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Systemic epinephrine and defensive burying in the rat Terlecki, Lori Janine 1981

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SYSTEMIC EPINEPHRINE AND DEFENSIVE BURYING IN THE RAT by LORI JANINE TERLECKI B.Sc. The U n i v e r s i t y of Calgary, 1975 M.Sc. The U n i v e r s i t y of Calgary, 1977 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in 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 March © L o r i Janine BRITISH COLUMBIA 1981 T e r l e c k i , 1981 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the requirements f o r an advanced degree a t the U n i v e r s i t y o f B r i t i s h Columbia, I agree t h a t the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and study. I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the head o f my department o r by h i s o r her r e p r e s e n t a t i v e s . I t i s understood t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without my w r i t t e n p e r m i s s i o n . Department of ~P~3 y c H o L n a c/ The U n i v e r s i t y o f B r i t i s h Columbia 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 Date MAILC.H ao /•?*•/ i i ABSTRACT Many i n v e s t i g a t o r s have suggested that e p i n e p h r i n e i n f l u e n c e s the behaviour of organisms i n a v e r s i v e s i t u a t i o n s ; however, attempts to co n f i r m t h i s p r e d i c t i o n by examining the e f f e c t s of a d r e n a l demedullation and epinephrine i n j e c t i o n s on the performance of r a t s i n t r a d i t i o n a l a v e r s i v e c o n d i t i o n i n g paradigms have f a i l e d to provide unambiguous support f o r t h i s p o i n t of view. In the present i n v e s t i g a t i o n s , the r e c e n t l y developed d e f e n s i v e burying paradigm was used to assess the e f f e c t s of ep i n e p h r i n e on the behaviour of r a t s i n a v e r s i v e s i t u a t i o n s . Defensive burying r e f e r s to the f a c t t h a t r a t s t y p i c a l l y respond to w e l l - d e f i n e d a v e r s i v e o b j e c t s by pushing moveable m a t e r i a l towards and over them. Rats with demedullated a d r e n a l glands, and t h e r e f o r e reduced systemic l e v e l s of e p i n e p h r i n e , e x h i b i t e d reduced l e v e l s of burying of an unconditioned a v e r s i v e stimulus (Experiments 5 and 6). T h i s r e d u c t i o n of burying observed i n demedullated r a t s was c o u n t e r a c t e d by replacement i n j e c t i o n s of ep i n e p h r i n e (Experiment 6 ) . I n t a c t r a t s given systemic i n j e c t i o n s of .01, .1, .5 or 1 mg/kg of epinephrine e x h i b i t e d i n c r e a s e d l e v e l s of burying of both unconditioned and c o n d i t i o n e d a v e r s i v e s t i m u l i (Experiments 1, 2, 3, 4, and 6); whereas, a l a r g e r dose (2 mg/kg) of e p i n e p h r i n e produced an obvious motor impairment (Experiment 4 ) . These f i n d i n g s c l e a r l y c o n f i r m the hypothesis of a r e l a t i o n between l e v e l s of epinephrine and the responsiveness of organisms t o a v e r s i v e s t i m u l a t i o n . Furthermore, the systematic and robust nature of these r e s u l t s i l l u s t r a t e s the u t i l i t y of i i i t he d e f e n s i v e b u r y i n g paradigm i n the i n v e s t i g a t i o n of e p i n e p h r i n e - b e h a v i o u r r e l a t i o n s and the mechanisms t h a t u n d e r l i e them. i v TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES v i i LIST OF FIGURES v i i i ACKNOWLEDGMENT i x INRODUCTION 1 EPINEPHRINE AND AVERSIVE RESPONDING IN RATS 2 The E f f e c t s of E p i n e p h r i n e A d m i n i s t r a t i o n 2 The E f f e c t s of E p i n e p h r i n e D e p l e t i o n 7 EVALUATION OF STUDIES EXAMINING THE RELATIONSHIP BETWEEN EPINEPHRINE AND AVERSIVE RESPONDING 7 GENERAL PURPOSE 12 D e f e n s i v e B u r y i n g 12 G e n e r a l D e s c r i p t i o n of D e f e n s i v e B u r y i n g 12 D e f e n s i v e B u r y i n g and E p i n e p h r i n e 14 PURPOSE 17 GENERAL METHODS 18 S u b j e c t s 18 App a r a t u s 18 G e n e r a l P r o c e d u r e s 19 H a b i t u a t i o n 19 B e h a v i o u r a l O b s e r v a t i o n and Q u a n t i f i c a t i o n 19 EFFECT OF EXOGENOUS EPINEPHRINE ON DEFENSIVE BURYING 19 Experiment 1 19 Method 20 R e s u l t s and D i s c u s s i o n 22 Experiment 2 25 Method 26 V R e s u l t s and D i s c u s s i o n 26 Experiment 3 30 Method 30 R e s u l t s and D i s c u s s i o n 31 Experiment 4 31 Method 34 R e s u l t s and D i s c u s s i o n 34 EFFECT OF DEMEDULLATION ON DEFENSIVE BURYING 38 A d r e n a l Anatomy .* 39 A d r e n a l D e m e d u l l a t i o n 39 Experiment 5 40 Method 40 Surg e r y 40 B e h a v i o u r a l t e s t i n g 42 H i s t o l o g y 42 R e s u l t s and D i s c u s s i o n 42 Experiment 6 45 Method . 45 R e s u l t s and D i s c u s s i o n 46 GENERAL DISCUSSION 49 Accomplishments of the P r e s e n t S t u d i e s 50 Ev i d e n c e f o r a B e h a v i o u r a l E f f e c t of E p i n e p h r i n e 50 Ev i d e n c e C o n c e r n i n g the Na t u r e of the R e l a t i o n s h i p Between E p i n e p h r i n e and A v e r s i v e Responding 51 Reasons f o r the P o p u l a r i t y of C o n d i t i o n e d A c t i v e A v o i d ance Paradigms 53 v i E f f e c t of E p i n e p h r i n e I n j e c t i o n s on Human Beha v i o u r 54 Mowrer's Theory of Avoidance C o n d i t i o n i n g 56 Why A c t i v e Avoidance Paradigms Have Not Been S u c c e s s f u l 57 C o n c l u s i o n 58 REFERENCES 60 v i i LIST OF TABLES Table 1. E f f e c t s of Epinephrine A d m i n i s t r a t i o n on A v e r s i v e Responding 3 Table 2. E f f e c t s of Adrenal Demedullation on A v e r s i v e Responding 8 v i i i LIST OF FIGURES F i g u r e 1. Mean d u r a t i o n of burying and mean f i n a l h e ight of bedding m a t e r i a l at the dowel on 4 t e s t i n g days f o r r a t s i n j e c t e d with e p i n e p h r i n e and r a t s i n j e c t e d with s a l i n e 23 F i g u r e 2. Mean d u r a t i o n of burying and mean f i n a l height of bedding m a t e r i a l at the f l a s h b u l b on 4 t e s t i n g days f o r r a t s i n j e c t e d with e p i n e p h r i n e and r a t s i n j e c t e d with s a l i n e 27 F i g u r e 3. Mean d u r a t i o n of burying and mean f i n a l h e ight of bedding m a t e r i a l at the t r a p on 4 t e s t i n g days f o r r a t s i n j e c t e d with e p i n e p h r i n e and r a t s i n j e c t e d with s a l i n e 32 F i g u r e 4. Mean d u r a t i o n Of burying and mean f i n a l h e ight of bedding m a t e r i a l at the dowel f o r r a t s i n j e c t e d with one of f i v e d i f f e r e n t doses of epinephrine 35 F i g u r e 5. Mean d u r a t i o n of burying and mean f i n a l h e ight of bedding m a t e r i a l at the t r a p f o r r a t s that had t h e i r a d r e n a l glands demedullated and r a t s that had "sham" o p e r a t i o n s . 43 F i g u r e 6. Mean d u r a t i o n of burying and mean f i n a l height of bedding m a t e r i a l at the t r a p f o r demedullated and "sham" c o n t r o l r a t s i n j e c t e d with one of three d i f f e r e n t doses of ep i n e p h r i n e 47 ix ACKNOWLEDGEMENT The author wishes to thank her s u p e r v i s o r Dr. John P.J. P i n e l f o r the a s s i s t a n c e and guidance he pr o v i d e d d u r i n g the res e a r c h f o r and p r e p a r a t i o n of t h i s d i s s e r t a t i o n . The author would a l s o l i k e to express her g r a t i t u d e to the remaining members of her s u p e r v i s o r y committee, Dr. B. Gorzalka and Dr. R. Corteen f o r t h e i r recommendations and encouragement. S p e c i a l thanks are extended to Marcia Spetch and D a l l a s T r e i t f o r t h e i r i n v a l u a b l e a i d and support, as c o l l e a g u e s and as f r i e n d s . S i n c e r e a p p r e c i a t i o n i s expressed to G. Renfrey f o r h i s a s s i s t a n c e with the p r e p a r a t i o n of the f i g u r e s i n c l u d e d i n t h i s d i s s e r t a t i o n . F i n a l l y the author i s indebted to Dr. D. Shaun Gray f o r h i s p a t i e n c e , suggestions, and i n v a l u a b l e encouragement d u r i n g her e n t i r e Ph.D. program. 1 INTRODUCTION S i n c e the o b s e r v a t i o n by Cannon and de l a Paz (1911) t h a t the hormone e p i n e p h r i n e was r e l e a s e d from the a d r e n a l g l a n d s of a c a t " f r i g h t e n e d " by a b a r k i n g dog, many s t u d i e s have c o n f i r m e d t h a t the a d r e n a l m e d u l l a of humans and o t h e r a n i m a l s s e c r e t e s e p i n e p h r i n e i n response t o a v e r s i v e s t i m u l a t i o n (Frankenhaeuser, 1971; Mason, 1968; Smith, 1973). For example, i n c r e a s e d e p i n e p h r i n e o u t p u t from the a d r e n a l m e d u l l a has been found t o occur i n response t o e l e c t r i c shock (McCarty & K o p i n , 1979), r a d i a l a c c e l e r a t i o n ( G o o d a l l , 1962), and d e n t a l t r e a t m e n t (Schmidt, Suss, Z i c h a , Suss, & Weiss, 1964). T h i s c o n s i s t e n t r e l a t i o n s h i p between a v e r s i v e s t i m u l a t i o n and the e l e v a t i o n of c i r c u l a t i n g e p i n e p h r i n e l e v e l s prompted some i n v e s t i g a t o r s ( e . g . , L a t a n e & S c h a c h t e r , 1962; L e v i n e & S o l i d a y , 1962) t o p r e d i c t t h a t e p i n e p h r i n e might a c t u a l l y cause or a t l e a s t enhance the changes i n a f f e c t and b e h a v i o u r t h a t o c c u r i n a v e r s i v e s i t u a t i o n s ( L e s h n e r , 1978). T h i s p r e d i c t i o n has been c o n f i r m e d by a few e x p e r i m e n t s . F o r example, s y s t e m i c a d m i n i s t r a t i o n of e p i n e p h r i n e has been found t o enhance two-way a c t i v e a v o i d a n c e r e s p o n d i n g i n r a t s (Latane' & S c h a c h t e r , 1962); t r e m b l i n g , u r i n a t i o n , and d e f e c a t i o n i n r a t s exposed t o a f l a s h i n g l i g h t and l o u d n o i s e ( S i n g e r , 1963); and a n g e r - r e l a t e d b e h a v i o u r i n humans ( S c h a c h t e r & S i n g e r , 1962). One of the most i n t e r e s t i n g a s p e c t s of the a b i l i t y of s y s t e m i c a l l y i n j e c t e d e p i n e p h r i n e t o enhance r e s p o n d i n g i n a v e r s i v e s i t u a t i o n s i s t h a t e p i n e p h r i n e does not p e n e t r a t e the b l o o d - b r a i n b a r r i e r i n a p p r e c i a b l e amounts ( W e i l - M a l h e r b e , A x e l r o d , & Tomchick, 1959). A l t h o u g h a number of p o t e n t i a l 2 mechanisms have been proposed, the means by which epinephrine a f f e c t s the c e n t r a l nervous system and consequently produces b e h a v i o u r a l changes i s s t i l l unknown (Gold, van B u s k i r k , & Haycock, 1977; McCarty & Kopin, 1979). I d e n t i f i c a t i o n of t h i s mechanism has been hampered by the f a c t that the e f f e c t s of p e r i p h e r a l e p i n e p h r i n e on behaviour i n a v e r s i v e s i t u a t i o n s have not been c o n s i s t e n t from experiment to experiment (Smith, 1973). In the f o l l o w i n g s e c t i o n s , the l i t e r a t u r e c o n cerning the r e l a t i o n s h i p between s y s t e i c e p i n e p h r i n e and " a v e r s i v e responding" i n r a t s w i l l be reviewed and e v a l u a t e d . Because so few r e l e v a n t s t u d i e s have been conducted on s u b j e c t s other than the l a b o r a t o r y r a t , t h e i r d i s c u s s i o n i s omitted here. The r e l e v a n t s t u d i e s performed on humans are b r i e f l y reviewed i n the General D i s c u s s i o n . EPINEPHRINE AND AVERSIVE RESPONDING IN RATS The r e l a t i o n s h i p between ep i n e p h r i n e and a v e r s i v e responding has been i n v e s t i g a t e d by a l t e r i n g c i r c u l a t i n g e p i n e p h r i n e l e v e l s and observing the e f f e c t s of t h i s a l t e r a t i o n on behaviour i n a v e r s i v e s i t u a t i o n s . There are two ways i n which systemic e p i n e p h r i n