n e r a l i z a t i o n t e s t s . I t was a n t i c i p a t e d that response s e l e c t i o n would be i n c o n s i s t a n t a f t e r the d e l i v e r y of these c u r r e n t s , due to t h e i r s i m i l a r i t y to both t r a i n i n g i n t e n s i t i e s . Subsequent manipulations that r e s u l t e d i n these i n t e r m e d i a t e c u r r e n t s being p e r c e i v e d as more s i m i l a r to one of the t r a i n i n g i n t e n s i t i e s would be expected to b i a s the response s e l e c t i o n a c c o r d i n g l y . In Experiment one, the r e l i a b i l i t y of t h i s d i s c r i m i n a t i o n procedure was assessed. F i r s t , the r a t s were given a number of b a s e l i n e g e n e r a l i z a t i o n t e s t s to determine 26 the s t a b i l i t y of responding with c o n d i t i o n s kept constant across t e s t s e s s i o n s . Second, the animals were given g e n e r a l i z a t i o n t e s t s i n which they r e c e i v e d e i t h e r a higher or a lower range of i n t e n s i t i e s than u s u a l . T h i s procedure was conducted to simulate the e f f e c t s that would be produced by drugs which a l t e r e d the p e r c e i v e d i n t e n s i t i e s of the EBS cues. I f the response s e l e c t i o n was a d i r e c t f u n c t i o n of the i n t e n s i t y of each cue, then t h i s manipulation should r e s u l t i n a d i r e c t i o n a l b i a s i n g of the reponses toward one of the l e v e r s . Such a r e s u l t would v e r i f y the s e n s i t i v i t y of the procedure f o r d e t e c t i n g a l t e r a t i o n s i n the cue p r o p e r t i e s of VTA b r a i n s t i m u l a t i o n . Methods Si x t e e n animals were given d i s c r i m i n a t i o n t r a i n i n g as o u t l i n e d i n the General Methods. Ten of the r a t s a c q u i r e d the d i s c r i m i n a t i o n and were subsequently t e s t e d f o r stimulus g e n e r a l i z a t i o n between the two t r a i n i n g i n t e n s i t i e s . During these t e s t s the r a t s r e c e i v e d 100 t r i a l s , with four e q u a l l y spaced i n t e r m e d i a t e c u r r e n t l e v e l s (2 uA apart) being randomly d e l i v e r e d on twenty of them. Responses made f o l l o w i n g i n t e r m e d i a t e i n t e n s i t i e s were not r e i n f o r c e d , and only r e s u l t e d i n t e r m i n a t i o n of the t r i a l . To maintain a s i m i l a r o v e r a l l r a t e of reinforcement as on t r a i n i n g days, responses to the two t r a i n i n g c u r r e n t s were rewarded on 85% of the t r i a l s . Three b a s e l i n e s e s s i o n s were run i n t h i s 27 manner, a l t e r n a t e d with r e g u l a r t r a i n i n g days. E i g h t of these animals were subsequently given four more g e n e r a l i z a t i o n s e s s i o n s , with a d i f f e r e n t i n t e n s i t y range being d e l i v e r e d during each t e s t . The new ranges were s i m i l a r , i n most r e s p e c t s , to those r e c e i v e d during b a s e l i n e t e s t s . However, the absolute i n t e n s i t i e s presented were unifo r m l y s h i f t e d up or down by e i t h e r 2 or 4 uA. These t e s t s were given on every t h i r d day with the usual t r a i n i n g s e s s i o n s being run on the i n t e r v e n i n g days. A l l s u b j e c t s r e c e i v e d each of the four p o s s i b l e i n t e n s i t y ranges, and the order i n which the t e s t s were given was counterbalanced among animals. Three days a f t e r the f o u r t h t r a n s f e r t e s t , a l l animals were given a b a s e l i n e g e n e r a l i z a t i o n s e s s i o n with the standard range of i n t e n s i t i e s . R e s u l t s The 10 animals that l e a r n e d the d i s c r i m i n a t i o n achieved an accuracy r a t e of over 80% c o r r e c t c h o i c e s per s e s s i o n . In these animals, the task was a c q u i r e d w i t h i n 2 to 4 wks of t r a i n i n g , and performance remained s t a b l e t h e r e a f t e r throughout the experiment. The e l e c t r o d e placements f o r these r a t s are shown i n F i g u r e 1. The other s i x animals developed i n a p p r o p r i a t e response b i a s e s which i n t e r f e r e d with the a c q u i s i t i o n , thus they were e l i m i n a t e d from the study. The average g e n e r a l i z a t i o n f u n c t i o n s f o r the three 28 Figu r e 1: E l e c t r o d e placements f o r the 10 r a t s used i n the present study. The black c i r c l e s r epresent the locu s of the e l e c t r o d e t i p . The numbers to the r i g h t of the diagrams represent the p l a t e numbers corresponding to these c o r o n a l s e c t i o n s found i n the b r a i n a t l a s of Konig and K l i p p e l (1963). The m a j o r i t y of the e l e c t r o d e s were placed i n the p o s t e r i o r VTA, d o r s a l to the in t e r p e n d u n c u l a r nucleus w i t h i n the d e c u s s a t i o n of the v e n t r a l tegmentum. Some e l e c t r o d e s were d i r e c t l y adjacent the red nucleus, and thus may have s t i m u l a t e d t h i s s t u c t u r e . 29 1 950 1 760 1 61 0 30 i n i t i a l b a s e l i n e days are shown i n F i g u r e 2. For c l a r i t y , the data are expressed as the percentage of responses to each c u r r e n t l e v e l that were made on the l e v e r a p p r o p r i a t e f o r the h i g h - i n t e n s i t y s t i m u l a t i o n (HS). As i s evident i n the f i g u r e , the tendancy f o r the animals to respond on the HS l e v e r i n c r e a s e d as a f u n c t i o n of i n c r e a s i n g c u r r e n t l e v e l (F(5,45) = 72.27; p < .0001). There was not a s i g n i f i c a n t e f f e c t of days (F(2,18) = 1.96; p > .05), nor was there an i n t e r a c t i o n of days with c u r r e n t l e v e l (F(10,80) = .56; p > .05). Thus the g e n e r a l i z a t i o n f u n c t i o n s remained s t a b l e with repeated t e s t i n g . The r e s u l t s of the i n t e n s i t y range manipulations are shown i n F i g u r e 3. An a n a l y s i s comparing HS responses during the four t r a n s f e r t e s t s and the p o s t - t r a n s f e r b a s e l i n e t e s t r e v e a l e d s i g n i f i c a n t d i f f e r e n c e s between HS responding on the separate days (F(4,28) = 16.96; p < .0001). Post-hoc comparisons using Newman-Keul's t e s t i n d i c a t e d that s h i f t i n g the c u r r e n t range down by both 2 and 4 uA (-2S and -4S c o n d i t i o n s , r e s p e c t i v e l y ) r e s u l t e d i n s i g n i f i c a n t l y l e s s o v e r a l l responses on the HS l e v e r (p < .05). By c o n t r a s t , s h i f t i n g the c u r r e n t range up by 4uA (+4S) r e s u l t e d i n more responding on the HS l e v e r (p < .05). S h i f t i n g the range up by 2 uA (+2S) produced an observable i n c r e a s e i n responses toward the HS l e v e r , but the change was not s i g n i f i c a n t (p > .05) The a n a l y s i s a l s o r e v e a l e d an i n t e r a c t i o n e f f e c t , 31 ure 2: B a s e l i n e response f u n c t i o n s f o r EBS g e n e r a l i z a -t i o n measured during three separate s e s s i o n s . The data are expressed i n terms of the percent of the responses emitted a f t e r the d e l i v e r y of each i n t e n s i t y l e v e l t h a t are made on the HS l e v e r . 32 33 ure 3: Response f u n c t i o n s f o r EBS g e n e r a l i z a t i o n measured during t e s t s with d i f f e r e n t i n t e n s i t y ranges. A) Tests with the i n t e n s i t y range s h i f t e d upwards by 2 uA (+2S), 4 uA (+4S) or 0 uA ( b a s e l i n e ) . B) Tes t s with the i n t e n s i t y ranges s h i f t e d down by 2 uA (-2S), k uA (-4S) or 0 uA ( b a s e l i n e ) . The b a s e l i n e curves i n A and B represent the same data taken from a s i n g l e g e n e r a l -i z a t i o n s e s s i o n . A. HIGHER RANGES B. LOWER RANGES T i i i i 1 "1 1 n 1 1 r 1 2 3 4 5 6 1 2 3 4 5 INTENSITY LEVEL 35 whereby the changes i n HS responding were manifest at d i f f e r e n t p o s i t i o n s of the g e n e r a l i z a t i o n g r a d i e n t , depending on whether the range was s h i f t e d up or down (F(20,140) = 3.90; p < .0001). T h i s i n t e r a c t i o n was due to the presence of f l o o r and c e i l i n g e f f e c t s i n h e r e n t i n the d i s c r i m i n a t i o n task. S h i f t i n g the c u r r e n t range up by 4 uA i n c r e a s e d HS responding at lower p o s i t i o n s i n the g r a d i e n t , but not at higher p o s i t i o n s where the amount of HS responding was already near maximal. S h i f t i n g the range down, on the other hand, decreased HS responses only at higher p o s i t i o n s along the g r a d i e n t , as HS responses at lower p o s i t i o n s were alr e a d y minimal. The s h i f t s i n the g e n e r a l i z a t i o n f u n c t i o n s evident i n Fig u r e 2 are due to a tendancy f o r the animals to e x h i b i t r e l a t i v e l y c o n s i s t e n t l e v e r s e l e c t i o n tendancies f o l l o w i n g a s p e c i f i c i n t e n s i t y , r e g a r d l e s s of the t e s t c o n d i t i o n s . To assess t h i s c o n s i s t e n c y , separate analyses were performed wherein: 1) responses to the four c u r r e n t s d e l i v e r e d during each of the b a s e l i n e , -2S and -4S c o n d i t i o n s were compared (F i g u r e 4a); and 2) responses to the 4 i n t e n s i t i e s o c c u r r i n g i n each of the b a s e l i n e , +2S and +4S c o n d i t i o n s were compared ( F i g u r e 4b). The a n a l y s i s i n d i c a t e d that responses to each c u r r e n t were not s i g n i f i c a n t l y d i f f e r e n t when the cu r r e n t ranges were s h i f t e d down r e l a t i v e to b a s e l i n e by 2 or 4 uA (F(2,14) = 2.13; p > .05). By c o n t r a s t , there was a s i g n i f i c a n t d i f f e r e n c e when b a s e l i n e responses were compared 36 F i g u r e 4: Measurement of response s e l e c t i o n b i a s e s to f i x e d i n t e n s i t i e s during t e s t s with d i f f e r e n t i n t e n s i t y ranges. A) Responses to the same i n t e n s i t i e s during s e s s i o n s with the c u r r e n t range s h i f t e d up by 2 uA (+2S), 4 uA (+4S) or 0 uA ( b a s e l i n e ) . B) Responses to the same i n t e n s i t i e s during t e s t s with the c u r r e n t ranges s h i f t e d down by 2 uA (-2S), 4 uA (-4S) or 0 uA ( b a s e l i n e ) . Because the absolute i n t e n s i t i e s w i t h i n a range v a r i e d between animals, the average i n t e n s i t y i s presented as the independent v a r i a b l e . The i n t e n s i t i e s presented i n A and B are those that were common to the OS, +2S and +4S ranges and to the OS, -2S and -4S ranges, r e s p e c t i v e l y . The b a s e l i n e curves represent data taken from opposite o v e r l a p p i n g extremes of the same g e n e r a l i z a t i o n f u n c t i o n . AVERAGE CURRENT INTENSITY (uA) 38 with those made to the same i n t e n s i t i e s w i t h i n the +2S and +4S c o n d i t i o n s (F(2,14) = 10.45; p < .002). Post-hoc comparisons r e v e a l e d that the percentage of HS l e v e r s e l e c t i o n s f o l l o w i n g the same i n t e n s i t i e s was reduced r e l a t i v e to b a s e l i n e when the range was s h i f t e d up by both 2 and 4 uA (Newraan-Keul's t e s t , p < .05). Al s o , fewer responses were made a f t e r these i n t e n s i t i e s during the +4S c o n d i t i o n than when the range was s h i f t e d up by only 2 uA (Newman-Keul's t e s t , p < .05). Thus, the magnidude of the change i n responding to f i x e d i n t e n s i t i e s was grea t e r with l a r g e r s h i f t s i n the c u r r e n t range. 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 that i n t e n s i t i e s of VTA b r a i n s t i m u l a t i o n which support d i f f e r e n t ICSS r a t e s can be d i s c r i m i n a t e d e a s i l y when employed as d i s c r i m i n a t i v e cues i n r a t s . During g e n e r a l i z a t i o n t e s t s , the r a t s tended to respond on the l e v e r a p p r o p r i a t e f o r low EBS l e v e l s f o l l o w i n g the lowest two i n t e n s i t i e s . Responses were made predominantly on the HS l e v e r a f t e r the highest two c u r r e n t s . As expected, responses a f t e r the two most in t e r m e d i a t e c u r r e n t s were i n c o n s i s t e n t w i t h i n s e s s i o n s , and d i r e c t e d towards both l e v e r s . More HS responses were made a f t e r the higher of the two i n t e n s i t i e s (Newman-Keul's, p < .05), however, suggesting that the response s e l e c t i o n was a monotonic f u n c t i o n of i n c r e a s i n g i n t e n s i t y . 39 The g e n e r a l i z a t i o n g r a d i e n t s remained remarkably s t a b l e d u r i n g three s eparate t e s t s i n which c o n d i t i o n s were kept c o n s t a n t . Of p a r t i c u l a r importance i s the f a c t that responses to the two most i n t e r m e d i a t e i n t e n s i t i e s remained c o n s i s t e n t a c r o s s s e s s i o n s . As noted p r e v i o u s l y , the responses to these c u r r e n t s would be expected to p r o v i d e the most s e n s i t i v e index of p h a r m a c o l o g i c a l modula t ion of the EBS c u e s . The l i m i t e d v a r i a t i o n i n l e v e r s e l e c t i o n , combined wi th the monotonic r e l a t i o n s h i p of the HS re spond ing to the c u r r e n t l e v e l at these i n t e n s i t i e s , suggests tha t the a n i m a l s ' responses are under r e l a t i v e l y p r e c i s e s t i m u l u s c o n t r o l . M a n i p u l a t i o n s which a l t e r the p e r c e i v e d magnitude of these cues would thus be expected to produce o b s e r v a b l e changes i n r e s p o n d i n g r e l a t i v e to b a s e l i n e . T h i s e x p e c t a t i o n was conf irmed d u r i n g g e n e r a l i z a t i o n t e s t s w i th d i f f e r e n t i n t e n s i t y r a n g e s . In these t e s t s , s i x c u r r e n t l e v e l s were d e l i v e r e d as u s u a l , but the a b s o l u t e i n t e n s i t i e s were e i t h e r h i g h e r or lower than d u r i n g b a s e l i n e s e s s i o n s . T h i s m a n i p u l a t i o n was in tended to mimick the c o n d i t i o n s t h a t might be produced by drugs t h a t modulate the p e r c e i v e d i n t e n s i t i e s of the EBS c u e s . When the r a t s were t e s t e d wi th lower c u r r e n t s than u s u a l , they tended to make p r o p o r t i o n a t e l y l e s s HS responses w i t h i n the s e s s i o n than d u r i n g b a s e l i n e . Dur ing t e s t s w i th the c u r r e n t range s h i f t e d upwards by 4 uA, the r a t s s e l e c t e d the HS l e v e r more o f t e n than d u r i n g b a s e l i n e s e s s i o n s . There was a l s o an o b s e r v a b l e , 40 but n o n - s i g n i f i c a n t , i n c r e a s e i n the s e l e c t i o n of the HS l e v e r when the range was s h i f t e d up by 2 uA. These r e s u l t s i n d i c a t e that the g e n e r a l i z a t i o n procedure employed i n the present study provides a s e n s i t i v e measure of changes i n the d i s c r i m i n a t i v e stimulus p r o p e r t i e s of EBS produced by manipulation of the cue i n t e n s i t i e s . In t h i s experiment, the cues were p h y s i c a l l y a l t e r e d by d e l i v e r i n g d i f f e r e n t ranges of EBS i n t e n s i t i e s . The o v e r a l l l e v e r s e l e c t i o n tendancies were observed to s h i f t i n the d i r e c t i o n a p p r o p r i a t e f o r the stimulus change. On the b a s i s of t h i s r e s u l t , i t would be p r e d i c t e d that drugs which s i m i l a r l y enhance or reduce the impact of the EBS cues w i l l a l s o r e s u l t i n comparable s h i f t s i n the l e v e r s e l e c t i o n t e n d a n c i e s . In c o n t r a s t , the absence of change i n the g e n e r a l i z a t i o n g r a d i e n t s f o l l o w i n g i n j e c t i o n s of a compound might reasonably r e f l e c t the l a c k of an e f f e c t of the drug on the cue p r o p e r t i e s of VTA b r a i n s t i m u l a t i o n . Comparison of l e v e r s e l e c t i o n tendancies f o l l o w i n g the d e l i v e r y of the same i n t e n s i t i e s w i t h i n d i f f e r e n t ranges i n d i c a t e d a source of p o s s i b l e confound i n the measure. The percentage of HS l e v e r s e l e c t i o n s a f t e r the same i n t e n s i t i e s during the +2S and +4s c o n d i t i o n s were s i g n i f i c a n t l y lower than during b a s e l i n e s e s s i o n s . T h i s i n c o n s i s t a n c y i s i n sharp c o n t r a s t to the r e l i a b i l i t y of response s e l e c t i o n with c o n d i t i o n s kept constant. I t appears that the presence of higher i n t e n s i t i e s w i t h i n the range of c u r r e n t s i n f l u e n c e s 41 the manner i n which the r a t s respond to each i n t e n s i t y . The animals may l e a r n to compare i n t e n s i t i e s across t r i a l s , and d i s c r i m i n a t e the r e l a t i v e d i f f e r e n c e s between them. When gr e a t e r i n t e n s i t i e s are d e l i v e r e d w i t h i n a s e s s i o n , t h i s may r e s u l t i n a higher r e f e r e n c e po i n t being e s t a b l i s h e d f o r the i n t e r - s t i m u l u s comparisons. A f i x e d i n t e n s i t y might then be per c e i v e d as much lower r e l a t i v e to t h i s t h i s new r e f e r e n c e c u r r e n t , and the tendancy to s e l e c t the HS l e v e r would be reduced a c c o r d i n g l y . An a l t e r n a t i v e e x p l a n a t i o n f o r t h i s e f f e c t i s that negative c o n t r a s t e f f e c t s are produced when higher i n t e n s i t i e s are d e l i v e r e d . These e f f e c t s may co n c e i v a b l y reduce the p e r c e i v e d i n t e n s i t i e s of each EBS cue r e s u l t i n g i n responses s e l e c t i o n being l e s s biased towards the HS l e v e r . The changes i n the response to f i x e d i n t e n s i t i e s observed with higher c u r r e n t ranges were not evident when the range was s h i f t e d downwards. The response s e l e c t i o n a f t e r cue d e l i v e r y was s i m i l a r at the same i n t e n s i t i e s i n each of the b a s e l i n e , -2S and -4S c o n d i t i o n s . The absence of changes i n responses to the same i n t e n s i t i e s during these s e s s i o n s may have r e s u l t e d from the lower c u r r e n t s being c l o s e to the cue t h r e s h o l d . Lowering the range of c u r r e n t s might not have r e s u l t e d i n a p p r e c i a b l y lower i n t e n s i t i e s being i n c l u d e d i n the range. Thus, the op p o r t u n i t y was not presented f o r e i t h e r a new r e f e r e n c e po i n t to be s e t , or f o r p o s i t i v e c o n t r a s t e f f e c t s to occur. 