e l e v e l s have been a l t e r e d : 1) e p i n e p h r i n e l e v e l s have been e l e v a t e d with systemic i n j e c t i o n s and 2) e p i n e p h r i n e l e v e l s have been reduced by removal of the main source of endogenous ep i n e p h r i n e , the a d r e n a l medulla (McCarty & Kopin, 1979). A c c o r d i n g l y , the e f f e c t s of these two m a n i p u l a t i o n s are d i s c u s s e d below under separate headings. The E f f e c t s of Epinephrine A d m i n i s t r a t i o n F i v e s t u d i e s (see Table 1) have demonstrated an enhancement of a v e r s i v e responding i n r a t s i n j e c t e d with e p i n e p h r i n e . Rats 3 Tab l e 1 E f f e c t s of E p i n e p h r i n e A d m i n i s t r a t i o n on A v e r s i v e Responding Paradigm I n v e s t i g a t o r Dosage R e s u l t s A c t i v e Avoidance Two-way S i n e s (1959) Latane & Sc h a c h t e r (1962) Stewart & B r o o k s h i r e (1967) Conner & L e v i n e (1969) Gupta & H o l l a n d (1969) Moran, Ahmad, & Meagher (1970) ( i n s t e r i l e w a t e r , i . p . ) .1 mg/kg .2 and .4 mg/kg ( i n o i l , s.c.) .125 mg/kg 2.5 & 5.0 mg/kg ( i n o i l , s . c . ) .125 mg/kg 5.0 mg/kg ( i n o i l , s.c.) .125 mg/kg ( i n d i s t i l l e d w a t e r , i . p . ) 1.0 mg/kg 2.0,3.0, 4.0, and 5.0 mg/kg ( i n s a l i n e -g l u c o s e , i . p . .125 mg/kg ( i n o i l , s.c. .125 mg/kg 0 no s i g n i f i c a n t e f f e c t s l o w e r a c q u i s i t i o n + f a s t e r a c q u i s i t i o n 0 no s i g n i f i c a n t e f f e c t no s i g n i f i c a n t e f f e c t s l o w e r a c q u i s i t i o n s l o w e r a c q u i s i t i o n ? not a s s e s s e d s t a t i s t i c a l l y d e c r e a s e d number of av o i d a n c e r e s p o n s e s s l o w e r a c q u i s i t i o n s l o w e r a c q u i s i t i o n no s i g n i f i c a n t e f f e c t on a c q u i r e d t a s k performance but i n c r e a s e d t r e m b l i n g and s h i f t s i n a c t i v i t y ( c o n t i n u e d ) 4 Tab l e 1 — C o n t i n u e d Paradigm I n v e s t i g a t o r Dosage R e s u l t s One-way C o n d i t i o n e d S u p p r e s s i o n Escape Remington & Anisman (1974) Kosman & G e r a r d (1955) Moyer & B u n n e l l (1959) D'Amato & S c h i f f (1964) Leshner & Stewart (1966) Stewart & B r o o k s h i r e (1968) S t e w a r t & B r o o k s h i r e (1968) ( i n s a l i n e , i .p.) .25 mg/kg ( i n o i l , s.c .) 6.0 mg/kg ( i n s a l i n e , i .p.) . 3, .6 and .9 mg/kg ( i .p.) .125 and .25 mg/kg ( i n o i l , s.c.) .1 and 1.0 mg/kg 3.0 mg/kg ( i n o i l , s.c.) .1, 1.0, 3.0, 5.0 and 7.0 mg/kg ( i n o i l , s.c.) .1, 1.0, 3.0, 5.0 and 7.0 mg/kg d e c r e a s e d number of a v o i d a n c e responses decrement i n a c q u i r e d t a s k pe rformance no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n 0 no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n 0 no s i g n i f i c a n t e f f e c t on ex t i n c t i o n g r e a t e r mean r u n n i n g t i m e s no s i g n i f i c a n t s u p p r e s s i o n of a l i c k i n g response no s i g n i f i c a n t e f f e c t on escape r e s p o n d i n g ( c o n t i n u e d ) 5 Tab l e 1 — C o n t i n u e d Paradigm I n v e s t i g a t o r Dosage R e s u l t s Exposure t o : L i g h t and N o i s e S i n g e r (1963) ( i n o i l , s.c .) .05 and .1 mg/kg + i n c r e a s e d d e f e c a t i o n , u r i n a t i o n , and t r e m b l i n g L e v e n t h a l & K i l l a c k e y (1968) ( i n s a l i n e , i .p.) .08 mg/kg + i n c r e a s e d time spent i n the f a m i l i a r compartment of a box Shocked i n One P a r t of a Two-Compartment Box and L a t e r R e p l a c e d i n Box Ramano (1968) ( i n s a l i n e , i . p.) .1 mg/kg + d e c r e a s e d time spent i n shock compartment Note. + i n c r e a s e d , - = d e c r e a s e d , 0 = no s i g n i f i c a n t , and = q u e s t i o n a b l e e f f e c t on a v e r s i v e r e s p o n d i n g . 6 r e c e i v i n g exogenous e p i n e p h r i n e and exposed t o a v e r s i v e s t i m u l i c o n s i s t i n g of a l o u d n o i s e ( e . g . , the sound made by a b u z z e r ) and a f l a s h i n g l i g h t were found t o e x h i b i t i n c r e a s e d t r e m b l i n g , u r i n a t i o n , and d e f e c a t i o n i n one s t u d y ( S i n g e r , 1963) and i n c r e a s e d d e f e c a t i o n and an i n c r e a s e i n the amount of time spent i n the f a m i l i a r compartment of a two-chamber box i n a n o t h e r ( L e v e n t h a l & K i l l a c k e y , 1968). In a s i m i l a r type of i n v e s t i g a t i o n (Kamano, 1968), r a t s i n j e c t e d w i t h e p i n e p h r i n e were found t o spend l e s s time i n the compartment of a box i n which they had p r e v i o u s l y r e c e i v e d f o o t s h o c k . S y s t e m i c e p i n e p h r i n e a d m i n i s t r a t i o n has a l s o been found t o f a c i l i t a t e a c q u i s i t i o n of s h u t t l e - b o x a v o i d a n c e (Latane & S c h a c h t e r , 1962); however, i n an a t t e m p t e d r e p l i c a t i o n (Moran, Ahmad, & Meagher, 1970) of t h i s s t u d y , a c q u i s i t i o n of a v o i d a n c e r e s p o n d i n g was not enhanced by e p i n e p h r i n e a d m i n i s t r a t i o n , but t r e m b l i n g and s h i f t s i n t y pe of a c t i v i t y were. In c o n t r a s t , i n the r e m a i n i n g 12 p u b l i s h e d s t u d i e s of the e f f e c t of e p i n e p h r i n e a d m i n i s t r a t i o n on responses t o a v e r s i v e s t i m u l a t i o n , e p i n e p h r i n e e i t h e r produced no s i g n i f i c a n t e f f e c t or a c t u a l l y reduced a v e r s i v e r e s p o n d i n g . E p i n e p h r i n e a d m i n i s t r a t i o n has e i t h e r f a i l e d t o a f f e c t or has i m p a i r e d two-way a c t i v e a v o i d a n c e r e s p o n d i n g (Conner & L e v i n e , 1969; Gupta & H o l l a n d , 1969; Moran et a l . , 1970; Remington & Anisman, 1974; S i n e s , 1959; Stewart & B r o o k s h i r e , 1968), one-way a c t i v e a v o i d a n c e r e s p o n d i n g (D'Amato & S c h i f f , 1964; Kosman & G e r a r d , 1955; Leshner & S t e w a r t , 1966; Moyer & B u n n e l l , 1959), c o n d i t i o n e d s u p p r e s s i o n of r e s p o n d i n g (Stewart & B r o o k s h i r e , 1968), and escape r e s p o n d i n g ( S t e w a r t & B r o o k s h i r e , 1968). 7 The E f f e c t s of Ep i n e p h r i n e D e p l e t i o n Four s t u d i e s (see Table 2) have demonstrated the p r e d i c t e d d i s r u p t i o n of responding to a v e r s i v e s t i m u l i i n r a t s with t h e i r main source of endogenous e p i n e p h r i n e , the adrenal medulla, s u r g i c a l l y removed. In these s t u d i e s , a d r e n a l e n u c l e a t i o n caused a d i s r u p t i o n of p a s s i v e avoidance ( S i l v a , 1973), c o n d i t i o n e d suppression (Pare _ C u l l e n , 1971), and two-way a c t i v e avoidance (Conner & L e v i n e , 1969; Levine & S o l i d a y , 1962). In one study (Conner & L e v i n e , 1969), t h i s e f f e c t was found to be r e v e r s i b l e by the a d m i n i s t r a t i o n of exogenous e p i n e p h r i n e . In c o n t r a s t , there have been almost twice as many p u b l i s h e d experiments ( i . e . , seven) i n which a d r e n a l e n u c l e a t i o n has been found to have no s i g n i f i c a n t e f f e c t on a v e r s i v e responding. A d r e n a l - e n u c l e a t i o n was found to have no s i g n i f i c a n t e f f e c t on a v e r s i v e responding i n p a s s i v e avoidance (Di G u i s t o , 1971; S i l v a , 1973), i n c o n d i t i o n e d s u p p r e s s i o n (Leshner, B r o o k s h i r e , & Stewart, 1971), i n two-way a c t i v e avoidance (Moyer _ Korn, 1965), and i n one-way a c t i v e avoidance (Clancy & C a l d w e l l , 1978; Moyer _ B u n n e l l , 1959; S i l v a , 1974) paradigms. EVALUATION OF THE STUDIES EXAMINING THE RELATIONSHIP BETWEEN EPINEPHRINE AND AVERSIVE RESPONDING The above s t u d i e s have o b v i o u s l y been u n s u c c e s s f u l i n e l u c i d a t i n g the r e l a t i o n s h i p between epinephrine l e v e l s and the behaviour of r a t s i n a v e r s i v e s i t u a t i o n s ; the experimental r e s u l t s are so i n c o n s i s t e n t that i t i s d i f f i c u l t to determine whether a r e l i a b l e r e l a t i o n s h i p between epinephrine and a v e r s i v e responding even e x i s t s (Leshner, 1978; Smith, 1973). Although a v a r i e t y of f a c t o r s may have c o n t r i b u t e d to the 8 Ta b l e 2 E f f e c t s of A d r e n a l D e m e d u l l a t i o n on A v e r s i v e Responding Paradigm I n v e s t i g a t o r R e s u l t s A c t i v e Avoidance Two-way One-way P a s s i v e A v o i d a n c e L e v i n e & S o l i d a y (1962) Moyer & Korn (1965) Conner & L e v i n e (1969) Moyer & B u n n e l l (1959) S i l v a (1974) C l a n c y & C a l d w e l l (1978) Di G u i s t o (1971) S i l v a (1973) + s l o w e r a c q u i s i t i o n ° no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n + s l o w e r a c q u i s i t i o n { r e s t o r e d by a d m i n i s t r a t i o n of of e p i n e p h r i n e (.125 mg/kg i n o i l , s.c.)} no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n no s i g n i f i c a n t e f f e c t on e x t i n c t i o n no s i g n i f i c a n t e f f e c t on a c q u i s i t i o n no s i g n i f i c a n t e f f e c t on performance no s i g n i f i c a n t e f f e c t on e x t i n c t i o n when e i t h e r 1.0-or .3-sec 1.0 mA shock was used f a s t e r e x t i n c t i o n when .2 sec shock was used ( c o n t i n u e d ) 9 T a b l e 2 — C o n t i n u e d Paradigm I n v e s t i g a t o r R e s u l t s C o n d i t i o n e d S u p p r e s s i o n Pare & C u l l e n (1971) Le s h n e r , B r o o k s h i r e , & S t ewart (1971) + l e s s s u p p r e s s i o n of bar p r e s s i n g f o r food ° no s i g n i f i c a n t e f f e c t on s u p p r e s s i o n of a l i c k i n g response Note. + = d e c r e a s e d and ° r e s p o n d i n g . = no s i g n i f i c a n t e f f e c t on a v e r s i v e 10 i n c o n s i s t e n c i e s i n the e x p e r i m e n t a l r e s u l t s , the f a c t t h a t some s t u d i e s have i n v o l v e d l e a r n e d responses and o t h e r s i n n a t e r e sponses t o a v e r s i v e s t i m u l a t i o n may account f o r a s u b s t a n t i a l p o r t i o n of the c o n f u s i o n . The term " i n n a t e " as used here r e f e r s t o r e s p o n s e s ( e . g . , f l e e i n g , f r e e z i n g , t r e m b l i n g , u r i n a t i o n , d e f e c a t i o n ) t h a t a r e e x h i b i t e d i n t h e i r complete form i n the absence of r e l e v a n t t r a i n i n g . I t i s i m p o r t a n t t o note t h a t i n o n l y one (Latane' & S c h a c h t e r , 1962) of the 12 s t u d i e s i n v o l v i n g a l e a r n e d response ( i . e . , c o n d i t i o n e d a c t i v e a v o i d a n c e ) as the dependent v a r i a b l e was t h e r e an enhancement of a v e r s i v e r e s p o n d i n g i n response t o the i n j e c t e d e p i n e p h r i n e . In c o n t r a s t , f o u r (Kamano, 1968; L e v e n t h a l & K i l l a c k e y , 1968; Moran e t a l . , 1970; S i n g e r , 1963) of the s i x p u b l i s h e d a t t e m p t s t o f a c i l i t a t e i n n a t e a v e r s i v e r esponses have met w i t h s u c c e s s . As a r e s u l t , some a u t h o r s ( e . g . , D i G u i s t o , C a i r n c r o s s , & K i n g , 1970) have suggested t h a t exogenous e p i n e p h r i n e may a f f e c t o n l y i n n a t e r e s p o n s e s t o a v e r s i v e s t i m u l a t i o n . A l t h o u g h the v a l i d i t y of t h i s p r o p o s i t i o n has y e t t o be e s t a b l i s h e d , i t i s u n d e n i a b l e t h a t i n n a t e r e s p o n s e s have proven t o be more u s e f u l than l e a r n e d r e s p o n s e s i n the study of the e f f e c t s of e p i n e p h r i n e on r e s p o n d i n g i n a v e r s i v e s i t u a t i o n s . R e p o r t s of a r e l a t i o n s h i p between e p i n e p h r i n e and i n n a t e r e s p o n s e s , u n f o r t u n a t e l