42 EXPERIMENT 2 Comparison of amphetamine and h a l o p e r i d o l e f f e c t s on ICSS and EBS d i s c r i m i n a t i o n The p revious experiment demonstrated the r e l i a b i l i t y of our d i s c r i m i n a t i o n procedure as a measure of EBS cue p r o p e r t i e s . The g e n e r a l i z e d responding of the animals remained s t a b l e during separate t e s t s with c o n d i t i o n s kept constant, and s h i f t e d a p p r o p r i a t e l y across s e s s i o n s when the abso l u t e p h y s i c a l i n t e n s i t i e s d e l i v e r e d were v a r i e d . These r e s u l t s i n d i c a t e that the paridigm should be s e n s i t i v e f o r d e t e c t i n g p h a r m a c o l o g i c a l l y induced changes i n the pe r c e i v e d i n t e n s i t i e s of the cues. Moreover, the remarkable s t a b i l i t y of the l e v e r s e l e c t i o n s a c r o s s s e s s i o n s l i m i t s the p o s s i b i l i t y that observed changes could be a r e s u l t of random v a r i a t i o n . The e l e c t r o d e placements and s t i m u l a t i o n parameters f o r the present study were chosen to i n c r e a s e the p r o b a b i l i t y that reward s u b s t r a t e s would be a c t i v a t e d by the EBS and thereby c o n s t i t u t e a s a l i e n t component of the d i s c r i m i n a t i v e s t i m u l i . To assess whether these methodological v a r i a b l e s produced t h i s r e s u l t , d i s c r i m i n a t e d responding was measured f o l l o w i n g i n j e c t i o n s of drugs known to a f f e c t ICSS. I f both response s e l e c t i o n and ICSS were a l t e r e d s i m i l a r l y by the same drugs, i t could be i n f e r r e d that the cue and r e i n f o r c i n g p r o p e r t i e s of the EBS share a 43 common s u b s t r a t e . D i f f e r e n t i a l drug e f f e c t s on d i s c r i m i n a n t and i n c e n t i v e responding would suggest a d i s s o c i a t i o n between the cue and reward p r o p e r t i e s of the EBS. The present experiment was designed to determine whether drugs which a l t e r DA t r a n s m i s s i o n would a f f e c t the stimulus values measured by t h i s d i s c r i m i n a t i o n procedure. As mentioned p r e v i o u s l y , mesolimbic DA neurons o r i g i n a t i n g i n the VTA mediate some aspect of the r e i n f o r c i n g p r o p e r t i e s of EBS d e l i v e r e d to a v a r i e t y of b r a i n s i t e s . I f the r a t s d i s c r i m i n a t e d the rewarding p r o p e r t i e s of the EBS, such drugs might i n f l u e n c e the l e v e r s e l e c t i o n tendancies at doses which a l t e r ICSS t h r e s h o l d s . For t h i s purpose, r a t s were i n j e c t e d with e i t h e r d-amphetamine or h a l o p e r i d o l before being given g e n e r a l i z a t i o n t e s t s . Amphetamine i n c r e a s e s s y n a p t i c c o n c e n t r a t i o n s of DA by i n c r e a s i n g r e l e a s e and i n t e r f e r i n g with i t s reuptake i n t o the synapse, and thus i n c r e a s e s the presence of DA at r e c e p t o r s i t e s ( I v e r s e n & Iversen, 1981). T h i s drug r e l i a b l y decreases ICSS t h r e s h o l d s ( Z a r e v i c s & S e t l e r , 1979), presumably by enhancing the impact of the s t i m u l a t i o n on reward systems (Wise, 1981). A c c o r d i n g l y , amphetamine would be expected to i n c r e a s e responses on the HS l e v e r during a g e n e r a l i z a t i o n t e s t i f DA neurons were mediating the EBS cues. H a l o p e r i d o l blocks DA r e c e p t o r s and consequently i n c r e a s e s ICSS t h r e s h o l d s (Schaefer & Holtzman, 1979). I f the EBS d i s c r i m i n a t i o n were mediated by a DA s u b s t r a t e , h a l o p e r i d o l 44 should block these cues and r e s u l t i n fewer HS responses. A second purpose of t h i s experiment was to determine whether the EBS r e t a i n e d i t s rewarding p r o p e r t i e s , and was a f f e c t e d by these drugs i n the p r e d i c t e d manner, when i t was d e l i v e r e d at the r e l a t i v e l y long i n t e r v a l s employed i n the d i s c r i m i n a t i o n procedure. The i n t e n s i t i e s used i n the present i n v e s t i g a t i o n were shown to support ICSS when the r a t s responded on a CRF schedule of reinforcement. However, the r e i n f o r c i n g e f f i c a c y of the s t i m u l a t i o n may not be the same when i t i s d e l i v e r e d at an average r a t e of four pulses every twenty seconds. To determine t h i s , the r a t s were t r a i n e d to s e l f - s t i m u l a t e f o r EBS rewards that were made a v a i l a b l e on the same schedule as i n the d i s c r i m i n a t i o n procedures. The e f f e c t s of the same doses of amphetamine and h a l o p e r i d o l used during the g e n e r a l i z a t i o n t e s t s were then measured to assess t h e i r a b i l i t y to a l t e r the t h r e s h o l d s f o r i n t e r m i t t e n t l y d e l i v e r e d EBS reward. Method Six of the 10 animals used i n experiment 1 were given g e n e r a l i z a t i o n t e s t s a f t e r r e c e i v i n g two separate doses of both d-amphetamine sulphate (1.0 and 2.0 mg/kg) and h a l o p e r i d o l (.075 and .10 mg/kg). These drug s e s s i o n s were conducted on every t h i r d day, with the order of drug a d m i n i s t r a t i o n counterbalanced across animals. Regular t r a i n i n g days were i n t e r p o s e d between the drug t e s t s . 45 Amphetamine was mixed i n s a l i n e to a c o n c e n t r a t i o n of 1.0 or 2.0 mg/ml and i n j e c t e d i n t r a p e r i t o n e a l l y ( i p ) i n a volume of 1 ml/kg 10 min before t e s t i n g . H a l o p e r i d o l was d i l u t e d i n s t e r i l e water to .075 mg/ml or .10 mg/ml and administered i p i n a volume of 1 ml/kg 45 min p r i o r to t e s t i n g . Three days a f t e r the f o u r t h drug t e s t , each animal was given a f u r t h e r g e n e r a l i z a t i o n s e s s i o n f o l l o w i n g an i p i n j e c t i o n of one of the drug v e h i c l e s o l u t i o n s . Three animals r e c e i v e d s a l i n e 10 min before the t e s t , while the other four r a t s were given s t e r i l e water 45 min p r i o r to t e s t i n g . Upon completion of a l l d i s c r i m i n a t i o n experiments, 6 r a t s were s e l e c t e d f o r ICSS t e s t i n g . The apparatus was the same as i n the previous experiments, except that only one l e v e r was provided i n each chamber. At the s t a r t of each s e l f - s t i m u l a t i o n s e s s i o n , the animals were placed i n the chambers and b a s e l i n e b a r - p r e s s i n g r a t e s were measured f o r 5 min i n the absence of b r a i n s t i m u l a t i o n . F o l l o w i n g t h i s p e r i o d , the animals could respond on the l e v e r to r e c e i v e four 200 ms t r a i n s of 60 Hz sin e wave s t i m u l a t i o n (200 msec i n t e r - t r a i n i n t e r v a l ) on a 20 sec v a r i a b l e i n t e r v a l (VI-20) schedule of reinforcement (range = 15 to 25 s e c ) . The c u r r e n t i n t e n s i t y was i n i t i a l l y set at 2 uA and t h e r e a f t e r i n c r e a s e d by 2 uA every 5 min. Each increment i n the i n t e n s i t y was s i g n a l l e d by the non-contingent d e l i v e r y of 4 t r a i n s of EBS at the new c u r r e n t l e v e l . The s e s s i o n was terminated a f t e r the completion of a 5 min p e r i o d with the 46 c u r r e n t set at 24 uA. A f t e r two weeks of b a s e l i n e r a t e - i n t e n s i t y s e s s i o n s , the r a t s were t e s t e d f o l l o w i n g i p i n j e c t i o n s of amphetamine (1.0 and 2.0 mg/kg) and h a l o p e r i d o l (.075 and .10 mg/kg). The i n j e c t i o n procedures were the same as d e s c r i b e d f o r the d i s c r i m i n a t i o n experiment. Test s e s s i o n s were given on every t h i r d day, with the order of drug a d m i n i s t r a t i o n counterbalanced among animals. Three days f o l l o w i n g the f i n a l drug s e s s i o n , the animals were given i n j e c t i o n s of the drug v e h i c l e s before s e l f - s t i m u l a t i o n t e s t i n g ; three r e c e i v e d s a l i n e and three were given s t e r i l e water using the same i n j e c t i o n procedure as when the r e s p e c t i v e drugs were ad m i n i s t e r e d . R e s u l t s To t e s t f o r s t a b i l i t y of the g e n e r a l i z a t i o n over the pe r i o d of drug t e s t i n g , the f u n c t i o n measured on the t h i r d b a s e l i n e day f o r the s i x r a t s was compared to that obtained from the v e h i c l e c o n t r o l t e s t on the l a s t day of the i n j e c t i o n phase. No d i f f e r e n c e was found between o v e r a l l HS responses across days ( F ( l , 5 ) = .71; p > .05), nor was there a s i g n i f i c a n t i n t e r a c t i o n of days and c u r r e n t l e v e l (F(5,25) = .27; p > .05). Thus the s t a b i l i t y of the g e n e r a l i z a t i o n was not a f f e c t e d by repeated t e s t i n g , i n j e c t i o n procedure or m u l t i p l e drug a d m i n i s t r a t i o n s . To assess the drug e f f e c t s , an a n a l y s i s of va r i a n c e was 47 performed to compare the g e n e r a l i z a t i o n f u n c t i o n s obtained a f t e r i n j e c t i o n of each drug or v e h i c l e s o l u t i o n ( F i g u r e 5). This a n a l y s i s i n d i c a t e d that the drug treatments d i d not produce any s i g n i f i c a n t d i f f e r e n c e s i n the tendancies to respond on the HS l e v e r across t e s t days (F(4,20) = 1.17; p > .05), nor was there evidence f o r changes i n responding at i n d i v i d u a l c u r r e n t i n t e n s i t i e s a c r o s s days (F(20,100) = .85; p > .05). However, as i n d i c a t e d i n F i g u r e 6, there was a s i g n i f i c a n t e f f e c t of the treatments on the l a t e n c i e s f o r d i s c r i m i n a t e d responses measured across t r i a l s (F(4,20) = 4.09; p < .02). Post hoc a n a l y s i s i n d i c a t e d that response l a t e n c i e s were longer f o l l o w i n g a d m i n i s t r a t i o n of the higher doses of both amphetamine and h a l o p e r i d o l than a f t e r i n j e c t i o n of v e h i c l e or the low dose of amphetamine (Duncans M u l t i p l e range t e s t , p < .05). R a t e - i n t e n s i t y f u n c t i o n s were obtained f o r 6 r a t s responding on a VI-20 sec schedule of EBS r e i n f o r c e m e n t . A seventh r a t d i d not respond f o r the EBS at any of the i n t e n s i t i e s used as d i s c r i m i n a t i v e s t i m u l i , and was d i s c a r d e d from the ICSS phase of the study. The r a t e - i n t e n s i t y f u n c t i o n s obtained with VI reinforcement were s i m i l a r i n form to those observed f o r the same animals responding on a CRF schedule, although the asymtotic response r a t e s were s u b s t a n t i a l l y lower. At low c u r r e n t l e v e l s the r a t s made few and i n f r e q u e n t responses on the l e v e r . At higher i n t e n s i t i e s , the r a t s i n c r e a s e d t h e i r 48 gure 5: Response f u n c t i o n s f o r EBS g e n e r a l i z a t i o n a f t e r i n j e c t i o n s of: A) v e h i c l e , 1.0 mg/kg and 2.0 mg/kg of amphetamine; or B) v e h i c l e , .075 mg/kg and .10 mg/kg of h a l o p e r i d o l . The v e h i c l e c o n d i t i o n s i n the two graghs represent the same data taken from a s i n g l e s e s s i o n . . AMPHETAMINE B. HALOPERIDOL INTENSITY LEVEL 50 ure 6: L a t e n c i e s f o r d i s c r i m i n a t e d responding to the EBS cues during drug t e s t s with: A) v e h i c l e , 1.0 mg/kg and 2.0 mg/kg amphetamine; or B) v e h i c l e , .075 mg/kg and .10 mg/kg h a l o p e r i d o l . The c o n d i t i o n s f o r each t e s t are s p e c i f i e d below the bars on the x - a x i s . L a t e n c i e s are expressed i n seconds. The v e r t i c a l l i n e s c r o s s i n g the tops of the bars represent the standard e r r o r of the mean. The s t a r s i n d i c a t e that the l a t e n c i e s are s i g n i f i c a n t l y d i f f e r e n t from the v e h i c l e c o n d i t i o n (p < . 05) 3n 2-A. AMPHETAMINE 1-VEH 1.0 2.0 B. HALOPERIDOL VEH .075 .10 52 response r a t e s as a l i n e a r f u n c t i o n of the increment i n the c u r r e n t i n t e n s i t y . Current t h r e s h o l d s f o r ICSS were obtained f o r each r a t by comparing the response r a t e at each c u r r e n t l e v e l to the r a t e s measured at a l l i n t e n s i t i e s lower than that l e v e l . T hreshold was def i n e d as the lowest i n t e n s i t y at which the response r a t e was 15 presses / 5 min higher than the mean operant r a t e at lower i n t e n s i t i e s . A comparison of th r e s h o l d s obtained from a pre-drug b a s e l i n e s e s s i o n and the l a s t v e h i c l e t e s t i n d i c a t e d that t h i s measure y i e l d e d an index of t h r e s h o l d that remained s t a b l e over the time during which the drug e f f e c t s were assessed ( t ( 5 ) = 0.00; p > .05) I n t e r e s t i n g l y , the c u r r e n t t h r e s h o l d f o r ICSS was higher than the lowest c u r r e n t used as a d i s c r i m i n a t i v e s t i m u l u s i n a l l r a t s . The t h r e s h o l d c u r r e n t s f o r ICSS ranged from the second to the f o u r t h lowest s t i m u l i used i n the g e n e r a l i z a t i o n procedure. A l l r a t s s e l f - s t i m u l a t e d at the high e s t three c u r r e n t s d e l i v e r e d during g e n e r a l i z a t i o n t e s t s . A n a l y s i s of the e f f e c t s of the drug i n j e c t i o n s on the ICSS t h r e s h o l d s ( F i g u r e 7) r e v e a l e d a s i g n i f i c a n t o v e r a l l d i f f e r e n c e between the amphetamine, h a l o p e r i d o l and v e h i c l e t e s t s (F(4,20) = 8.24; p < .0005). Post-hoc a n a l y s i s (Duncan's M u l t i p l e Range t e s t ) r e v e a l e d that the t h r e s h o l d s a f t e r 2.0 mg/kg amphetamine were s i g n i f i c a n t l y lower than those f o l l o w i n g v e h i c l e i n j e c t i o n s (p < .05). A l s o , .10 mg/kg h a l o p e r i d o l e l e v a t e d ICSS t h r e s h o l d s r e l a t i v e to those 53 Fi g u r e 7: Current t h r e s h o l d s f o r ICSS with a VI-20 schedule of reinforcement f o l l o w i n g i n j e c t i o n s of: A) v e h i c l e , 1.0 mg/kg and 2.0 mg/kg amphetamine; or B) v e h i c l e , .075 mg/kg and .10 mg/kg h a l o p e r i d o l . Thresholds are expressed i n uA of c u r r e n t . A. AMPHETAMINE Q O X C O L U cc LU DC 20 n 15 10-5-VEH 1.0 2.0 B. HALOPERIDOL VEH .075 .10 55 observed a f t e r v e h i c l e (p < .05). F i n a l l y , t h r e s h o l d s a f t e r i n j e c t i o n s of both doses of amphetamine were d i f f e r e n t from those measured f o l l o w i n g both doses of h a l o p e r i d o l (p < .05) . The e f f e c t s of the drugs on ICSS r a t e s was assessed by comparing the r a t e - i n t e n s i t y f u n c t i o n s measured a f t e r each i n j e c t i o n of amphetamine, h a l o p e r i d o l and v e h i c l e (see Fi g u r e 8 ) . The a n a l y s i s r e v e a l e d a s i g n i f i c a n t o v e r a l l e f f e c t of the i n j e c t i o n s (F(4,20) = 38.29; p < .0001). Post-hoc comparisons i n d i c a t e d that responding a f t e r both doses of amphetamine was s i g n i f i c a n t l y e l e v a t e d r e l a t i v e to that observed a f t e r v e h i c l e or h a l o p e r i d o l i n j e c t i o n s (Duncans m u l t i p l e range t e s t , p < .05). The r a t e s a f t e r h a l o p e r i d o l i n j e c t i o n , however, were not s i g n i f i c a n t l y d i f f e r e n t from those measured f o l l o w i n g v e h i c l e i n j e c t i o n s (p > .05) In a d d i t i o n to the main e f f e c t of drug i n j e c t i o n , the a n a l y s i s r e v e a l e d a s i g n i f i c a n t i n t e r a c t i o n between the e f f e c t s of the drugs and the c u r r e n t i n t e n s i t y . (F(48,240) = 7.28; p < .0001) T h i s i n t e r a c t i o n was due p r i m a r i l y to the f a c t t h a t amphetamine produced a s i g n i f i c a n t e l e v a t i o n i n the response r a t e at s u p r a - t h r e s h o l d i n t e n s i t i e s , but d i d not s i g n i f i c a n t l y i n c r e a s e responding at sub-t h r e s h o l d i n t e n s i t i e s . D i s c u s s i o n The r e s u l t s of t h i s study i n d i c a t e that doses of 56 gure 8: R a t e - i n t e n s i t y f u n c t i o n s f o r VI-20 ICSS measured a f t e r a d m i n i s t r a t i o n of A) v e h i c l e , 1.0 mg/kg and 2.0 mg/kg amphetamine; or B) v e h i c l e , .075 mg/kg and .10 mg/kg halop e r i d o l . The data are expressed i n terms of presses / 5 min as a f u n c t i o n of the c u r r e n t i n t e n s i t y (0 to 24 uA). ICSS RATE (responses / 5 min.) 58 amphetamine and h a l o p e r i d o l which r e l i a b l y a l t e r t h r e s h o l d s f o r VTA ICSS have no e f f e c t on d i s c r i m i n a t i v e responding to EBS cues e l i c i t e d from the same e l e c t r o d e s . These f i n d i n g s c o r r o b o r a t e and extend previous r e p o r t s that these drugs have no e f f e c t on LH EBS d e t e c t i o n (Schaefer & M i c h a e l , 1985). In a d d i t i o n , they are i n agreement with Kornetsky and E s p o s i t o (1981) i n as much as they suggest a d i s s o c i a t i o n of the cue p r o p e r t i e s of EBS from the DA processes mediating ICSS. The l a c k of e f f e c t s of amphetamine and h a l o p e r i d o l on the d i s c r i m i n a t i o n of EBS suggests that the cues p r o p e r t i e s of EBS are not dependant on the a c t i v a t i o n of DA neurons. Rather, the r a t s appear to have been responding to non-dopaminergic s t i m u l i e l l i c i t e d by the EBS. I t i s u n l i k e l y t h at the absence of drug e f f e c t s i s due to the i n s e n s i t i v i t y of the measure. The r e s u l t s of the ICSS t e s t s i n d i c a t e t hat the drugs can a f f e c t reward t h r e s h o l d s when the r a t s respond f o r s t i m u l a t i o n parameters that are i d e n t i c a l to those i n the d i s c r i m i n a t i o n procedure. At the hig h e s t dose of each drug, t h r e s h o l d s were s h i f t e d an average of 4 ua r e l a t i v e to those measured f o l l o w i n g v e h i c l e i n j e c t i o n s . In Experiment 1, changes of t h i s magnitude produced c l e a r s h i f t s i n response s e l e c t i o n . The f a c t that the drugs produced a s h i f t i n ICSS t h r e s h o l d s to t h i s extent and yet had no e f f e c t on d i s c r i m i n a t e d responding i n d i c a t e s that the cueing p r o p e r t i e s of the EBS are d i s s o c i a b l e from 59 those rewarding e f f e c t s of VTA EBS that are r e l a t e d to DA a c t i v i t y . An unexpected r e s u l t was the minimal e f f e c t of h a l o p e r i d o l on ICSS r a t e s . Of p a r t i c u l a r i n t e r e s t i s the f a c t that t h r e s h o l d s were s u b s t a n t i a l l y a l t e r e d i n the absence of any a p p r e c i a b l e change of response r a t e at s u p r a t h r e s h o l d c u r r e n t s . T h i s uncoupling of n e u r o l e p t i c e f f e c t s on the separate rate-dependent and r a t e - f r e e measures of ICSS has not p r e v i o u s l y been rep o r t e d f o r s e l f - s t i m u l a t i o n with CRF schedules. U s u a l l y , n e u r o l e p t i c s decrease the r e i n f o r c i n g e f f i c a c y of a l l c u r r e n t i n t e n s i t i e s , so that the r a t e - i n t e n s i t y f u n c t i o n i s s h i f t e d to the r i g h t ( S t e l l a r , K e l l y & C o r b e t t , 1983). There may, however, be d i f f e r e n c e s between VI and CRF responding which could account f o r the present r e s u l t s . Dickenson (1985) has argued that animals responding on a VI schedule are l e s s i n f l u e n c e d by d e v a l u a t i o n s of food rewards than animals responding on a CRF or f i x e d r a t i o schedule. Presumably the l a c k of a c o n s i s t e n t c o r r e l a t i o n between response and reward during t r a i n i n g r e s u l t s i n the animals' performance becoming independent of r e i n f o r c e r c o n t r o l . As i s the case i n o v e r t r a i n e d animals, responding i s i n i t i a t e d and maintained by stimulus-response a s s o c i a t i o n s , or h a b i t s . In the present study, the occurrance of ICSS may have depended on the EBS i n t e n s i t y being above a c r i t i c a l t h r e s h o l d l e v e l f o r reinforcement. Once t h i s t h r e s h o l d was reached however, 60 performance may have been predominantly under the c o n t r o l of non-dopaminergic stimulus p r o p e r t i e s of the EBS. A c c o r d i n g l y , h a l o p e r i d o l was able to e l e v a t e the reinforcement t h r e s h o l d , but i t d i d not i n t e r f e r e with the maintainance of the response h a b i t . I t i s u n c l e a r , however, why t h i s b e h a v i o r a l process d i d not prevent the i n c r e a s e i n response r a t e observed with both doses of amphetamine. 