y , have had l i t t l e impact i n t h i s a r e a of b e h a v i o u r a l e n d o c r i n o l o g y . P a r t of the reason f o r t h i s l a c k of i n f l u e n c e may be the p r e d i l e c t i o n of p s y c h o l o g i s t s f o r c o n d i t i o n e d r esponses (Di G u i s t o e t a l . , 1970). For example, Gupta and H o l l a n d (1969) r e f e r t o the f r e e z i n g and c r o u c h i n g p o s t u r e s t h a t d e l a y a c q u i s t i o n of a c o n d i t i o n e d a v o i d a n c e 11 response as "abnormal reactions". There do, however, seem to be two s p e c i f i c problems with the p a r t i c u l a r innate responses to aversive stimuli that have been used to examine the behavioural e f f e c t s of epinephrine. F i r s t , some of these responses, such as defecation and urination, are under the d i r e c t control of the sympathetic nervous system, and hence i t i s d i f f i c u l t to determine i f an increased frequency of these behaviours i s anything more than a d i r e c t peripheral nervous system e f f e c t of epinephrine. The most important question raised by behavioural studies of epinephrine is how epinephrine can influence complex behaviours under central nervous system control without penetrating the blood brain b a r r i e r . Second, other aversive responses (e.g., a c t i v i t y l e v e l and freezing) are ambiguous. Freezing, for example, i s an ambiguous response in that i t i s d i f f i c u l t to determine i f the rat i s motionless (frozen) as a result of exposure to an aversive stimulus or is simply t i r e d or otherwise d e b i l i t a t e d . It appears then that i f innate responses are to be used in the study of the relationship between epinephrine and aversive responding, the response chosen for study should meet at least two c r i t e r i a . F i r s t , the behaviour in question should be a response to aversive stimulation that i s not under dire c t sympathetic control; i t should r e f l e c t an action of epinephrine mediated by the central nervous system. Second, the response topography must be unambiguous; the response should be c l e a r l y distinguishable as a response to aversive stimuli and should not c l o s e l y resemble behaviours that occur in other sit u a t i o n s . 12 GENERAL PURPOSE The g e n e r a l purpose of the present r e s e a r c h was to determine the r e l a t i o n s h i p between epinephrine l e v e l s and d e f e n s i v e b u r y i n g , an innate response to a v e r s i v e s t i m u l a t i o n c that appears to s a t i s f y both of the aforementioned c r i t e r i a . D efensive b u r y i n g , r e f e r s to the f a c t that r a t s t y p i c a l l y respond to w e l l - d e f i n e d a v e r s i v e s t i m u l i by pushing moveable m a t e r i a l towards and over them. T h i s behaviour was f i r s t d e s c r i b e d by Hudson (1950) and has r e c e n t l y been l a b e l l e d , q u a n t i f i e d , and i n v e s t i g a t e d by P i n e l and h i s co-workers (e.g., P i n e l _ T r e i t , 1978; T e r l e c k i , P i n e l , & T r e i t , 1979; W i l k i e , MacLennan, & P i n e l , 1979). The f o l l o w i n g review of d e f e n s i v e burying r e v e a l s that i t s a t i s f i e s the two c r i t e r i a d i s c u s s e d above, and i n a d d i t i o n o f f e r s a number of other advantages for use i n the study of the r e l a t i o n s h i p between epi n e p h r i n e and responses to a v e r s i v e s t i m u l i . Defensive Burying  General D e s c r i p t i o n of Defensive Burying In the standard burying paradigm, r a t s are exposed to an e a s i l y d i s c e r n a b l e a v e r s i v e s t i m u l u s l o c a t e d i n a s m a l l P l e x i g l a s t e s t chamber c o n t a i n i n g commercial bedding m a t e r i a l . Rats p l a c e d i n t h i s s i t u a t i o n d i s p l a c e the bedding m a t e r i a l towards the a v e r s i v e o b j e c t — an a c t i v i t y that u s u a l l y r e s u l t s i n the o b j e c t being covered with bedding by the end of the standard 15-min t e s t p e r i o d . Although the r a t s can use a v a r i e t y of movements to d i r e c t m a t e r i a l towards an a v e r s i v e o b j e c t , when commercial bedding or a s i m i l a r homogenous m a t e r i a l such as sand c o n s t i t u t e s the only a v a i l a b l e m a t e r i a l , burying behaviour i s 13 h i g h l y s t e r e o t y p e d ( P i n e l & T r e i t , 1979). The r a t t y p i c a l l y approaches the a v e r s i v e o b j e c t from a d i s t a n t p a r t of the chamber and sprays the bedding forward with r a p i d pushing movements of i t s f o r e l i m b s . Thus, burying behaviour i n t h i s t e s t s i t u a t i o n i s u s u a l l y measured by r e c o r d i n g the amount of time the r a t spends engaged in t h i s d i r e c t e d f o r e l i m b s p r a y i n g and a l s o by measuring the height of the bedding m a t e r i a l accumulated at the t e s t o b j e c t at the end of the t e s t s e s s i o n . Burying behaviour occurs i n response to both u n c o n d i t i o n e d and c o n d i t i o n e d a v e r s i v e s t i m u l i . I t has been found that r a t s enter the experimental environment with a p r e - e x i s t i n g tendency to bury some s t i m u l i (unconditioned d e f e n s i v e burying) but not o t h e r s . For example, r a t s b u r i e d an unset mousetrap or an unspent f l a s h b u l b when they were f i r s t encountered i n a f a m i l i a r t e s t chamber, but not a l e n g t h of p o l y e t h y l e n e tubing or a wire-wrapped wooden dowel (e.g., P i n e l , Hoyer, & T e r l e c k i , 1980; T e r l e c k i , P i n e l , & T r e i t , 1979). Rats have a l s o been found to bury s e l e c t i v e l y p r e v i o u s l y n e u t r a l s t i m u l i that have been p a i r e d with any one of a v a r i e t y of a v e r s i v e s t i m u l i ( c o n d i t i o n e d d e f e n s i v e b u r y i n g ) . For example, in the most f r e q u e n t l y used v e r s i o n of t h i s paradigm r a t s bury a wire-wrapped wooden dowel once i t has been the source of an e l e c t r i c shock (e.g., P i n e l & T r e i t , 1978). However, r a t s have a l s o been shown to bury n e u t r a l o b j e c t s p a i r e d with such v a r i e d u n c o n d i t i o n e d a v e r s i v e s t i m u l i as a i r b l a s t , f l a s h i n g l i g h t , p h y s i c a l impact, t o x i c o s i s , or noxious t a s t e (e.g., T e r l e c k i et a l . , 1979; W i l k i e , MacLennan, & P i n e l , 1979). Although most s t u d i e s of d e f e n s i v e burying have i n v o l v e d 14 a d u l t , male, hooded, Long-Evans r a t s , b u r y i n g i s not s p e c i f i c t o t h e s e s u b j e c t s . B u r y i n g b e h a v i o u r has been obser v e d i n both male and female r a t s and i n r a t s as young as 30 days of age ( T r e i t , T e r l e c k i , & P i n e l , 1980). Moreover, d e f e n s i v e b u r y i n g i s e x h i b i t e d by o t h e r s t r a i n s ( e . g . , F i s h e r , Long-Evans, Sprague-Dawley, W i s t a r ) of r a t s (McKim _ L e t t , 1979; T r e i t e t a l . , 1980) and a l s o by o t h e r r o d e n t s such as ground s q u i r r e l s (Owings & Coss, 1977) and mice ( T r e i t e t a l . , 1980). L a b o r a t o r y i n v e s t i g a t i o n s and n a t u r a l i s t i c o b s e r v a t i o n s have suggested t h a t d e f e n s i v e b u r y i n g has an a d a p t i v e f u n c t i o n . T h i s d i r e c t e d f o r e l i m b s p r a y i n g response can have at l e a s t t h r e e d i f f e r e n t b e n e f i c i a l p h y s i c a l consequences f o r the r a t . F i r s t , t h i s response can r e s u l t i n p o t e n t i a l l y hazardous o b j e c t s b e i n g c o m p l e t e l y c o v e r e d w i t h m a t e r i a l (Coss & Owings, 1978; T e r l e c k i et a l . , 1979). Second, i t can s e r v e t o d r i v e o f f p r e d a t o r s ( e . g . , snakes) and a g g r e s s i v e c o n s p e c i f i c s ( c f . Coss _ Owings, 1978; Owings _ Coss, 1977). And t h i r d , i t can r e s u l t i n the f o r m a t i o n of b a r r i e r s t h a t can impede the approach of a g g r e s s i v e c o n s p e c i f i c s ( C a l h o u n , 1962) or members of o t h e r s p e c i e s (Coss & Owings, 1978; T e r l e c k i , P i n e l , & S p e t c h , 1980). D e f e n s i v e B u r y i n g and E p i n e p h r i n e D e f e n s i v e b u r y i n g c l e a r l y meets b o t h of the p r e v i o u s l y d e s c r i b e d c r i t e r i a f o r a b e h a v i o u r a l response i n t e n d e d f o r use i n s t u d y i n g the r e l a t i o n s h i p between e p i n e p h r i n e and b e h a v i o u r i n a v e r s i v e s i t u a t i o n s . F i r s t , b u r y i n g b e h a v i o u r i s a complex b e h a v i o u r t h a t o b v i o u s l y i s not under the e x c l u s i v e c o n t r o l of the s y m p a t h e t i c nervous system. Second, b u r y i n g i s a h i g h l y s t e r e o t y p e d response t o a v e r s i v e s t i m u l i t h a t i s e a s i l y 15 recognized and scored. High degrees of agreement have been found between independent observers scoring the duration of thi s behaviour: Davis, Whiteside, Heck, Dickson, & Tram i l l (in press); P i n e l , Hoyer, & Terlecki (1980); Pinel, T r e i t , and Wilkie (1980); and Davis and Rossheim (in press) have reported correlations of .95, .98, .988, and .93, respectively. The defensive burying paradigm also has a number of other features that may prove useful in the study of the eff e c t s of epinephrine on aversive responding. F i r s t , because burying behaviour occurs in response to both conditioned (e.g., Pinel & T r e i t , 1978; Terlecki et a l . , 1979) and unconditioned (e.g., McKim & Lett, 1.979; Terlecki et a l . , 1979) aversive s t i m u l i , i t is possible to assess the eff e c t of epinephrine on aversive responding to both of these types of aversive stimulation. Some investigators (e.g., Stewart & Brookshire, 1968) have argued that exogenous epinephrine may enhance innate responses to unconditioned aversive stimuli but not those to conditioned aversive s t i m u l i . The v a l i d i t y of t h i s proposition can be assessed by examining the eff e c t s of a l t e r i n g epinephrine levels on both kinds of defensive burying. Second, by using the defensive burying paradigm to study the e f f e c t s of epinephrine on aversive responding, i t i s possible to avoid one of the confounds inherent in most of the previously described studies. In many of the epinephrine-administration studies and in a l l of the epinephrine-depletion studies, epinephrine levels have been altered during both the conditioning and testing phases of the experiment, thereby confounding the effects of epinephrine on aversive responding 16 with i t s possible effects on conditioning and memory; besides a f f e c t i n g the animals' response to aversive stimulation, a l t e r a t i o n of epinephrine l e v e l s may be a f f e c t i n g such processes as the formation of associations (cf. Stewart & Brookshire, 1968) and t h e i r storage in memory (Gold & van Buskirk, 1975). Interpretation of the results of such studies i s therefore d i f f i c u l t . The unconditioned defensive burying paradigm involves no conditioning phase, and thus could be used to circumvent t h i s d i f f i c u l t y . The conditioned defensive burying paradigm may also prove to be useful in t h i s respect because s i g n i f i c a n t amounts of burying are displayed by rats tested many days afte r a single conditioning t r i a l (Pinel & T r e i t , 1978). Because conditioning and testing phases can be e a s i l y separated in time using t h i s paradigm, epinephrine lev e l s could be s e l e c t i v e l y altered during the testing phase of the experiment. Third, i t i s easy to produce a control l e v e l of burying against which an enhancement or disruption i s readily detectable. The amount of burying displayed by rats during a given test session can be controlled by varying the amount of pr i o r exposure to the aversive stimulus (Terlecki et a l . , 1979), the length of