61 Experiment 3 Measurement of EBS d i s r i m i n a t i o n a f t e r i n j e c t i o n s of physostigmine and scopolamine The r e s u l t s of the previous experiment i n d i c a t e that dopaminergic neurons do not mediate the d i s c r i m i n a t i v e s t i m u l i e l i c i t e d by the VTA EBS i n the present procedure. T h i s suggests that the cue p r o p e r t i e s of VTA b r a i n s t i m u l a t i o n are d i s s o c i a b l e from those rewarding e f f e c t s that r e s u l t from the a c t i v a t i o n of DA neurons. T h i s r e s u l t does not preclude the p o s s i b i l i t y that the EBS cues are r e l a t e d to other reward processes, however. The s t i m u l i e l i c i t e d by the EBS may be mediated by reward pathways which descend from the diagona l band of Broca and pass through the VTA. These pathways c o n t a i n r e l a t i v e l y l a r g e , myelinated, f a s t - c o n d u c t i n g f i b e r s that are more e a s i l y e x c i t e d by EBS than DA neurons, and which may represent the primary, f i r s t stage s u b s t r a t e f o r MFB and VTA ICSS ( G a l l i s t e l et a l , 1981; Yeomans, 1983). The descending reward pathway has been shown to be comprised of a heterogeneous p o p u l a t i o n of f i b e r s , some of which appear to be c h o l i n e r g i c ( G r a t t o n & Wise, 1985). A c c o r d i n g l y , a t r o p i n e sulphate blocks the c o n t r i b u t i o n of short r e f r a c t o r y p e r i o d (.4 to .6 ms) neurons to the maintainance of LH ICSS (Gratton & Wise, 1985). Yeomans et a l (1985) have shown that a t r o p i n e sulphate i n j e c t e d 62 d i r e c t l y i n t o the VTA i n c r e a s e s t h r e s h o l d s f o r LH ICSS. These i n v e s t i g a t o r s a l s o demonstrated that r a t s developed a preference f o r a chamber which was p a i r e d with i n j e c t i o n s of c a r b a c o l i n t o the VTA, over one that was p a i r e d with s a l i n e i n j e c t i o n s . I f the cue p r o p e r t i e s of VTA b r a i n s t i m u l a t i o n are mediated by descending c h o l i n e r g i c reward pathways then d i s c r i m i n a t e d responding might be a l t e r e d by drugs that a f f e c t ACH t r a n s m i s s i o n . To i n v e s t i g a t e t h i s p o s s i b i l i t y , r a t s i n the present experiment were given EBS stimulus g e n e r a l i z a t i o n t e s t s f o l l o w i n g i n j e c t i o n s of e i t h e r physostigmine or scopolamine hydrobromide. Physostigmine blocks the i n a c t i v a t i o n of ACH by i n t e r f e r i n g with a c e t y l c h o l i n e s t e r a s e , an enzyme i n v o l v e d i n the metabolic breakdown of ACH ( I v e r s e n & Iversen, 1981). Hence, i t would be expected to enhance EBS s t i m u l i r e s u l t i n g from a c t i v a t i o n of c h o l i n e r g i c processes. Scopolamine i s a r e l a t i v e l y s e l e c t i v e blocker of m u s c a r i n i c ACH r e c e p t o r s ( I v e r s e n & I versen, 1981). Cues mediated by a c h o l i n e r g i c s u b s t r a t e i n v o l v i n g m u s c a r i n i c r e c e p t o r s would a c c o r d i n g l y be blocked by t h i s drug. As suggested by experiment 1, modulation of the EBS cues i n t h i s manner should be r e f l e c t e d by s h i f t s i n the g e n e r a l i z a t i o n g r a d i e n t s measured a f t e r a d m i n i s t r a t i o n of these drugs. 63 Method The e i g h t r a t s given c u r r e n t range manipulations i n Experiment 1 were used f o r t h i s experiment. Four of these animals a l s o had been given g e n e r a l i z a t i o n t e s t s with each dose of amphetamine and h a l o p e r i d o l . During the course of other experiments not repor t e d here, the animals were t r a i n e d to perform the d i s c r i m i n a t i o n without the h o u s e l i g h t s i g n a l l i n g the t r i a l s . T h i s m o d i f i c a t i o n of the procedure was r e t a i n e d f o r the present experiment so that g e n e r a l i z a t i o n t e s t s were conducted with only the EBS s i g n a l l i n g the onset of the t r i a l . The r a t s were given g e n e r a l i z a t i o n t e s t s a f t e r r e c e i v i n g e i t h e r physostigmine (.25 & .50 mg/kg) or scopolamine hydrobromide (.10 and .25 mg/kg) on separate s e s s i o n s . As i n experiment 2, the drug s e s s i o n s were conducted on every t h i r d day, with r e g u l a r t r a i n i n g days i n t e r p o s e d between t e s t s . Physostigmine was mixed i n p h y s i o l o g i c a l (.9 %) s a l i n e to a c o n c e n t r a t i o n of .25 or .50 mg/ml and i n j e c t e d i p i n a volume of 1 ml/kg 20 min before t e s t i n g . A s i n g l e dose of .50 mg/kg scopolamine methylbromide (methy1-scopolamine) was administered 10 min p r i o r to a l l physostigmine i n j e c t i o n s to block the p e r i p h e r a l enhancement of ACH t r a n s m i s s i o n (Iverson & Iverson, 1981). T h i s drug was d i s o l v e d i n s a l i n e to a c o n c e n t r a t i o n of .5 mg/kg and administered i p i n a volume of lml/kg. Scopolamine hydrobromide was mixed i n s a l i n e to a 64 c o n c e n t r a t i o n of .10 or .25 mg/ml and i n j e c t e d i p i n a volume of 1 ml/kg 15 before t e s t i n g . The order of drug a d m i n i s t r a t i o n was counterbalanced across animals. A f t e r the scopolamine and physostigmine t e s t s , the animals were given separate g e n e r a l i z a t i o n t e s t s f o l l o w i n g a d m i n i s t r a t i o n of methyl-scopolamine or v e h i c l e i n j e c t i o n s , as w e l l as a s i n g l e b a s e l i n e s e s s i o n without p r i o r i n j e c t i o n s . For the v e h i c l e s e s s i o n s , h a l f of the animals r e c e i v e d a s i n g l e i n j e c t i o n of 1 ml/kg s a l i n e 15 min before t e s t i n g while the remainder were given two such i n j e c t i o n s , 30 and 20 minutes before the t e s t . For the methyl-scopolamine t e s t , the i n j e c t i o n procedure was s i m i l a r to that used f o r physostigmine s e s s i o n s , except that s a l i n e was i n j e c t e d 20 min before the t e s t i n s t e a d of physostigmine. R e s u l t s The r e s u l t s shown i n F i g u r e 9 i n d i c a t e t h a t , r e l a t i v e to v e h i c l e s e s i o n s , responses a f t e r i n j e c t i o n s of physostigmine were biased more toward s e l e c t i o n of the HS l e v e r at most i n t e n s i t y l e v e l s . Scopolamine d i d not have the expected opposite e f f e c t , however, and was a c t u a l l y a s s o c i a t e d with a g r e a t e r tendancy to s e l e c t the HS l e v e r . An a n a l y s i s of v a r i a n c e comparing g e n e r a l i z a t i o n g r a d i e n t s measured a f t e r scopolamine, physostigmine and s a l i n e i n j e c t i o n s r e v e a l e d a s i g n i f i c a n t e f f e c t of drug c o n d i t i o n 65 ure 9: Response f u n c t i o n s f o r g e n e r a l i z a t i o n of EBS a f t e r i n j e c t i o n s of: A) v e h i c l e , .25 mg/kg and .50 mg/kg physostigmine; or B) v e h i c l e , .10 mg/kg and .25 mg/kg scopolamine. The v e h i c l e curves i n A and B represent the same data measured during a s i n g l e t e s t . INTENSITY LEVEL 67 (F(4,28) = 3.33; p < .025). Post hoc comparisons i n d i c a t e d that the r a t s responded s i g n i f i c a n t l y more on the HS l e v e r a f t e r .50 mg/kg physostigmine than a f t e r .25 mg/kg physostigmine or s a l i n e (Newman-Keul's t e s t , p < .05). Responding a f t e r scopolamine i n j e c t i o n s was not d i f f e r e n t from that observed a f t e r e i t h e r dose of physostigmine or v e h i c l e i n j e c t i o n s (Newman-Keuls t e s t , p > .05). A separate comparison of response s e l e c t i o n s during b a s e l i n e , v e h i c l e and methyl-scopolamine t e s t s d i d not i n d i c a t e s i g n i f i c a n t d i f f e r e n c e s of e i t h e r t e s t c o n d i t i o n (F(2,14) = .49; p > .05) or the i n t e r a c t i o n of the c o n d i t i o n with c u r r e n t l e v e l (F(10,70) = 1.61; p > .05). Thus, the changes observed are not a t t r i b u t a b l e to i n j e c t i o n procedures or the p e r i p h e r a l e f f e c t s of methyl-scopolamine. In a d d i t i o n to the changes observed with the response s e l e c t i o n measure, there was a s i g n i f i c a n t e f f e c t of drug treatment on l a t e n c y to respond a f t e r EBS d e l i v e r y (F(4,28) = 6.31; p < .001; F i g u r e 10), and a change i n the t o t a l number of t r i a l s w i t h i n a s e s s i o n on which the r a t s responded (F(4,28) = 4.78; p < .005; see Fi g u r e 11). Post hoc analyses r e v e a l e d that response l a t e n c i e s were longer f o l l o w i n g i n j e c t i o n s of .50 mg/kg physostigmine than those measured a f t e r a l l other i n j e c t i o n s (Newman-Keul 1s t e s t , p < .05). The r a t s a l s o responded on a fewer percentage of the t r i a l s a f t e r t h i s dose of physostigmine than a f t e r v e h i c l e i n j e c t i o n (Newman-Keuls t e s t , p < .05; Fi g u r e 11). A n a l y s i s 68 gure 10: L a t e n c i e s f o r d i s c r i m i n a t e d responding to the EBS cues during t e s t s with; A) v e h i c l e , .25 mg/kg and .50 mg/kg physostigmine; or B) v e h i c l e , .10 mg/kg and .25 mg/kg scopolamine. V e r t i c a l l i n e s on bars represent the standard e r r o r of the mean. St a r s i n d i c a t e that the mean i s s i g n i f i c a n t l y d i f f e r e n t from v e h i c l e (p < .05). A. PHYSOSTIGMINE B. SCOPOLAMINE VEH .10 .25 70 ure 11: Percentage of d i s c r i m i n a t i o n t r i a l s on which a response occurred during t e s t s with i n j e c t i o n s of A) v e h i c l e , .25 mg/kg and .50 mg/kg physostigmine; or B) v e h i c l e , .10 mg/kg and .25 mg/kg scopolamine. 