the i n t e r v a l between conditioning and testing (Pinel & T r e i t , 1978), the intensity of the aversive stimulus (Treit et a l . , 1980), or the size of the chamber (Pinel, T r e i t , Ladak, & MacLennan, 1980). Fourth, because the burying response i s an active motor behaviour, any enhancement of t h i s response i s readily distinguishable from an impairment of motor functioning. Because a number of studies (e.g., Kosman & Gerard, 1955; Leshner & 17 S t e w a r t , 1966; Manto, 1967) have e s t a b l i s h e d t h a t h i g h l e v e l s of e p i n e p h r i n e a r e p h y s i c a l l y d e b i l i t a t i n g , some e x p e r i m e n t e r s ( e . g . , D i G u i s t o et a l . , 1971) have warned t h a t a d m i n i s t r a t i o n of e p i n e p h r i n e may be an u n s u i t a b l e t e c h n i q u e f o r a s s e s s i n g the e f f e c t s of e p i n e p h r i n e on a v e r s i v e r e s p o n d i n g . T h i s c r i t i c i s m may be v a l i d when a p p l i e d t o paradigms t h a t i n v o l v e an i n h i b i t i o n of a c t i v e r e s p o n d i n g ( e . g . , c o n d i t i o n e d s u p p r e s s i o n and p a s s i v e a v o i d a n c e paradigms) because i t might be d i f f i c u l t j t o d i f f e r e n t i a t e between an enhancement of r e s p o n d i n g and an impairment of locomotor f u n c t i o n u s i n g these paradigms. The b u r y i n g paradigm, however, i s f r e e from t h i s problem. PURPOSE The g e n e r a l purpose of the p r e s e n t i n v e s t i g a t i o n s was t o deter m i n e the r e l a t i o n between s y s t e m i c e p i n e p h r i n e and the d e f e n s i v e b u r y i n g r e s p o n s e . The e x p e r i m e n t a l approach t h a t was used t o e s t a b l i s h t h i s r e l a t i o n i n v o l v e d the m a n i p u l a t i o n of c i r c u l a t i n g e p i n e p h r i n e l e v e l s . P e r i p h e r a l l e v e l s of e p i n e p h r i n e were e i t h e r i n c r e a s e d by i n j e c t i o n of exogenous e p i n e p h r i n e or d e p l e t e d by removing the p r i m a r y s o u r c e of endogenous e p i n e p h r i n e , the a d r e n a l m e d u l l a . The i n d i v i d u a l e x p e r i m e n t s were, t h u s , of two t y p e s . The f i r s t s e t of s t u d i e s i n v o l v e d the e f f e c t s of s y s t e m i c e p i n e p h r i n e i n j e c t i o n s on d e f e n s i v e b u r y i n g ( E x p e r i m e n t s 1 t o 4 ) . The second i n v o l v e d an e x a m i n a t i o n of the e f f e c t of a d r e n a l d e m e d u l l a t i o n on d e f e n s i v e b u r y i n g ( E x p e r i m e n t s 5 and 6) and a l s o of the a b i l i t y of replacement i n j e c t i o n s of e p i n e p h r i n e t o r e v e r s e t h i s e f f e c t (Experiment 6 ) . A l t h o u g h the r e s u l t s of p r e v i o u s s t u d i e s had sug g e s t e d t h a t e p i n e p h r i n e c o u l d a f f e c t r e s p o n s e s i n a v e r s i v e s i t u a t i o n s , no 18 p r e v i o u s s t u d i e s had been able to demonstrate a r e l i a b l e and systematic r e l a t i o n between p e r i p h e r a l epinephrine and such behaviour. GENERAL METHODS There are a number of methodological f e a t u r e s that are common to the s i x experiments i n c l u d e d i n t h i s d i s s e r t a t i o n . These g e n e r a l f e a t u r e s are d e s c r i b e d below. Subjects The s u b j e c t s used i n each of the experiments were naive, male, Long-Evans hooded r a t s purchased from Canadian Breeding Farm and L a b o r a t o r i e s , La P r a i r i e , Quebec. The r a t s were housed in groups of e i t h e r four or s i x i n 41 X 25 X 18 cm and 63 X 25 X 18 cm wire-mesh cages, r e s p e c t i v e l y . P u r i n a l a b o r a t o r y chow and water were a v a i l a b l e c o n t i n u o u s l y i n the home cages. The r a t s were housed under a 12-hr l i g h t / 1 2 - h r dark c y c l e . Apparatus The r a t s were t e s t e d i n d i v i d u a l l y i n a s m a l l , i s o l a t e d room adjacent to the b e h a v i o u r a l r e c o r d i n g apparatus. The t e s t chamber was a 44 X 30 X 44 cm tr a n s p a r e n t P l e x i g l a s box, the f l o o r of which was covered with a 5 cm l a y e r of r e g u l a r grade S a n - i - c e l , a commercial bedding m a t e r i a l made of ground corncob (Paxton P r o c e s s i n g Co., Paxton, I l l i n o i s ) . The r a t ' s behaviour was monitored v i a a t e l e v i s i o n camera mounted 50 cm d i r e c t l y above the t e s t chamber. The d u r a t i o n of bur y i n g , that i s , the amount of time the r a t spent engaging i n d i r e c t e d f o r e l i m b s p r a y i n g , was recorded on an event r e c o r d e r . The o c c a s i o n a l movement of m a t e r i a l with responses other than f o r e l i m b s p r a y i n g and/or i n d i r e c t i o n s not towards the a v e r s i v e o b j e c t was noted 19 s e p a r a t e l y . T h i s type of behaviour, observed only once i n these s t u d i e s , d i d not c o n t r i b u t e to the d u r a t i o n - o f - b u r y i n g s c o r e . General Procedures H a b i t u a t i o n P r i o r to each experiment, a l l r a t s were given a subcutaneous (s.c.) i n j e c t i o n of i s o t o n i c s a l i n e (1 ml/kg) and pl a c e d i n the t e s t chamber with t h e i r cagemates i n groups of four or s i x f o r 30-min p e r i o d s , each day f o r 4 c o n s e c u t i v e days. Be h a v i o u r a l Observation and Q u a n t i f i c a t i o n Although the c o n d i t i o n i n g phase d i f f e r e d from experiment to experiment, a l l t e s t i n g phases were conducted s i m i l a r l y . On the t e s t i n g day, d u r i n g the l i g h t phase of the r a t s ' l i g h t / d a r k housing c y c l e each r a t was p l a c e d i n d i v i d u a l l y i n t o the t e s t chamber and a 15 min t e s t s e s s i o n was i n i t i a t e d . During t h i s t e s t s e s s i o n , the d u r a t i o n of burying was recorded, and f o l l o w i n g each t e s t , the a b s o l u t e height of the bedding m a t e r i a l at the a v e r s i v e stimulus was measured and recorded. EFFECT OF EXOGENOUS EPINEPHRINE ON DEFENSIVE BURYING Experiment 1 The purpose of the f i r s t experiment was to demonstrate that an i n c r e a s e i n systemic e p i n e p h r i n e l e v e l s enhances the d e f e n s i v e burying of a c o n d i t i o n e d a v e r s i v e s t i m u l u s . C o n d i t i o n e d r a t h e r than uncon d i t i o n e d d e f e n s i v e burying was s e l e c t e d f o r study f o r two reasons. F i r s t , c o n d i t i o n e d d e f e n s i v e b u r y i n g had proven to be s l i g h t l y more robust; i t had been more common f o r burying behaviour to be d i s p l a y e d by every r a t i n a group exposed to a c o n d i t i o n e d a v e r s i v e stimulus than an unco n d i t i o n e d stimulus ( c f . P i n e l , Hoyer, & T e r l e c k i , 1980; 20 T e r l e c k i e t a l . , 1979). Second, c o n d i t i o n e d d e f e n s i v e b u r y i n g had been more t h o r o u g h l y i n v e s t i g a t e d than had u n c o n d i t i o n e d b u r y i n g , thus t h e r e was a more s o l i d f o u n d a t i o n of p a r a m e t r i c d a t a f o r t h i s form of the b u r y i n g paradigm. P r e v i o u s i n v e s t i g a t i o n s had shown t h a t the c o n d i t i o n e d d e f e n s i v e b u r y i n g response i s e x t r e m e l y r e l i a b l e and i s r e a d i l y c o n t r o l l e d by v a r i o u s e x p e r i m e n t a l parameters t h a t a r e e a s i l y m a n i p u l a t e d by the e x p e r i m e n t e r . For example, a d i r e c t and r e l i a b l e r e l a t i o n had been demonstrated between c o n d i t i o n e d d e f e n s i v e b u r y i n g and the i n t e n s i t y of the UCS; T r e i t , P i n e l , and T e r l e c k i (1980) had found t h a t r a t s spent more time b u r y i n g a wooden dowel i f i t had been the s o u r c e of h i g h i n t e n s i t y shock. C o n d i t i o n e d d e f e n s i v e b u r y i n g had a l s o been found t o d e c r e a s e as the d e l a y between c o n d i t i o n i n g and t e s t i n g i n c r e a s e d ( P i n e l & T r e i t , 1978) and as a f u n c t i o n of r e p e a t e d t e s t s w i t h the a v e r s i v e o b j e c t f o l l o w i n g a s i n g l e c o n d i t i o n i n g t r i a l ( T e r l e c k i , u n p u b l i s h e d d a t a ) . By m a n i p u l a t i n g t h e s e e x p e r i m e n t a l parameters ( i . e . , i n t e n s i t y , d e l a y , and e x p o s u r e ) , a l e v e l of d e f e n s i v e b u r y i n g can be produced t h a t i s s u i t a b l e f o r d e m o n s t r a t i n g a f a c i l i t a t o r y e f f e c t of e p i n e p h r i n e . P i l o t s t u d i e s c o n f i r m e d the e f f i c a c y of t h i s a p proach, and the e x p e r i m e n t a l parameters used i n Experiment 1 were chosen on the b a s i s of the r e s u l t i n g d a t a . Method On Day 5, f o l l o w i n g the 4 h a b i t u a t i o n days, a 6.5 X .5 X .5 cm wooden, wire-wrapped dowel was mounted i n the c e n t r e of one end w a l l of the t e s t chamber. The dowel was a t t a c h e d so t h a t i t was p a r a l l e l t o the- f l o o r and s i d e w a l l s of the chamber, a t a h e i g h t 2 cm above the bedding m a t e r i a l . D u r i n g t h i s c o n d i t i o n i n g 21 day, each of the 20 306- t o 402-gm r a t s used i n Experiment 1 was p l a c e d i n d i v i d u a l l y i n the c e n t r e of the chamber, f a c i n g away from the dowel. Each r a t then r e c e i v e d a s i n g l e c o n d i t i o n i n g t r i a l ; the f i r s t forepaw c o n t a c t w i t h the dowel r e s u l t e d i n the r a t r e c e i v i n g a b r i e f e l e c t r i c shock. The shock, i n i t i a t e d by the e x p e r i m e n t e r and t e r m i n a t e d by the w i t h d r a w a l of the r a t , was d e l i v e r e d between the two u n i n s u l a t e d w i r e s t h a t were wrapped around the dowel and c o n n e c t e d t o a c o n s t a n t - c u r r e n t s h o c k e r . The a c t u a l d u r a t i o n and i n t e n s i t y of the shock r e c e i v e d by each r a t was m o n i t o r e d w i t h a s t o r a g e o s c i l l o s c o p e . A n a l y s i s of t h e s e d a t a showed t h a t the r a t s r e c e i v e d shocks a v e r a g i n g 1.9 mA (SD = .2 mA) i n i n t e n s i t y and 36 msec (SD =12.6 msec) i n d u r a t i o n . A f t e r a r a t was shocked, i t was i m m e d i a t e l y removed from the chamber. Each r a t was then randomly a s s i g n e d t o e i t h e r an e p i n e p h r i n e e x p e r i m e n t a l group (n= 10) or a s a l i n e c o n t r o l group (n=10). On the f o l l o w i n g day, p r i o r t o b e i n g p l a c e d i n the t e s t chamber, the r a t s i n the e x p e r i m e n t a l group were i n j e c t e d ( s . c . ) w i t h a .1 mg/kg dose of e p i n e p h r i n e HC1, d i l u t e d i n i s o t o n i c s a l i n e t o a c o n c e n t r a t i o n of .2 mg/ml, and the r a t s i n the c o n t r o l group were i n j e c t e d ( s . c . ) w i t h an e q u i v a l e n t volume (.5 ml/kg) of i s o t o n i c s a l i n e . The i n j e c t i o n s were a d m i n i s t e r e d 1 min p r i o r t o t e s t i n g because e p i n e p h r i n e i n a s a l i n e v e h i c l e s t a r t s t o produce i t s p e r i p h e r a l nervous system e f f e c t s w i t h i n 5 min of i t s subcutaneous a d m i n i s t r a t i o n ( G o l d & van B u s k i r k , 1975; Goodman & Gilman, 1975). A l t h o u g h no f u r t h e r shocks were a d m i n i s t e r e d , the r a t s were g i v e n an i n j e c t i o n and were t e s t e d each day f o r 4 c o n s e c u t i v e days. T e s t i n g was c a r r i e d out over 4 days i n o r d e r t o i n c r e a s e the p r o b a b i l i t y of f i n d i n g an 22 enhancement of d e f e n s i v e b u r y i n g ; as p r e v i o u s l y mentioned, the amount of b u r y i n g e x h i b i t e d by r a t s d e c r e a s e s as the amount of exposure t o t h e c o n d i t i o n e d s t i m u l u s i n c r e a s e s . R e s u l t s and D i s c u s s i o n I t i s apparent from F i g u r e 1 t h a t s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e enhanced the c o n d i t i o n e d d e f e n s i v e b u r y i n g of the shock s o u r c e . The e p i n e p h r i n e - i n j e c t e d r a t s spent s i g n i f i c a n t l y [ F ( l , 1 8 ) = 4.39, p_ < .05] more time s p r a y i n g bedding m a t e r i a l a t the dowel (see p a n e l A) than d i d t h e i r s a l i n e - i n j e c t e d c o n t r o l s . These b e h a v i o u r a l o b s e r v a t i o n s were c o n f i r m e d by a n a l y s i s of the h e i g h t of the m a t e r i a l a c c umulated by the r a t s a t the dowel (see p a n e l B ) . The r a t s t h a t were i n j e c t e d w i t h e p i n e p h r i n e accumulated s i g n i f i c a n t l y [ F ( l , 1 8 ) = 4.45, p < .05] h i g h e r p i l e s of bedding a t the dowel than d i d the r a t s t h a t were i n j e c t e d w i t h s a l i n e . These r e s u l t s e s t a b l i s h e d t h a t i n j e c t e d e p i n e p h r i n e can enhance a v e r s i v e r e s p o n d i n g and demonstrated t h a t the c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm i s s e n s i t i v e t o t h i s e f f e c t . I t i s a l s o e v i d e n t from F i g u r e 1 t h a t the amount of b u r y i n g e x h i b i t e d by b o t h groups of r a t s d e c l i n e d over t e s t i n g s e s s i o n s . T h i s f i n d i n g c o n f i r m s my u n p u b l i s h e d o b s e r v a t i o n t h a t the t o t a l amount of b u r y i n g e x h i b i t e d by r a t s d u r i n g a g i v e n t e s t s e s s i o n d e c r e a s e s w i t h r e p e a t e d exposure t o the c o n d i t i o n e d a v e r s i v e s t i m u l u s . S t a t i s t i c a l a n a l y s e s c o n f i r m e d t h a t the d u r a t i o n of b u r y i n g [ F i g u r e IA; F(3,54) = 27.73, r; < « 0 5 ] a n d h e i g h t of m a t e r i a l a t t h e dowel [ F i g u r e I B ; F(3,54) = 27.01, p < « 0 5 ] d e c r e a s e d s i g n i f i c a n t l y over t e s t i n g days. A l t h o u g h the d e c l i n e i n the d u r a t i o n of b u r y i n g o b s e r v e d over days was not 23 F i g u r e 1. Mean d u r a t i o n of b u r y i n g ( p a n e l A) and mean f i n a l h e i g h t of bedding m a t e r i a l a t the dowel ( p a n e l B) on 4 t e s t i n g days f o r r a t s i n j e c t e d w i t h e p i n e p h r i n e and r a t s i n j e c t e d w i t h s a l i n e . The d o t t e d l i n e i n p a n e l B i n d i c a t e s the o r i g i n a l h e i g h t of the bedding m a t e r i a l . MEAN DURATION OF BU.RYING ( s e c ) MEAN HEIGHT OF MATERIAL AT THE DOWEL ( c m ) 25 s i g n i f i c a n t l y d i f f e r e n t i n the two groups [F(3,54) = .15, p > . 0 5 ] , the e p i n e p h r i n e - i n j e c t e d r a t s d i s p l a y e d l e s s of a r e d u c t i o n i n h e i g h t s c o r e s over days than d i d the s a l i n e -i n j e c t e d r a t s [F(3,54) = 5.85, p_ < .05]. T h i s may have been due t o the f a c t t h a t even though the amount of time t h a t t h e e p i n e p h r i n e - i n j e c t e d r a t s spent b u r y i n g was d e c r e a s i n g , they appeared t o be p e r f o r m i n g a g r e a t e r p e r c e n t a g e of t h e i r f o r e l i m b s p r a y i n g from p o s i t i o n s c l o s e t o the dowel, and thus c o u l d have been p r o g r e s s i v e l y more e f f i c i e n t i n a c c u m u l a t i n g m a t e r i a l d i r e c t l y over i t . Experiment 2 Almost a l l the s t u d i e s of the e f f e c t of exogenous e p i n e p h r i n e on r e s p o n d i n g i n a v e r s i v e s i t u a t i o n s have employed shock as the a v e r s i v e s t i m u l u s t h e r e b y l i m i t i n g the g e n e r a l i t y ( L e s h n e r , 1978) and perhaps the e t h o l o g i c a l s i g n i f i c a n c e of the r e s u l t s . Thus, the purpose of the second experiment was t o e x t e n d the r e s u l t s of Experiment 1 by u s i n g a f l a s h of l i g h t i n s t e a d of e l e c t r i c shock as the u n c o n d i t i o n e d a v e r s i v e s t i m u l u s . T e r l e c k i , P i n e l , and T r e i t (1979) were the f i r s t t o r e p o r t t h a t r a t s would bury a p r e v i o u s l y " n e u t r a l " o b j e c t t h a t had been the s o u r c e of a f l a s h of l i g h t . They found t h a t r a t s b u r i e d an unspent f l a s h b u l b i n a p r o t e c t i v e c o l l a r when they f i r s t e n c o u n t e r e d i t i n the t e s t chamber, and t h a t t h i s u n c o n d i t i o n e d b u r y i n g d i s a p p e a r e d f o l l o w i n g 4 h a b i t u a t i o n days. When h a b i t u a t e d s u b j e c t s were s u b s e q u e n t l y exposed t o a f l a s h from the b u l b , however, 7 out of 10 r a t s b u r i e d the f l a s h assembly. The b e s t e v i d e n c e t h a t the b u r y i n g of f l a s h s o u r c e s r e f l e c t s a 26 form of a s s o c i a t i v e l e a r n i n g was p r o v i d e d by an experiment i n which two comparable f l a s h assemblies were present i n the t e s t chamber d u r i n g h a b i t u a t i o n , c o n d i t i o n i n g , and t e s t i n g . In t h i s s i t u a t i o n r a t s pushed bedding towards, the source of the l i g h t f l a s h , but not towards the c o n t r o l assembly. Method The experimental procedure was the same as that employed i n Experiment 1 with the f o l l o w i n g e x c e p t i o n s . F i r s t , the uncon d i t i o n e d a v e r s i v e stimulus was a f l a s h of l i g h t produced by an AG1B f l a s h b u l b . T h i s f l a s h b u l b was encased i n a grey p l a s t i c c o l l a r (3 cm i n diameter and 5 cm i n length) i n order to p r o t e c t the 20 338- to 472-gm s u b j e c t s from the heat generated by the f l a s h b u l b . The c l o s e d end of t h i s assembly was a t t a c h e d to the t e s t chamber so that i t was 1 cm above the l e v e l of the bedding m a t e r i a l . During the c o n d i t i o n i n g s e s s i o n , the f l a s h was t r i g g e r e d by the experimenter when the r a t s were f a c i n g the f l a s h b u l b and touching the c o l l a r with a forepaw. Second, the f l a s h assembly was present i n the t e s t chamber for the 4 h a b i t u a t i o n days i n order to reduce any neophobic responses to the assembly that c o u l d p o t e n t i a l l y i n t e r f e r e with the c o n d i t i o n i n g s e s s i o n . R e s u l t s and D i s c u s s i o n F i g u r e 2 shows the mean d u r a t i o n of burying (panel A) and the height of the p i l e s of m a t e r i a l accumulated at the f l a s h b u l b assembly (panel B) by both groups of r a t s d u r i n g the 4 t e s t days. Rats i n j e c t e d with e p i n e p h r i n e spent s u b s t a n t i a l l y more time s p r a y i n g bedding towards the f l a s h b u l b , and thus accumulated higher p i l e s of bedding at the f l a s h b u l b , than d i d 27 F i g u r e 2. Mean d u r a t i o n of burying (panel A) and mean f i n a l h e i ght of bedding m a t e r i a l at the f l a s h b u l b (panel B) on 4 t e s t i n g days f o r r a t s i n j e c t e d with epinephrine and r a t s i n j e c t e d with s a l i n e . The dotted l i n e i n panel B i n d i c a t e s the o r i g i n a l h eight of the bedding m a t e r i a l . DAY OF TESTING 29 r a t s i n j e c t e d w i t h s a l i n e . The s i g n i f i c a n c e of the s e d i f f e r e n c e s was e s t a b l i s h e d by a n a l y s e s of v a r i a n c e f o r r e p e a t e d measures [ d u r a t i o n e f f e c t : F ( l , 5 4 ) = 10.5, p < .05; h e i g h t e f f e c t : F ( l , 5 4 ) = 12.01, £ < .05 ] . The o b s e r v a t i o n t h a t s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e enhance d e f e n s i v e b u r y i n g of a f l a s h b u l b assembly p a i r e d w i t h a f l a s h of l i g h t p r o v i d e s e v i d e n c e t h a t the f a c i l i t a t i v e e f f e c t of e p i n e p h r i n e on c o n d i t i o n e d b u r y i n g i s not s p e c i f i c t o s i t u a t i o n s i n which e l e c t r i c shock i s the u n c o n d i t i o n e d s t i m u l u s . A n a l y s i s of the e f f e c t of r e p e a t e d t e s t i n g showed t h a t both groups of r a t s spent l e s s time b u r y i n g the f l a s h b u l b i n the l a t e r t e s t s e s s i o n s [F(3,54) = 3.33, p_ < .05 ] . T h i s d e c r e a s e , however, was not as pronounced f o r the s a l i n e - i n j e c t e d r a t s because t h e i r d u r a t i o n of b u r y i n g s c o r e s were so low t o b e g i n w i t h [ i n t e r a c t i o n e f f e c t : F(3,53)= 2.88, p < .05]. T h i s d e c r e a s e i n b u r y i n g over days was a l s o r e f l e c t e d i n the h e i g h t of bedding s c o r e s [F(3,54) = 2.86, p <.05]. No s i g n i f i c a n t i n t e r a c t i o n e f f e c t [F(3,54) = 2.15, p > .05] o c c u r r e d f o r t h i s s c o r e , however. A f t e r the second day of t e s t i n g , two of the r a t s i n the s a l i n e group a c t u a l l y spent a p o r t i o n of the t e s t p e r i o d d i g g i n g i n the S a n - i - c e l underneath the f l a s h b u l b assembly t h e r e b y p r o d u c i n g mean h e i g h t s c o r e s below the 5 cm b a s e l i n e . A l t h o u g h 6 of the 10 r a t s i n j e c t e d w i t h s a l i n e d i s p l a y e d some b u r y i n g on the f i r s t day of t e s t i n g , the mean d u r a t i o n of b u r y i n g was o n l y .9 s e c . P i n e l and T r e i t (1978) had found t h a t the c o n d i t i o n e d d e f e n s i v e b u r y i n g of a shock source d e c l i n e s w i t h i n c r e a s e s i n the d u r a t i o n of the c o n d i t i o n i n g - t e s t i n t e r v a l . The low l e v e l s of b u r y i n g i n the p r e s e n t study suggest 30 that the bu r y i n g c o n d i t i o n e d by a f l a s h of a bulb a l s o d e c l i n e s with i n c r e a s e s i n the time between c o n d i t i o n i n g and t e s t i n g ; r a t s t e s t e d immediately a f t e r the f l a s h spent about 31.8 sec burying the bulb i n the T e r l e c k i et a l . study. Experiment 3 Because f a c i l i t a t i v e e f f e c t s of epinephrine on responses to c o n d i t i o n e d a v e r s i v e s t i m u l i had been d i f f i c u l t to demonstrate, i t had been suggested that e p i n e p h r i n e might have a d i f f e r e n t i a l e f f e c t on responding to c o n d i t i o n e d and uncondi t i o n e d a v e r s i v e s t i m u l i (e.g., Stewart & B r o o k s h i r e , 1968). The purpose of the t h i r d experiment was to demonstrate that e p i n e p h r i n e would f a c i l i t a t e u n conditioned d e f e n s i v e burying as i t had c o n d i t i o n e d d e f e n s i v e b u r y i n g . Method The experimental procedure employed i n Experiment 3 was s i m i l a r to that used i n Experiments 1 and 2 except f o r the f o l l o w i n g changes. F i r s t , because no c o n d i t i o n i n g s e s s i o n was necessary, t e s t i n g of the 20 367- to 575-gm r a t s s e r v i n g as s u b j e c t s s t a r t e d on the day f o l l o w i n g the f o u r t h h a b i t u a t i o n s e s s i o n (Day 5). Second, on the t e s t i n g day, an unset 9.8 X 4.5 X .5 cm wooden mousetrap ( V i c t o r ; Woodstream C o r p o r a t i o n , L i l i t z , P e n n s y l v a n i a ) , an o b j e c t p r e v i o u s l y demonstrated to be an e f f e c t i v e u nconditioned a v e r s i v e s t i m u l u s f o r d e f e n s i v e burying ( T e r l e c k i et a l . , 1979), was atta c h e d to the t e s t chamber w a l l . The s i d e of the t r a p was fastened h o r i z o n t a l l y to the c e n t r e of the end w a l l so that i t was 1 cm above the l e v e l of the bedding m a t e r i a l . 