100 - i A. PHYSOSTIGMINE Q UJ Q Z o CL CO UJ QC CO < 75-50-25-VEH .25 .50 B. SCOPOLAMINE i — i — i VEH .10 .25 72 of the ITI response r a t e s i n d i c a t e d a s i g n i f i c a n t change across drug t e s t s (F(4,28) = 11.43; p < .0001), with responses f o l l o w i n g a l l drug i n j e c t i o n s being reduced r e l a t i v e to the s a l i n e c o n d i t i o n (Newman-Keul's t e s t , p < .05). In c o n t r a s t to the response s e l e c t i o n during d i s c r i m i n a t i o n t r i a l s , physostigmine treatment d i d not r e s u l t i n s i g n i f i c a n t changes across t e s t s i n the percentage of responses made on the HS l e v e r during the ITI (F(4,28) = 1.11; p > .05). D i s c u s s i o n In t h i s experiment, a d m i n i s t r a t i o n of .50 mg/kg physostigmine was fol l o w e d by s i g n i f i c a n t l y more d i s c r i m i n a t e d responses on the HS l e v e r than were.observed a f t e r i n j e c t i o n of s a l i n e or .25 mg/kg physostigmine. F i g u r e 8 r e v e a l s that the i n c r e a s e i n HS responding i s evident at most c u r r e n t l e v e l s , and i s s i m i l a r to the e f f e c t produced by d e l i v e r i n g a range of higher i n t e n s i t i e s w i t h i n a s e s s i o n (see F i g u r e 3 ) . The s i m i l a r i t y of the changes i n response s e l e c t i o n f o l l o w i n g .50 mg/kg physostigmine and upward s h i f t s i n the i n t e n s i t i e s d e l i v e r e d suggests that t h i s drug e f f e c t may be r e l a t e d to a pharmacological enhancement of the p e r c e i v e d i n t e n s i t i e s of each EBS cue. Such a mechanism would r e q u i r e the involvement of c h o l i n e r g i c neurons i n the mediation of the cue p r o p e r t i e s of VTA b r a i n - s t i m u l a t i o n . An a l t e r n a t i v e e x p l a n a t i o n of these data may be that 73 the observed s h i f t s r e f l e c t n o n - s p e c i f i c d i s r u p t i o n of d i s c r i m i n a t e d responding. I t i s noteworthy that the dose of physostigmine which a l t e r s response s e l e c t i o n a l s o produces s i g n i f i c a n t i n c r e a s e s i n response l a t e n c i e s , and r e s u l t s i n a decrease i n the number of d i s c r i m i n a t e d responses emitted w i t h i n a s e s s i o n . Conceivably, physostigmine may simply be d i s r u p t i n g the stimulus c o n t r o l over responding, thus a l l o w i n g normal response b i a s e s to p r e v a i l . However, examination of ITI responding does not r e v e a l any such response b i a s toward the HS l e v e r . On average, the r a t s responded on both l e v e r s e q u a l l y o f t e n during the I T I ' s f o l l o w i n g s a l i n e i n j e c t i o n (average % HS responses = 44 % ) . Moreover, there was l i t t l e change i n ITI response b i a s e s across drug t e s t s , and almost no d i f f e r e n c e a f t e r i n j e c t i o n s of s a l i n e and .50 mg/kg physostigmine (% HS responses a f t e r physostigmine = 45 % ) . T h e r e f o r e , the ITI data appear to render untenable an i n t e r p r e t a t i o n based on n o n - s e l e c t i v e response b i a s i n g . As the i n f l u e n c e of physostigmine on d i s c r i m i n a t e d responding was not evident during the I T I , a necessary c o n c l u s i o n would be that the e f f e c t s of t h i s drug are s p e c i f i c to the cuing of responses by the EBS s t i m u l i . A parsimonius e x p l a n a t i o n may be r e l a t e d to the modulation of the p e r c e i v e d i n t e n s i t i e s of the EBS cues by the a c t i o n s of physostigmine on a d i r e c t l y s t i m u l a t e d c h o l i n e r g i c s u b s t r a t e , or through the a l t e r a t i o n of secondary 74 c h o l i n e r g i c processes i n v o l v e d i n the i n t e g r a t i o n and p e r c e p t i o n of the EBS cue i n f o r m a t i o n . At present, there i s no c l e a r e x p l a n a t i o n f o r the absence of an e f f e c t of scopolamine on response s e l e c t i o n . I f the cue p r o p e r t i e s of the EBS were mediated by a c h o l i n e r g i c s u b s t r a t e , scopolamine would be expected to block the cues and b i a s the response s e l e c t i o n away from the HS l e v e r . Instead, there was a v i s i b l e but n o n - s i g n i f i c a n t b i a s i n g of the response toward the HS l e v e r . Conceivably, the doses employed i n t h i s experiment may have been to low to produce e f f e c t s on the EBS cues. However, data from recent experiments i n d i c a t e that higher doses a l s o do not s e l e c t i v e l y reduce HS responses. In f a c t , these doses d i s r u p t the d i s c r i m i n a t i o n (unpublished o b s e r v a t i o n s ) . The p o s s i b i l i t y of n i c o t i n i c r a t h e r than muscarinic r e c e p t o r mediation of the cues a l s o must be c o n s i d e r e d . As physostigmine i n t e r f e r e s with ACH degradation, i t enhances c h o l i n e r g i c b i n d i n g to both r e c e p t o r types and thus would i n f l u e n c e both n i c o t i n i c and muscarinic systems. As scopolamine i s a r e l a t i v e l y s e l e c t i v e b l ocker of muscarinic r e c e p t o r s , s u b s t a n t i a l n i c o t i n i c blockade would only occur at high doses. However, high doses of scopolamine i n t e r f e r e with d i s c r i m i n a t i v e performance ( K s i r and S l i f e r , 1982), thus the s e l e c t i v e blockade of the EBS s t i m u l i by t h i s drug might be masked by i t s n o n - s p e c i f i c e f f e c t s on behavior. 75 GENERAL DISCUSSION Past attempts to i d e n t i f y n e u r a l systems mediating the rewarding e f f e c t s of i n c e n t i v e s t i m u l i have been c o n s t r a i n e d by the i n a b i l i t y to d i s s o c i a t e b e h a v i o r a l changes r e s u l t i n g from general r e s p o n s e - d i s r u p t i o n e f f e c t s of CNS manipulations from more s p e c i f i c e f f e c t s on the hedonic impact of rewarding s t i m u l i . Consequently, recent r e s e a r c h on the neurobiology of m o t i v a t i o n and emotion has been c h a r a c t e r i z e d by an emphasis on the development of b e h a v i o r a l i n d i c e s which s e l e c t i v e l y r e f l e c t the hedonic r e a c t i o n of an animal to rewarding events (Hand & F r a n k l i n , 1983; M a r t i n - I v e r s o n , 1985; Z a r e v i c s & S e t l e r , 1979). D i s c r i m i n a t i o n procedures may provide such a b e h a v i o r a l measure, when the d i s c r i m i n a t i v e cues are rewarding s t i m u l i with d i f f e r e n t r e i n f o r c i n g c a p a b i l i t i e s . I f hedonic a t t r i b u t e s of a sti m u l u s can a c q u i r e d i s c r i m i n a t i v e c o n t r o l over responding, then manipulations of CNS systems mediating a f f e c t i v e processes should r e s u l t i n a p p r o p r i a t e b i a s i n g of d i s c r i m i n a t e d response s e l e c t i o n . The response s e l e c t i o n measure should be l e s s confounded by a l t e r a t i o n s of an animal's response c a p a c i t y , and d i s r u p t i o n s of a t t e n t i o n a l processes would be expected to produce a general decrease i n the accuracy of the d i s c r i m i n a t i o n r a t h e r than s p e c i f i c b i a s i n g of the response. In the present s e r i e s of experiments, the u t i l i t y of 76 the d i s c r i m i n a t i o n procedure f o r measuring the hedonic p r o p e r t i e s of v e n t r a l tegmental EBS was assessed. To make t h i s e v a l u a t i o n , drugs which are known to a l t e r the rewarding e f f e c t s of the EBS were administered p r i o r to d i s c r i m i n a t i o n s e s s i o n s and the subsequent responses to g e n e r a l i z a t i o n i n t e n s i t i e s were measured. I f i t were demonstrated that the d i s c r i m i n a t e d responding was a l t e r e d by these drugs i n a manner analogous with t h e i r e f f e c t s on ICSS, then i t might be concluded that the two p r o p e r t i e s of EBS share a common s u b s t r a t e . In c o n t r a s t , d i f f e r e n t i a l e f f e c t s of the drugs might i n d i c a t e a d i s s o c i a t i o n of the EBS sti m u l u s and reward processes. The f i r s t experiment demonstrated the a b i l i t y of r a t s to d i s c r i m i n a t e two EBS i n t e n s i t i e s t h a t were rewarding i n an operant context. Furthermore, the responses to in t e r m e d i a t e i n t e n s i t i e s r e f l e c t e d a tendancy f o r g e n e r a l i z a t i o n between EBS s t i m u l i , which remained s t a b l e a c r o s s repeated t e s t s with constant c o n d i t i o n s . When t e s t s were given with higher or lower i n t e n s i t y ranges, the o v e r a l l response tendancy was s h i f t e d so that a p p r o p r i a t e l y more or l e s s responses were made on the HS l e v e r . T h i s l a t t e r r e s u l t i s an i n d i c a t i o n that the d i s c r i m i n a t i v e