31 R e s u l t s and D i s c u s s i o n F i g u r e 3 shows t h a t i n j e c t e d e p i n e p h r i n e enhanced u n c o n d i t i o n e d d e f e n s i v e b u r y i n g . R a t s t h a t had been i n j e c t e d w i t h e p i n e p h r i n e spent s i g n i f i c a n t l y [ F ( l , 5 4 ) = 8.97, £ < .05] more time b u r y i n g the t r a p (see p a n e l A) and as a r e s u l t a c cumulated s i g n i f i c a n t l y [ F ( l , 5 4 ) = 8.92, £ < .05] h i g h e r p i l e s of bedding a t the t r a p (see p a n e l B) than d i d r a t s t h a t had been i n j e c t e d w i t h s a l i n e . The r e s u l t s of t h i s experiment e x t e n d the f i n d i n g s of Ex p e r i m e n t s 1 and 2; i n c r e a s e d p e r i p h e r a l l e v e l s of e p i n e p h r i n e enhance d e f e n s i v e b u r y i n g of u n c o n d i t i o n e d as w e l l as c o n d i t i o n e d a v e r s i v e s t i m u l i . A n a l y s i s of the e f f e c t of r e p e a t e d t e s t i n g r e v e a l e d t h a t both groups of r a t s engaged i n d e c r e a s i n g amounts of b u r y i n g over days [ d u r a t i o n e f f e c t : F(3,54) = 10.45, £ < .05; h e i g h t e f f e c t : F(3,54) = 8.31, £ < .05]. R a t s i n both i n j e c t i o n c o n d i t i o n s d i s p l a y e d a s i m i l a r p a t t e r n of r e d u c t i o n of u n c o n d i t i o n e d d e f e n s i v e b u r y i n g over days [ i n t e r a c t i o n e f f e c t f o r d u r a t i o n : F(3,54) = 1.05, £ > .05; i n t e r a c t i o n e f f e c t f o r h e i g h t : F(3,54) = 1.14, £ > . 0 5 ] . Experiment 4 A l t h o u g h the r e s u l t s of the f i r s t t h r e e e x p e r i m e n t s had c l e a r l y d emonstrated t h a t s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e can enhance the d e f e n s i v e b u r y i n g of b o t h c o n d i t i o n e d and u n c o n d i t i o n e d a v e r s i v e s t i m u l i , the same dose (.1 mg/kg) of e p i n e p h r i n e had been a d m i n i s t e r e d i n a l l t h r e e s t u d i e s . The purpose of t h e f o u r t h experiment was t o e s t a b l i s h t h a t the e f f e c t of s y s t e m i c e p i n e p h r i n e on c o n d i t i o n e d d e f e n s i v e b u r y i n g i s not r e s t r i c t e d t o t h i s one p a r t i c u l a r dose and t h a t the 32 F i g u r e 3. Mean d u r a t i o n of b u r y i n g ( p a n e l A) and mean f i n a l h e i g h t of bedding m a t e r i a l a t the t r a p ( p a n e l B) on 4 t e s t i n g days f o r r a t s i n j e c t e d w i t h e p i n e p h r i n e and r a t s i n j e c t e d w i t h s a l i n e . The d o t t e d l i n e i n p a n e l B i n d i c a t e s the o r i g i n a l h e i g h t of the bedding m a t e r i a l . MEAN DURATION OF BURYING ( s e c ) 34 magnitude of the e f f e c t i s a f u n c t i o n of dose. Method The p r o c e d u r e used i n t h i s experiment was the same as t h a t employed i n Experiment 1 e x c e p t f o r the f o l l o w i n g changes. A n a l y s i s of the a c t u a l d u r a t i o n and i n t e n s i t y of shock r e c e i v e d by each r a t r e v e a l e d t h a t t h e 50 410- t o 687-gm r a t s s e r v i n g as s u b j e c t s i n t h i s experiment r e c e i v e d shocks a v e r a g i n g 1.84 mA (SD = .23 mA) i n i n t e n s i t y and 47.5 msec (SD =40.07 msec) i n d u r a t i o n ( c f . Experiment 1 ) . A f t e r b e i n g shocked, the r a t s were a s s i g n e d t o one of f i v e i n j e c t i o n c o n d i t i o n s (n = 1 0 ) . Each r a t was then g i v e n a subcutaneous i n j e c t i o n of one of f o u r d i f f e r e n t doses (.01, .1, .5, or 2 mg/kg) of e p i n e p h r i n e d i l u t e d i n s a l i n e so t h a t each r a t was g i v e n the same volume (3 ml/kg) of f l u i d , or an e q u i v a l e n t volume of the s a l i n e v e h i c l e (0 d o s e ) . A s i n g l e t e s t s e s s i o n was conducted 1 min a f t e r each r a t was i n j e c t e d . The d u r a t i o n of b u r y i n g and the f i n a l h e i g h t of m a t e r i a l a t the dowel were r e c o r d e d by an o b s e r v e r t h a t was unaware of the dose of e p i n e p h r i n e a d m i n i s t e r e d t o each r a t . R e s u l t s and D i s c u s s i o n I t i s apparent from F i g u r e 4 t h a t the dose of e p i n e p h r i n e a d m i n i s t e r e d t o the r a t s produced an e f f e c t on the amount of c o n d i t i o n e d d e f e n s i v e b u r y i n g . One-way a n a l y s e s of v a r i a n c e c o n f i r m e d t h a t t h e r e was a s i g n i f i c a n t e f f e c t of dose on both the d u r a t i o n of b u r y i n g [F(4,45) = 9.86, p_ < .05] and the h e i g h t of m a t e r i a l accumulated a t the dowel [F(4,45) = 8.82, p_ <.053 . Subsequent t r e n d a n a l y s e s ( t r e n d a n a l y s i s f o r an independent v a r i a b l e w i t h unequal s p a c i n g ; K e p p e l , 1973) i n d i c a t e d a s i g n i f i c a n t l i n e a r t r e n d [ d u r a t i o n e f f e c t : 35 F i g u r e 4. Mean d u r a t i o n of b u r y i n g ( p a n e l A) and mean f i n a l h e i g h t of bedding m a t e r i a l a t the dowel ( p a n e l B) f o r r a t s i n j e c t e d w i t h one of f i v e d i f f e r e n t doses of e p i n e p h r i n e . The d o t t e d l i n e i n p a n e l B i n d i c a t e s t h e o r i g i n a l h e i g h t of the bedding m a t e r i a l . DOSE OF EPINEPHRINE (mg/kg) 37 F ( l , 4 5 ) = 14.23, 2 < - 0 5 ? h e i g h t e f f e c t : F ( l , 4 5 ) =19.64, £ < .05] and a l s o a s i g n i f i c a n t q u a d r a t i c t r e n d [ d u r a t i o n e f f e c t : F ( l , 4 5 ) = 19.95, £ < .05; h e i g h t e f f e c t : F ( l , 4 5 ) = 13.53, 2 < .05] i n both s e t s of s c o r e s . As can be seen i n F i g u r e 4, b o t h the d u r a t i o n of b u r y i n g ( p a n e l A) and the h e i g h t of m a t e r i a l a t the dowel ( p a n e l B) i n c r e a s e d w i t h the i n c r e a s i n g doses of e p i n e p h r i n e up t o the 2 mg/kg dose, which produced a s u b s t a n t i a l decrement i n c o n d i t i o n e d d e f e n s i v e b u r y i n g . The b e h a v i o u r of the r a t s t h a t r e c e i v e d the 2 mg/kg of e p i n e p h r i n e was s t r i k i n g l y d i f f e r e n t from the b e h a v i o u r of the r a t s r e c e i v i n g e i t h e r s a l i n e or one of the o t h e r t h r e e doses of e p i n e p h r i n e . Only 3 of the 10 r a t s i n j e c t e d w i t h 2 mg/kg of e p i n e p h r i n e moved any bedding i n the d i r e c t i o n of the dowel d u r i n g the t e s t s e s s i o n ; whereas, a l l 10 of the r a t s i n each of the o t h e r f o u r i n j e c t i o n c o n d i t i o n s engaged i n b u r y i n g b e h a v i o u r . The r a t s r e c e i v i n g the 2 mg/kg dose of e p i n e p h r i n e spent most of t h e t e s t p e r i o d l y i n g r e l a t i v e l y m o t i o n l e s s a t the back of the t e s t chamber. The i n f r e q u e n t locomotor movements e x h i b i t e d by t h e s e r a t s u s u a l l y i n v o l v e d a "swimming" type motion i n which the r a t ' s l i m b s were s p l a y e d t o the s i d e and i t s v e n t r a l s u r f a c e was t o u c h i n g the bedding m a t e r i a l , t h u s i n d i c a t i n g a g r o s s impairment of motor f u n c t i o n . The r e s u l t s of t h i s experiment c o n f i r m those of Experiment 1 and demonstrate t h a t the f a c i l i t a t i v e e f f e c t of e p i n e p h r i n e on c o n d i t i o n e d d e f e n s i v e b u r y i n g i s not r e s t r i c t e d t o a s i n g l e dose of e p i n e p h r i n e . In a d d i t i o n the amount of d e f e n s i v e b u r y i n g was found t o i n c r e a s e w i t h the i n c r e a s i n g doses of e p i n e p h r i n e used i n t h i s s tudy u n t i l a l e v e l of e p i n e p h r i n e was reached t h a t 38 produced gross motor impairment. EFFECT OF DEMEDULLATION ON DEFENSIVE BURYING Although the r e s u l t s of the f i r s t four experiments c l e a r l y demonstrated that systemic i n j e c t i o n s of epi n e p h r i n e have a f a c i l i t a t i v e e f f e c t on both c o n d i t i o n e d and uncondi t i o n e d d e f e n s i v e b u r y i n g , these f i n d i n g s do not allow one to make c o n c l u s i v e statements r e g a r d i n g the r o l e of endogenous epinephrine i n a v e r s i v e s i t u a t i o n s . I t i s p o s s i b l e that the enhancement of d e f e n s i v e burying observed i n the f i r s t s e r i e s of experiments i s simply an a r t i f i c i a l e f f e c t r e s u l t i n g from i n c r e a s i n g e pinephrine l e v e l s w e l l beyond those normally produced i n a v e r s i v e s i t u a t i o n s , and that the f l u c t u a t i o n s i n the l e v e l s of endogenous ep i n e p h r i n e normally produced i n a v e r s i v e s i t u a t i o n s would be without e f f e c t on behaviour. Another way of o b t a i n i n g evidence that the epinephrine r e l e a s e d from the a d r e n a l glands i n response to a v e r s i v e s t i m u l a t i o n has a modulating e f f e c t on a v e r s i v e responding i s to assess the e f f e c t of r e d u c t i o n s i n the l e v e l of e p i n e p h r i n e . A c c o r d i n g l y , the purpose of the second set of s t u d i e s was to examine the e f f e c t on d e f e n s i v e burying of reducing e p i n e p h r i n e l e v e l s . E p i nephrine l e v e l s were reduced by removing the r a t s ' primary source of epi n e p h r i n e , the ad r e n a l medulla. I f the f u n c t i o n of endogenous epinephrine i s c o n s i s t e n t with the r o l e suggested by the f i r s t set of s t u d i e s i n c l u d e d i n t h i s d i s s e r t a t i o n , then r e d u c t i o n s i n epinephrine l e v e l s should reduce d e f e n s i v e b u r y i n g . 39 A d r e n a l Anatomy The a d r e n a l g l a n d s of the r a t a r e two s m a l l ( a p p r o x i m a t e l y 4 X 3 X 2.8 mm), rounded, brown b o d i e s s i t u a t e d i n the r e t r o p e r i t o n e a l f a t s l i g h t l y a n t e r i o r t o the k i d n e y s (Hebel & Stromberg, 1976; Rowett, 1974). The a d r e n a l i s e n c l o s e d by a t h i n c a p s u l e of c o n n e c t i v e t i s s u e and c o n s i s t s of two d i s t i n c t and f u n c t i o n a l l y d i f f e r e n t t y p e s of e n d o c r i n e t i s s u e . The s u p e r f i c i a l l a y e r of t i s s u e , the a d r e n a l c o r t e x , a r i s e s e m b r y o l o g i c a l l y from the c o e l e m i c mesoderm on the m e d i a l s i d e of the u r o g e n i t a l r i d g e . The a d r e n a l c o r t e x which i s d i v i d e d i n t o t h r e e m o r p h o l o g i c a l l y d i s t i n g u i s h a b l e zones, the zona g l o m e r u l o s a , the zona f a s c i c u l a t a , and the zona r e t i c u l a r i s , p roduces a number of hormones i n c l u d i n g the m i n e r a l c o r t i c o i d s , the g l u c o c o r t i c o i d s , and the a d r e n a l sex s t e r o i d s . C o m p l e t e l y s u r r o u n d e d by the a d r e n a l c o r t e x i s the second type of t i s s u e , the a d r e n a l m e d u l l a . I t a r i s e s e m b r y o l o g i c a l l y from the e c t o d e r m a l n e u r a l c r e s t , t i s s u e and i s a f u n c t i o n a l p a r t of the s y m p a t h e t i c nervous system. The a d r e n a l m e d u l l a i s i n n e r v a t e d by the s p l a n c h n i c n e r v e , which forms a c h o l i n e r g i c synapse w i t h the c h r o m a f f i n c e l l s of the m e d u l l a . S t i m u l a t i o n of the s p l a n c h n i c nerve c a u s e s the c h r o m a f f i n c e l l s t o r e l e a s e the hormones e p i n e p h r i n e and n o r e p i n e p h r i n e d i r e c t l y i n t o the a d r e n a l v e i n ( c f . Bloom & F a w c e t t , 1968; K o p i n , 1980). Almost a l l ( g r e a t e r than 90 %) of the r a t s ' c i r c u l a t i n g e p i n e p h r i n e comes from the c h r o m a f f i n c e l l s of the a d r e n a l m e d u l l a (McCarty & K o p i n , 1979). A d r e n a l D e m e d u l l a t i o n When the a d r e n a l g l a n d i s d e m e d u l l a t e d , the a d r e n a l c a p s u l e i s c u t and the a d r e n a l m e d u l l a p l u s most of the s u r r o u n d i n g 40 c o r t e x i s g e n t l y squeezed o u t , l e a v i n g b e h i n d o n l y t h e c a p s u l e and a t h i n s u b c a p s u l a r p o r t i o n of c o r t i c a l t i s s u e ( e . g . , Evans, 1936; I n g l e & G r i f f i t h , 1949). In the weeks f o l l o w i n g t h i s o p e r a t i o n , the a d r e n a l c o r t e x r e g e n e r a t e s . C o r t i c a l r e g e n e r a t i o n i s t y p i