responding i s s e n s i t i v e to changes i n the absolute i n t e n s i t y values of the cues d e l i v e r e d w i t h i n a s e s s i o n . A c c o r d i n g l y , s i m i l a r s h i f t s i n the response s e l e c t i o n b i a s e s would be expected i f the pe r c e i v e d 77 i n t e n s i t i e s of the EBS were m o d i f i e d by p h a r m a c o l o g i c a l m a n i p u l a t i o n of the cue s u b s t r a t e . The observed s h i f t s i n the o v e r a l l response s e l e c t i o n b i a s when d i f f e r e n t i n t e n s i t y ranges were d e l i v e r e d i n d i c a t e s t h a t the r a t s , to some e x t e n t , responded to the a b s o l u t e i n t e n s i t i e s of the c u e s . For example, when more h i g h i n t e n s i t y cues were d e l i v e r e d w i t h i n a s e s s i o n , the r a t s made a p p r o p r i a t e l y more s e l e c t i o n s of the HS l e v e r . I t a p p e a r s , however, t h a t the re spond ing was not on ly a f u n c t i o n of the p h y s i c a l i n t e n s i t y of each EBS cue . As i s e v i d e n t from F i g u r e 4, the response s e l e c t i o n b i a s to the same a b s o l u t e i n t e n s i t i e s d i f f e r e d between the b a s e l i n e s e s s i o n and t e s t s w i th h i g h e r r a n g e s . I t appears t h a t the presence of h i g h e r i n t e n s i t i e s w i t h i n a s e s s i o n i n f l u e n c e d the r e s p o n d i n g to each cue so tha t i t was responded to as though i t were lower than d u r i n g the b a s e l i n e t e s t . The d i f f e r e n t i a l r e s p o n d i n g to f i x e d i n t e n s i t i e s may be accounted f o r i n terms of two p o s s i b l e p r o c e s s e s . On the one hand, the an imal s may p a r t l y d i s c r i m i n a t e the r e l a t i o n s between i n t e n s i t i e s d e l i v e r e d on s epara te t r i a l s . When the i n t e n s i t y range i s s h i f t e d upwards r e l a t i v e to b a s e l i n e , a g i v e n c u r r e n t occup ie s a r e l a t i v e l y low p o s i t i o n i n the range , and i s responded to as s u c h . A l t e r n a t i v e l y , the r a t s may respond d i r e c t l y to the a b s o l u t e p e r c e i v e d i n t e n s i t y of a cue , independent of the o t h e r s . However, the presence of h i g h e r i n t e n s i t i e s w i t h i n the s e s s i o n may r e s u l t i n n e g a t i v e 78 c o n t r a s t e f f e c t s , with the consequence that the pe r c e i v e d magnitude of each p h y s i c a l i n t e n s i t y i s reduced r e l a t i v e to b a s e l i n e . The l a c k of a symmetrical i n c r e a s e i n HS l e v e r s e l e c t i o n with lower c u r r e n t ranges may be due to the c l o s e p r o x i m i t y of the low t r a i n i n g i n t e n s i t y to the cue t h r e s h o l d . S h i f t i n g the range downward may not r e s u l t i n a p p r e c i a b l y lower c u r r e n t s being i n c l u d e d w i t h i n the s e s s i o n . The present s e r i e s of experiments was not designed to determine the b e h a v i o r a l nature of the d i s c r i m i n a t i o n . Evidence from previous s t u d i e s , however, suggests that the c o n t r a s t e x p l a n a t i o n may be more a p p r o p r i a t e . The a v a i l a b l e evidence suggests that s u c c e s s i v e d i s c r i m i n a t i o n s are r a r e l y , i f ever, performed by r a t s on the b a s i s of r e l a t i o n s between s t i m u l i (Mackintosh, 1974). R e l a t i o n a l s t r a t e g i e s appear to occur only with r e l a t i v e l y d i f f i c u l t simultaneous d i s c r i m i n a t i o n t a s k s . C o n t r a s t e f f e c t s , on the other hand, are r e a d i l y o b t a i n a b l e with s h i f t s i n EBS i n t e n s i t y when LH s t i m u l a t i o n i s used as a r e i n f o r c e r (Koob, 1977; Panksep & T r o w e l l , 1969). T h i s e f f e c t has been r e p l i c a t e d i n our l a b o r a t o r y with VTA EBS s e r v i n g as the reward (unpublished o b s e r v a t i o n s ) . I t i s co n c e i v a b l e that the c o n t r a s t e f f e c t s observed i n ICSS r e f l e c t the same process that o c c u r r s i n the present d i s c r i m i n a t i o n procedure. Whereas Experiment one i n v e s t i g a t e d the f a c t o r s i n f l u e n c i n g response s e l e c t i o n , the second and t h i r d 79 experiments were intended to i d e n t i f y the n e u r a l b a s i s f o r the e f f e c t i v e d i s c r i m i n a t i v e s t i m u l i . In Experiment two, g e n e r a l i z a t i o n t e s t s were given f o l l o w i n g i n j e c t i o n s of amphetamine and h a l o p e r i d o l , to assess whether DA neurons were mediating the EBS cues. Doses of these drugs which a l t e r e d both ICSS t h r e s h o l d s and d i s c r i m i n a t e d response l a t e n c i e s were found to have no e f f e c t on the g e n e r a l i z a t i o n g r a d i e n t s . T h i s r e s u l t suggests that the e f f e c t i v e cues i n the present procedure were mediated by non-dopaminergic processes, and thus were d i s s o c i a b l e from DA mediated reward proc e s s e s . Despite previous r e p o r t s of EBS cues being independent of DA systems (Schaefer & M i c h a e l , 1985), the r e s u l t s of Experiment two are somewhat of a s u r p r i s e . There i s abundant evidence i n d i c a t i n g that c e n t r a l DA neurons are capable of mediating psychomotor s t i m u l a n t cues (Silverman & Ho, 1977). In p a r t i c u l a r , mesolimbic p r o j e c t i o n s to the NAS appear to be i n v o l v e d i n mediating amphetamine cues ( N i e l s e n & S c h e e l -Kruger, 1984). Dopamine neurons a l s o have been shown to be i n v o l v e d i n mediating LH EBS cues i n some s t u d i e s ( C o l p a e r t et a l , 1977; C o l p a e r t , 1977). I f DA neurons were capable of mediating s e n s a t i o n s produced by drugs and LH EBS as these s t u d i e s suggest, then they might be expected to mediate the cue p r o p e r t i e s of s t i m u l a t i o n of the VTA at i n t e n s i t i e s t h a t were rewarding i n an operant context. I t i s p o s s i b l e that the EBS i n t h i s study evoked 80 sen s a t i o n s r e l a t e d to DA a c t i v a t i o n , but stimulus c o n t r o l by these s e n s a t i o n s was overshadowed by other sensory p r o p e r t i e s of the s t i m u l a t i o n . I t i s q u i t e common f o r a s i n g l e stimulus w i t h i n a heterogeneous complex to gain complete or predominant stimulus c o n t r o l over behavior (Mackintosh, 1975). T h i s process commonly occurs when one stimulus i s more s a l i e n t than the others ( M i l e s & J e n k i n s , 1973) or when one event i s a b e t t e r p r e d i c t o r of reinforcement ( H a l l , Mackintosh, Goodall & M a r t e l l o , 1977). In the case of d i s c r i m i n a t i o n of psychomotor s t i m u l a n t s , s e n s a t i o n s r e l a t e d to changes i n DA t r a n s m i s s i o n may be the most s a l i e n t of the cues produced by that c l a s s of drugs. When EBS i s used as a d i s c r i m i n a t i v e s t i m u l u s , the b e h a v i o r a l c o n t r o l exerted by DA-dependent s e n s a t i o n s may be attenuated i n the presence of more s a l i e n t s t i m u l i . The f i n d i n g s of C o l p a e r t (1977) and C o l p a e r t et a l (1977) suggest that there are c o n d i t i o n s which may favor the development of d i s c r i m i n a t i v e c o n t r o l of responding by endogenous s t i m u l i r e l a t e d to DA a c t i v i t y . In these s t u d i e s the EBS was presented i n a very d i f f e r e n t manner from that used i n the present study, and the experiments by Schaefer & Michael (1985) and Kornetsky and E s p o s i t o (1981). Rather than d e l i v e r i n g the EBS as a d i s c r e t e s t i m u l u s , C o l p a e r t (1977) and C o l p a e r t et a l (1977) d e l i v e r e d i n t e r m i t t e n t pulses of s t i m u l a t i o n f o r 5 min before a l l o w i n g the animals to respond. T h i s p a t t e r n of s t i m u l a t i o n was then mainained 81 throughout the remainder of a 15 min s e s s i o n while the r a t s responded f o r water on an f i x e d r a t i o schedule of r e i n f o r c e m e n t . To make the a p p r o p r i a t e response s e l e c t i o n w i t h i n a s e s s i o n , the r a t s were r e q u i r e d to d i s t i n g u i s h between the presence or absence of the EBS. 