c a l l y complete w i t h i n 3 t o 6 weeks ( e . g . , de G r o o t & F o r t i e r , 1959; Evans, 1936; I n g l e & G r i f f i t h , 1949), and a t t h i s time plasma f r e e c o r t i c o s t e r o i d s a r e found t o be a t normal l e v e l s (Conner & L e v i n e , 1969; F o r t i e r & de G r o o t , 1959). Plasma e p i n e p h r i n e , on the o t h e r hand, i s found t o remain a t l e s s than 10% of b a s a l l e v e l s f o l l o w i n g d e m e d u l l a t i o n (McCarty & K o p i n , 1979; M i c a l i z z i & P a l s , 1979). Experiment 5 The purpose of the f i f t h e x p eriment was t o a s s e s s the e f f e c t of r e d u c i n g e p i n e p h r i n e l e v e l s on d e f e n s i v e b u r y i n g . As was p r e v i o u s l y mentioned, one problem w i t h a l l p r e v i o u s s t u d i e s of the e f f e c t of e p i n e p h r i n e d e p l e t i o n on b e h a v i o u r i n a v e r s i v e s i t u a t i o n s i s t h a t the e f f e c t of r e d u c i n g e p i n e p h r i n e l e v e l s on a v e r s i v e r e s p o n d i n g has been confounded w i t h i t s p o s s i b l e e f f e c t on c o n d i t i o n i n g . T h i s problem was a v o i d e d i n the p r e s e n t experiment by u s i n g the u n c o n d i t i o n e d d e f e n s i v e b u r y i n g paradigm. Method The 24 287- t o 348-gm r a t s used i n t h i s experiment were randomly d i v i d e d i n t o two groups (n = 1 2 ) . Rats i n one group ( d e m e d u l l a t e d ) had t h e i r a d r e n a l g l a n d s e n u c l e a t e d , and t h e r a t s i n the o t h e r group ("sham-surgery") were t r e a t e d comparably except t h a t t h e i r a d r e n a l g l a n d s were l e f t i n t a c t . S u r g e r y . A l l . r a t s were a n e s t h e t i z e d w i t h sodium p e n t o b a r b i t a l 41 (Nembutal, 50 mg/kg, i.p.) and were shaved j u s t caudal to the r i b cage on both s i d e s . The r a t s i n the demedullated group were then given b i l a t e r a l a drenal medullectomies f o l l o w i n g the procedure d e s c r i b e d by Ingle and G r i f f i t h (1949). Using a p a i r of s c i s s o r s , a l a t e r a l i n c i s i o n was made i n the s k i n and the muscle of the body w a l l , caudal to the r i b cage and adjacent to the kidney. The kidney was manipulated through the opening i n the body w a l l , and the a d r e n a l gland was l o c a t e d and exposed. The a d r e n a l gland was brought i n t o the opening and h e l d there with a p a i r of small curved f o r c e p s , the t i p s of which had been covered with p o l y e t h y l e n e t u b i n g . A pie c e of s i l a s t i c t u b i ng had been p l a c e d over the arms of the forceps i n such a way that the po l y e t h y l e n e - c o v e r e d t i p s c o u l d be brought together r e a d i l y without being completely c l o s e d . T h i s made i t p o s s i b l e to h o l d the a d r e n a l gland at i t s base without c r u s h i n g the ad r e n a l a r t e r y or v e i n . With the a i d of a 16-power s u r g i c a l microscope, an i n c i s i o n was made i n the d i s t a l end of the a d r e n a l gland with a s m a l l , sharp p a i r of s c i s s o r s . Next the ad r e n a l medulla and surrounding c o r t e x were g e n t l y squeezed out of the ad r e n a l c a p s u l e with a second p a i r of small curved p o l y e t h y l e n e - t i p p e d f o r c e p s . The kidney was then r e t u r n e d to the body c a v i t y and the i n c i s e d muscle and s k i n were sutured. T h i s e n t i r e procedure was then repeated on the other s i d e of the body. The r a t s i n the sham-surgery group were s u b j e c t e d to the same s u r g i c a l procedure except that the adrenal gland was not cut and en u c l e a t e d . F o l l o w i n g surgery both water and .9 % s a l i n e were made f r e e l y a v a i l a b l e to the r a t s i n t h e i r home cages. The p r e s e n t a t i o n of s a l i n e i s a standard procedure a f t e r a d r e n a l medullectomy 42 because i t i n v o l v e s damage t o the a d r e n a l c o r t e x , a l t h o u g h t h i s p r o c e d u r e may not be n e c e s s a r y (Gacent, R e n z i , G i s o l d i , & Howie, 1967). B e h a v i o u r a l t e s t i n g . B e h a v i o u r a l t e s t i n g commenced 2 months a f t e r s u r g e r y . F o l l o w i n g the 4 h a b i t u a t i o n days, the unset mousetrap used i n Experiment 3 was a t t a c h e d t o one end w a l l of the t e s t chamber. Each r a t was then p l a c e d i n d i v i d u a l l y i n the chamber and t e s t e d i n the presence of the t r a p . H i s t o l o g y . At the c o n c l u s i o n of t e s t i n g , the d e m e d u l l a t e d r a t s were s a c r i f i c e d i n a C0 2 chamber and p e r f u s e d i n t r a c a r d i a l l y w i t h .9 % s a l i n e and a 10 % s o l u t i o n of f o r m a l i n . The a d r e n a l g l a n d s were then removed, f i x e d i n f o r m a l i n , s e c t i o n e d a t 40 m i c r o n i n t e r v a l s w i t h a f r e e z i n g microtome, and s t a i n e d w i t h h e m a t o x y l i n ( m o d i f i e d D e l a f i e l d ' s H e m a t o x l y i n , F i s h e r S c i e n t i f i c Company) and e o s i n ( E o s i n Y, F i s h e r S c i e n t i f i c Company). R e s u l t s and D i s c u s s i o n As can be seen i n F i g u r e 5, a d r e n a l d e m e d u l l a t i o n r e s u l t e d i n a s u b s t a n t i a l d e c r e a s e i n u n c o n d i t i o n e d d e f e n s i v e b u r y i n g . S t a t i s t i c a l a n a l y s e s , t - t e s t s f o r independent measures, c o n f i r m e d t h a t the d e m e d u l l a t e d r a t s spent s i g n i f i c a n t l y [ t ( 2 2 ) = 2.10,rj < '05] l e s s time b u r y i n g and accumulated s i g n i f i c a n t l y [ t ( 2 2 ) = 2.09, £ < .05] s m a l l e r p i l e s of bedding a t the t r a p than d i d r a t s i n the sham-surgery group. H i s t o l o g i c a l e x a m i n a t i o n of the a d r e n a l g l a n d s of the r a t s t h a t had undergone a d r e n a l e n u c l e a t i o n r e v e a l e d r e g e n e r a t i o n of the c o r t e x but not the m e d u l l a , t h u s c o n f i r m i n g the completeness of t h e d e m e d u l l a t i o n . 43 F i g u r e 5. Mean d u r a t i o n of b u r y i n g ( p a n e l A) and mean f i n a l h e i g h t of bedding m a t e r i a l a t the t r a p ( p a n e l B) f o r r a t s t h a t had t h e i r a d r e n a l g l a n d s d e m e d u l l a t e d and r a t s t h a t had "sham" o p e r a t i o n s . The d o t t e d l i n e i n p a n e l B i n d i c a t e s the o r i g i n a l h e i g h t of t h e bedding m a t e r i a l . 44 45 The r e s u l t s of t h i s study demonstrate that d e p l e t i n g e p i n e p h r i n e l e v e l s by demedullating the adrenal glands can cause a s i g n i f i c a n t r e d u c t i o n i n a v e r s i v e responding and that the uncondit i o n e d d e f e n s i v e burying paradigm i s s e n s i t i v e to t h i s e f f e c t . T h i s f i n d i n g p r o v i d e s s u p p o r t i n g evidence f o r the p r o p o s i t i o n t h at the e p i n e p h r i n e - i n d u c e d enhancement of de f e n s i v e burying found i n the f i r s t set of s t u d i e s r e f l e c t s the e f f e c t s of endogenous epinephrine i n a v e r s i v e s i t u a t i o n s . Experiment 6 The r e s u l t s of Experiment 5 demonstrated that a d r e n a l demedullation can cause a r e d u c t i o n i n unconditioned d e f e n s i v e b u r y i n g . I f as was suggested t h i s e f f e c t i s due to the d e p l e t i o n of endogenous e p i n e p h r i n e , then i n j e c t i o n s of ep i n e p h r i n e should attenuate or negate the r e d u c t i o n i n unconditioned burying caused by a d r e n a l d e m e d u l l a t i o n . The purpose of Experiment 6 was to c o n f i r m the r e s u l t s of Experiment 5 and to demonstrate that the e f f e c t s of adrenal demedullation on unconditioned d e f e n s i v e burying can be reversed by replacement i n j e c t i o n s of e p i n e p h r i n e . Method The s u r g i c a l and b e h a v i o u r a l t e s t i n g procedures used i n t h i s experiment were the same as those employed i n Experiment 5 except f o r the f o l l o w i n g changes. In the present experiment, there were 36 325- to 468-gm r a t s i n both the demedullated and the sham-surgery groups. P r i o r to b e h a v i o u r a l t e s t i n g , the r a t s in each of these two groups were randomly assigned to one of three d i f f e r e n t drug c o n d i t i o n s (n = 12). The r a t s were i n j e c t e d (s.c.) with e i t h e r a .5 or 1 mg/kg dose of epinephrine d i l u t e d 46 in s a l i n e to c o n c e n t r a t i o n s of .25 mg/ml and .5 mg/ml r e s p e c t i v e l y or an e q u i v a l e n t volume (2 ml/kg) of the s a l i n e v e h i c l e (0 dose). Thus, the design was a 2 by 3 f a c t o r i a l with two types of o p e r a t i o n and three d i f f e r e n t doses of e p i n e p h r i n e . The r a t s were i n j e c t e d 1 min p r i o r to t e s t i n g . The d u r a t i o n of burying and height of m a t e r i a l at the t r a p were recorded by an observer that was unaware of each s u b j e c t ' s experimental h i s t o r y . R e s u l t s and D i s c u s s i o n F i g u r e 6 shows the amount of burying e x h i b i t e d by the r a t s in each of the s i x groups. The demedullated r a t s i n ge n e r a l engaged i n l e s s burying behaviour than d i d the r a t s i n the sham-surgery group. I t i s a l s o evident from F i g u r e 6 that e p i n e p h r i n e dosage had an e f f e c t on uncondi t i o n e d d e f e n s i v e b u r y i n g . The amount of burying e x h i b i t e d by r a t s i n both the demedullated and sham-surgery groups i n c r e a s e d with i n c r e a s i n g doses of ep i n e p h r i n e . The s i g n i f i c a n c e of these d i f f e r e n c e s was e s t a b l i s h e d with two-way analyses of v a r i a n c e f o r independent measures. The r a t s i n the demedullated group spent s i g n i f i c a n t l y [ F ( l , 6 6 ) = 5.57, p < .05] l e s s time s p r a y i n g bedding m a t e r i a l at the t r a p , and as a consequence they accumulated s i g n i f i c a n t l y [ F ( l , 6 6 ) = 4.13, p < .05] l e s s m a t e r i a l at the t r a p than d i d the r a t s i n the sham-surgery group. There was a l s o 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 dose of ep i n e p h r i n e on the the amount of time spent burying [ d u r a t i o n e f f e c t : F(12,66) = 4.77, p < .05; i n t e r a c t i o n e f f e c t : F(2,66) = .86, p > .05] and the amount of m a t e r i a l accumulated at the t r a p [ h e i g h t e f f e c t : F(2,66) = 4.06, p < .05; i n t e r a c t i o n e f f e c t : F(2,66) = .87, p > .05]. 