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 before a s t i m u l a t i o n t r i a l r e s u l t e d i n a l l r a t s s e l e c t i n g the l e v e r a p p r o p r i a t e f o r EBS absence, i n d i c a t i n g that the drug blocked the cue p r o p e r t i e s of the s t i m u l a t i o n . In order to understand how C o l p a e r t ' s procedure might r e s u l t i n g r e a t e r stimulus c o n t r o l by DA r e l a t e d cues, i t i s important to c o n s i d e r the nature of s e n s a t i o n s a s s o c i a t e d with dopaminergic a c t i v i t y . Wise (1982) has proposed that DA neurons may be r e s p o n s i b l e f o r producing the m o t i v a t i o n a l a r o u s a l a s s o c i a t e d with d i f f e r e n t forms of reinforcement. T h i s m o t i v a t i o n a l a r o u s a l has never been measured d i r e c t l y , and the concept i s p r i m a r i l y a h y p o t h e t i c a l one which can be used h e u r i s t i c a l l y to draw the d i s t i n c t i o n between d i s c r e t e cue f u n c t i o n s of reward s t i m u l i , and the presumed a f f e c t i v e consequences of reinforcement (Young, 1961). As such i t i s d i f f i c u l t to determine what a t t r i b u t e s the s e n s a t i o n of a r o u s a l might have, although i t might best be d e s c r i b e d as a change i n the general s t a t e of an animal ( B i n d r a , 1959). I t i s c o n c e i v a b l e that the i n t e r m i t t e n t d e l i v e r y of s t i m u l a t i o n i n C o l p a e r t ' s procedure prevented a p r e d i c t i v e r e l a t i o n from being e s t a b l i s h e d between the d i s c r e t e EBS cues and the 82 d i s c r i m i n a t e d response. Instead, the r a t s may have learned to perform one response while i n an aroused s t a t e , and an a l t e r n a t i v e response while i n a non-aroused s t a t e . Such a d i s c r i m i n a t i o n would be analogous to a drug d i s c r i m i n a t i o n procedure, wherein animals must d i s t i n g u i s h between drug and non-drug s t a t e s . In f a c t , the s e n s a t i o n of a r o u s a l r e s u l t i n g from rewarding EBS may be s i m i l a r to that produced by psychomotor s t i m u l a n t s , as the cues e l i c i t e d by these drugs a l s o appear to be mediated by DA (Silverman & Ho, 1977). The t h i r d experiment i n the present study i n v e s t i g a t e d the r e l a t i o n s h i p of the EBS cues to non-dopaminergic reward s u b s t r a t e s . As noted p r e v i o u s l y , the VTA c o n t a i n s non-dopaminergic processes which appear to mediate ICSS. These neurons are l a r g e , myelinated, f a s t conducting and have shor t r e f r a c t o r y p e r i o d s (Yeomans, 1982), and would be a l i k e l y s u b s t r a t e f o r the d i s c r e t e cues produced by the EBS i n our procedure. Previous r e p o r t s have i n d i c a t e d t hat c h o l i n e r g i c neurons represent a subpopulation of t h i s p r o j e c t i o n (Gratton & Wise, 1985; Yeomans et a l , 1985). A c c o r d i n g l y , physostigmine and scopolamine were a d m i n i s t e r e d p r i o r to g e n e r a l i z a t i o n t e s t s and the subsequent e f f e c t s on d i s c r i m i n a t e d responding were measured. The r e s u l t s of the t e s t s with physostigmine i n d i c a t e t h at c h o l i n e r g i c reward s u b s t r a t e s may be i n v o l v e d i n the mediation of the EBS cues. A f t e r the higher dose of physostigmine, the response s e l e c t i o n s of the animals were 83 s i g n i f i c a n t l y more biased toward the HS l e v e r than during v e h i c l e c o n t o l s e s s i o n s . T h i s r e s u l t suggests that physostigmine acted to enhance the pe r c e i v e d i n t e n s i t i e s of the EBS cues. However, t h i s r o l e f o r c h o l i n e r g i c neurons i n the mediation of the EBS s t i m u l i was not confirmed by t e s t s with scopolamine. Scopolamine d i d not s i g n i f i c a n t l y s h i f t the l e v e r s e l e c t i o n b i a s towards the l e v e r a p p r o p r i a t e f o r low i n t e n s i t i e s . In f a c t there was a v i s i b l e but n o n s i g n i f i c a n t s h i f t i n the same d i r e c t i o n as was seen with physostigmine. Recent experiments i n our l a b o r a t o r y i n d i c a t e that the absence of a scopolamine e f f e c t was not a t t r i b u t a b l e to an i n s u f f i c i e n t dose range. Higher doses of the drug r e s u l t i n general response d i s r u p t i o n without producing a decrease i n HS responses (unpublished o b s e r v a t i o n s ) . The absence of an e f f e c t of scopolamine may be due to the mediation of the EBS s t i m u l i by n i c o t i n i c ACH r e c e p t o r s . Scopolamine has g r e a t e r a f f i n i t y f o r muscarinic r e c e p t o r s and thus might not be expected to produce s u b s t a n t i a l i n t e r f e r e n c e with n i c o t i n i c t r a n s m i s s i o n . At present, there i s l i t t l e evidence to i n d i c a t e which ACH r e c e p t o r s might be mediating the EBS s t i m u l i . With r e s p e c t to LH s t i m u l a t i o n , i t has been shown that n i c o t i n e has no e f f e c t on the d i s c r i m i n a t i o n of EBS ( C l a r k e & Kumar, 1983; Schaefer & Mi c h a e l , 1983). Furthermore, i t has been suggested that m u s c a r i n i c r e c e p t o r s i n the VTA mediate the c h o l i n e r g i c 84 component of the descending reward pathways. I f the cues i n the present procedure are i n f a c t n i c o t i n i c , then t h i s would c o n s t i t u t e a d i s s o c i a t i o n of the stimulus p r o p e r t i e s of the EBS from the rewarding e f f e c t s mediated by the c h o l i n e r g i c system. An a l t e r n a t i v e e x p l a n a t i o n f o r the l a c k of a scopolamine e f f e c t i s that c h o l i n e r g i c neurons are i n v o l v e d at more than one l e v e l of p r o c e s s i n g of the stimulus i n f o r m a t i o n . For i n s t a n c e , the d i r e c t l y a c t i v a t e d neurons may be c h o l i n e r g i c , and the perc e i v e d i n t e n s i t y of the EBS might be a d i r e c t f u n c t i o n of ACH r e l e a s e from these c e l l s . At another l e v e l of the nervous system, however, c h o l i n e r g i c neurons might have an opposing e f f e c t . In t h i s r e s p e c t , i t i s of i n t e r e s t than a n t i - c h o l i n e r g i c drugs can both decrease responding f o r EBS (Gratton & Wise, 1985; Yeomans et a l , 1985) and reverse the h a l o p e r i d o l induced suppression of ICSS (Murzi & Herberg, 1982). In c o n c l u s i o n , the r e s u l t s of the present s e r i e s of experiments re p r e s e n t a p r e l i m i n a r y i n d i c a t i o n of a r e l a t i o n between the processes mediating VTA b r a i n - s t i m u l a t i o n cues and systems u n d e r l y i n g the rewarding e f f e c t s of the EBS. Rather than being r e l a t e d to DA-dependent reward processes, however, the cues appear to be mediated by c h o l i n e r g i c neurons. These c e l l s may be the same as those i d e n t i f i e d by Gratton & Wise (1985), although the p o s s i b i l i t y remains that the cues are mediated by c h o l i n e r g i c processes independent 85 of those u n d e r l y i n g VTA ICSS. An important l i n e of r e s e a r c h f o r the f u t u r e w i l l be the i d e n t i f i c a t i o n of the r e c e p t o r s i n v o l v e d i n mediating the two p r o p e r t i e s of the EBS. Systematic t e s t s with d i f f e r e n t a g o n i s t s and a n t a g o n i s t s might i n d i c a t e commonalities or d i f f e r e n c e s between the r e s p e c t i v e n e u r a l s u b s t r a t e s f o r these e f f e c t s . The r e s u l t s of t h i s i n v e s t i g a t i o n may p o t e n t i a l l y c o n t r i b u t e to our understanding of the ne u r a l b a s i s of reward i n two important ways. F i r s t , although the present study does not provide d i r e c t evidence to t h i s e f f e c t , there i s a suggestion on l o g i c a l grounds that DA neurons may be i n v o l v e d i n the mediation of s t a t e changes a s s o c i a t e d with reward . B r a i n s t i m u l a t i o n cues appear to i n v o l v e DA neurons when the s t i m u l a t i o n i s d e l i v e r e d over a long p e r i o d of time, but not when i t i s d e l i v e r e d as a s i n g l e d i s c r e t e b u r s t . T h i s may be an i n d i c a t i o n that DA neurons mediate a more s u b t l e and general change i n the i n t e r n a l s t a t e of the animal. These s e n s a t i o n s may only gain stimulus c o n t r o l when the more d i s c r e t e aspects of the EBS are d e l i b e r a t l y uncoupled from the d i s c r i m i n a t e d response. A second i m p l i c a t i o n of these r e s u l t s has to do with the o r g a n i z a t i o n of n e u r a l processes mediating ICSS. I t has been suggested that the l a r g e , mylenated, f a s t conducting reward neurons which descend to the VTA from the di a g o n a l band of Broca represent the f i r s t stage processes being a c t i v a t e d during LH ICSS. Dopamine neurons have been 86 suggested as a second stage w i t h i n the reward system, on which the descending pathways synapse ( G a l l i s t e l et a l , 1981; Gratton & Wise, 1985). According to t h i s h y p o t h e s i s , drugs which a f f e c t DA t r a n s m i s s i o n should modify not only i n f o r m a t i o n r e l a y e d through the DA neurons, but i n f o r m a t i o n t r a n s m i t t e d by previous stages of the reward c i r c u i t r y as w e l l . In the present study, the EBS cues were modified by physostigmine but not by h a l o p e r i d o l or amphetamine. I f the cue s u b s t r a t e i n the present procedure r e p r e s e n t s the same c h o l i n e r g i c s u b s t r a t e as mediates ICSS, then t h i s system must be e i t h e r c o l l a t e r a l l i z e d or independent of dopaminergic s u b s t r a t e s of reward. The f i n d i n g s of the present study suggest . that the d i s c r i m i n a t i o n procedure developed here may be of great u t i l i t y i n measuring reward proc e s s e s . The measure employed i n t h i s i n v e s t i g a t i o n provided a r e l i a b l e assessment of r a t s ' p e r c e p t i o n s of EBS i n t e n s i t y which remained c o n s i s t e n t across t e s t s e s s i o n s . When the cues were a l t e r e d , both p h y s i c a l l y and p h a r m a c o l o g i c a l l y , the responding w i t h i n the t e s t s e s s i o n s was a l t e r e d a c c o r d i n g l y . T h e r e f o r e , the a b i l i t y to measure these changes at doses of drugs which would normally d i s r u p t operant responding may represent an important advance i n r e s e a r c h of the neurobiology of m o t i v a t i o n and reward. 87 REFERENCES Bass, R.W. (1974). D e t e c t i o n of e l e c t r i c a l b r a i n s t i m u l a t i o n at hypothalamic and s e p t a l s i t e s i n r a t s . J o u r n a l of  Comparative and P h y s i o l o g i c a l Psychology, 87, 458-465. Bi n d r a , D. (1959). 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