47 F i g u r e 6. Mean d u r a t i o n of b u r y i n g ( p a n e l A) and mean f i n a l h e i g h t of bedding m a t e r i a l a t the t r a p f o r d e m e d u l l a t e d and "sham" c o n t r o l r a t s i n j e c t e d w i t h one of t h r e e d i f f e r e n t doses of e p i n e p h r i n e . The d o t t e d l i n e i n p a n e l B i n d i c a t e s the o r g i n a l h e i g h t of the bedding m a t e r i a l . MEAN DURATION OF BURYING (sec) MEAN HEIGHT OF MATERIAL AT THE TRAP (cm) cn CO N CO CD 87 49 Subsequent t r e n d a n a l y s e s performed on the dosage e f f e c t i n d i c a t e d a s i g n i f i c a n t l i n e a r t r e n d [ d u r a t i o n e f f e c t : F ( l , 6 6 ) = 9.5, £ < .05; h e i g h t e f f e c t : F ( l , 6 6 ) = 7.5, 2 < - ° 5 ^ i n b o t h s e t s of d a t a ; b o t h the d u r a t i o n of b u r y i n g and the h e i g h t of m a t e r i a l a t the t r a p i n c r e a s e d as the dosage of e p i n e p h r i n e i n c r e a s e d . The f i n d i n g s of t h i s s tudy c o n f i r m those of Experiment 5 and p r o v i d e a d d i t i o n a l s u p p o r t f o r the p r o p o s i t i o n t h a t endogenous e p i n e p h r i n e modulates a v e r s i v e r e s p o n d i n g . As i n Experiment 5, a d r e n a l d e m e d u l l a t i o n r e s u l t e d i n a s u b s t a n t i a l r e d u c t i o n of u n c o n d i t i o n e d d e f e n s i v e b u r y i n g . T h i s e f f e c t was r e v e r s e d , however, by the a d m i n i s t r a t i o n of exogenous e p i n e p h r i n e ; s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e enhanced the d e f e n s i v e b u r y i n g e x h i b i t e d by d e m e d u l l a t e d r a t s . In a d d i t i o n , the r e s u l t s of t h i s experiment e x t e n d the r e s u l t s of Experiment 4. In Experiment 4 the f a c i l i t a t i v e e f f e c t of e p i n e p h r i n e on c o n d i t i o n e d d e f e n s i v e b u r y i n g was found t o be dose-dependent; c o n d i t i o n e d b u r y i n g i n c r e a s e d w i t h the i n c r e a s i n g doses of e p i n e p h r i n e used i n t h i s s t u d y u n t i l a l e v e l of e p i n e p h r i n e was reached t h a t produced a g r o s s motor impairment. The r e s u l t s of the p r e s e n t experiment e s t a b l i s h t h a t t h i s dose dependency i s not r e s t r i c t e d t o c o n d i t i o n e d d e f e n s i v e b u r y i n g ; the amount of u n c o n d i t i o n e d b u r y i n g e x h i b i t e d by i n t a c t r a t s i n c r e a s e d w i t h the i n c r e a s i n g doses of e p i n e p h r i n e used i n t h i s s t u d y . GENERAL DISCUSSION The g e n e r a l d i s c u s s i o n i s o r g a n i z e d around two main t o p i c s . F i r s t , the two major accomplishments of the p r e s e n t s t u d i e s a r e 50 s e p a r a t e l y d i s c u s s e d . Second, p o s s i b l e reasons f o r the c o n c e n t r a t i o n of previous experimenters i n t e r e s t e d i n the r e l a t i o n s h i p between e p i n e p h r i n e l e v e l s and behaviour on c o n d i t i o n e d a c t i v e avoidance paradigms are d i s c u s s e d along with a p o s s i b l e reason f o r the i n c o n s i s t e n c y of the r e s u l t s obtained from such s t u d i e s . Accomplishments of the Present S t u d i e s The i n t r o d u c t i o n of the burying paradigm as a v e h i c l e f o r s t u d y i n g the r e l a t i o n s h i p between ep i n e p h r i n e and responding to a v e r s i v e s t i m u l a t i o n r e s u l t e d i n two major accomplishments. F i r s t , the present s i x experiments p r o v i d e d two complementary types of evidence s u p p o r t i n g the hypothesis that e p i n e p h r i n e has a modulating e f f e c t on behaviour i n a v e r s i v e s i t u a t i o n s . Second, t h i s t h e s i s p rovided an important e x t e n s i o n of p r e v i o u s l y e x i s t i n g evidence suggesting that the r e l a t i o n s h i p between epi n e p h r i n e l e v e l s and responding to a v e r s i v e s t i m u l a t i o n can be c h a r a c t e r i z e d by an i n v e r t e d U-shaped curve. These two c o n t r i b u t i o n s are d i s c u s s e d below under separate headings. Evidence f o r a B e h a v i o u r a l E f f e c t of Epinephrine Two types of evidence were pr o v i d e d by the present s i x experiments that support the hypothesis that systemic e p i n e p h r i n e can have a modulating e f f e c t on behaviour e x h i b i t e d i n response to a v e r s i v e s t i m u l a t i o n . F i r s t , i n j e c t i o n s of e p i n e p h r i n e were found to f a c i l i t a t e d e f e n s i v e b u r y i n g . T h i s enhancement of d e f e n s i v e b u r y i n g was found to be both r e l i a b l e and g e n e r a l ; i t was not s p e c i f i c to e i t h e r a p a r t i c u l a r type of a v e r s i v e stimulus or to a p a r t i c u l a r dose of e p i n e p h r i n e . E p i n e p h r i n e i n j e c t i o n s enhanced the d e f e n s i v e burying of both 51 u n c o n d i t i o n e d (of an unset mousetrap, Experiment 3) and c o n d i t i o n e d (of a wire-wrapped wooden dowel p a i r e d w i t h shock, Experiment 1; of a f l a s h b u l b assembly p a i r e d w i t h a f l a s h of l i g h t , E xperiment 2) a v e r s i v e s t i m u l i . A l s o , f i v e d i f f e r e n t doses of e p i n e p h r i n e r a n g i n g from .01 t o 2 mg/kg were used i n the s t u d i e s i n c l u d e d i n t h i s d i s s e r t a t i o n . A l l of t h e s e doses except f o r the 2 mg/kg dose, which produced an o b v i o u s impairment of l o c o m o t i o n , were found t o have a f a c i l i t a t i v e e f f e c t on d e f e n s i v e b u r y i n g . F u r t h e r m o r e , the i n j e c t i o n s of e p i n e p h r i n e appeared t o a f f e c t d e f e n s i v e b u r y i n g i n a dose-r e l a t e d f a s h i o n . B u r y i n g of both c o n d i t i o n e d (Experiment 4) and u n c o n d i t i o n e d (Experiment 6) a v e r s i v e s t i m u l i was found t o i n c r e a s e w i t h the i n c r e a s i n g doses of e p i n e p h r i n e (except f o r the 2 mg/kg dose) used i n the p r e s e n t s t u d i e s . The second type of e v i d e n c e f o r the h y p o t h e s i s t h a t e p i n e p h r i n e has a m o d u l a t i n g e f f e c t on responses t o a v e r s i v e s t i m u l a t i o n was p r o v i d e d by two e x p e r i m e n t s i n which the a d r e n a l g l a n d was d e m e d u l l a t e d . In E x p e r i m e n t s 5 and 6, removal of the r a t s ' main sou r c e of endogenous e p i n e p h r i n e , the a d r e n a l m e d u l l a , reduced u n c o n d i t i o n e d d e f e n s i v e b u r y i n g . Moreover, a replacement i n j e c t i o n of e p i n e p h r i n e a d m i n i s t e r e d t o d e m e d u l l a t e d s u b j e c t s c o u n t e r a c t e d t h e e f f e c t s of d e m e d u l l a t i o n on b u r y i n g ; s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e were found t o i n c r e a s e t h e amount of b u r y i n g e x h i b i t e d by d e m e d u l l a t e d r a t s . E v i d e n c e C o n c e r n i n g The Nature Of The R e l a t i o n s h i p Between  E p i n e p h r i n e and A v e r s i v e Responding I t has been r e p e a t e d l y suggested t h a t the r e l a t i o n s h i p between e p i n e p h r i n e l e v e l and b e h a v i o u r i n a v e r s i v e s i t u a t i o n s 52 can b e s t be c h a r a c t e r i z e d by an i n v e r t e d U-shaped c u r v e ( e . g . , Conner & L e v i n e , 1969; Latane' & S c h a c h t e r , 1962; Sm i t h , 1973). I n v e s t i g a t o r s have s u g g e s t e d : 1) t h a t t h e r e i s reduced r e s p o n d i n g t o a v e r s i v e s t i m u l a t i o n i n the absence of e p i n e p h r i n e , 2) t h a t l e v e l s of r e s p o n d i n g i n c r e a s e as l e v e l s of e p i n e p h r i n e approach normal l e v e l s , 3) t h a t they c o n t i n u e t o i n c r e a s e as l e v e l s of e p i n e p h r i n e a r e i n c r e a s e d above normal l e v e l s , and f i n a l l y 4) t h a t a t h i g h l e v e l s of e p i n e p h r i n e performance i s d i s r u p t e d . Four t y p e s of e v i d e n c e have been p r o v i d e d t o support t h e s e s u g g e s t i o n s . Smith (1973), f o r example, l i s t e d the f o l l o w i n g f i n d i n g s as e v i d e n c e f o r such an i n v e r t e d U-shaped r e l a t i o n s h i p between e p i n e p h r i n e l e v e l and a v e r s i v e r e s p o n d i n g : 1) Conner and L e v i n e ' s (1969) f i n d i n g t h a t a d r e n a l d e m e d u l l a t i o n r e t a r d e d a c q u i s i t i o n of a two-way a c t i v e a v o i d a n c e r e s p o n s e , 2) Conner and L e v i n e ' s (1969) f i n d i n g t h a t s y s t e m i c i n j e c t i o n of a s m a l l dose of e p i n e p h r i n e i n c r e a s e d the r a t e of a c q u i s i t i o n of a v o i d a n c e r e s p o n d i n g i n d e m e d u l l a t e d r a t s , 3) Latane and S c h a c h t e r ' s f i n d i n g t h a t s y s t e m i c i n j e c t i o n of a s m a l l dose of e p i n e p h r i n e f a c i l i t a t e d a c q u i s t i o n of a two-way a c t i v e a v o i d a n c e response i n i n t a c t r a t s , and 4) Kosman and Ge r a r d ' s (1950) f i n d i n g t h a t s y s t e m i c i n j e c t i o n of a l a r g e dose of e p i n e p h r i n e d i s r u p t e d performance of one-way a c t i v e a v o i d a n c e response i n i n t a c t r a t s . Such e v i d e n c e i s q u e s t i o n a b l e f o r two r e a s o n s . F i r s t , e v i d e n c e of a p a r t i c u l a r f u n c t i o n t h a t r e q u i r e s comparison between d i f f e r e n t t y p e s of e x p e r i m e n t s performed by d i f f e r e n t e x p e r i m e n t e r s u s i n g d i f f e r e n t paradigms i s tenuous a t b e s t . Second, the s t u d i e s c i t e d t o su p p o r t the i d e a of such an 53 i n v e r t e d U-shaped r e l a t i o n a r e not r e p r e s e n t a t i v e of the e x i s t i n g l i t e r a t u r e . When e x p e r i m e n t a l r e s u l t s a r e so i n c o n s i s t e n t , s u p p o r t g a r n e r e d from a few c a r e f u l l y s e l e c t e d s t u d i e s i s u n c o n v i n c i n g t o say the l e a s t . The p r e s e n t f i n d i n g s a l l p r o v i d e e v i d e n c e of such an i n v e r t e d U-shaped r e l a t i o n s h i p . For example, Experiment 6 c o n s t i t u t e s the o n l y i n s t a n c e i n which responses t o an a v e r s i v e s t i m u l u s were reduced by e p i n e p h r i n e d e p l e t i o n , the e f f e c t of d e p l e t i o n was c o u n t e r a c t e d by replacement i n j e c t i o n s of e p i n e p h r i n e , and r e s p o n d i n g was i n c r e a s e d above c o n t r o l l e v e l s i n i n t a c t s u b j e c t s i n j e c t e d w i t h e p i n e p h r i n e — a l l i n a s i n g l e e x p e r i m e n t . The o n l y p r e v i o u s s t u d y t o f i n d b oth a r e d u c t i o n of re s p o n d i n g t o an an a v e r s i v e s t i m u l u s r e s u l t i n g from a d r e n a l d e m e d u l l a t i o n and an a t t e n u a t i o n of t h i s e f f e c t w i t h replacement e p i n e p h r i n e (Conner & L e v i n e , 1969) d i d not f i n d t h a t i n j e c t i o n of e p i n e p h r i n e enhanced r e p o n d i n g i n i n t a c t s u b j e c t s . Experiment 4 c o n s t i t u t e s the o n l y w i t h i n - e x p e r i m e n t d e m o n s t r a t i o n of an enhancement of r e s p o n d i n g t o an a v e r s i v e s t i m u l u s by a low dose of e p i n e p h r i n e and a d i s r u p t i o n of t h i s r e s p o n d i n g by a h i g h dose of e p i n e p h r i n e . Gupta and H o l l a n d (1969) might have found a s i m i l a r e f f e c t (see Ta b l e 1 ) , but because the a p p r o p r i a t e s t a t i s t i c a l comparison was not made i n t h e i r m u l t i p l e f a c t o r i a l d e s i g n , i t i s i m p o s s i b l e t o t e l l whether t h e i r l o w e s t dose s i g n i f i c a n t l y enhanced two-way a c t i v e a v o i d a n c e r e s p o n d i n g . Reasons f o r the P o p u l a r i t y of C o n d i t i o n e d A c t i v e A v o i dance Paradigms In l i g h t of the s u c c e s s of s t u d i e s of the r e l a t i o n s h i p between e p i n e p h r i n e and i n n a t e reponses t o a v e r s i v e s t i m u l i , the 54 c o n c e n t r a t i o n by experimenters on c o n d i t i o n e d a c t i v e avoidance paradigms ( c f . Tables 1 and 2) might seem p a r a d o x i c a l . Because the c o n d i t i o n e d a c t i v e avoidance paradigms have been the most p r e v a l e n t means of studying epinephrine-behaviour r e l a t i o n s i t i s important to be aware of the reason why they have been employed. An examination of the i n t r o d u c t i o n s to r e l e v a n t s t u d i e s suggests that two f a c t o r s have c o n t r i b u t e d to the prevalence of the c o n d i t i o n e d a c t i v e avoidance paradigm: 1) the r e s u l t s of s t u d i e s i n which e p i n e p h r i n e was i n j e c t e d to humans suggested that e p inephrine a f f e c t e d emotions and emotional behaviour and, 2) Mowrer's (Mowrer & Lamoureaux, 1946; Mowrer, 1947) popular theory of a c t i v e avoidance c o n d i t i o n i n g suggested that fear was an important i n t e r v e n i n g v a r i a b l e i n the a c q u i s i t i o n of an a c t i v e avoidance response. These two f a c t o r s w i l l be d i s c u s s e d below under a p p r o p r i a t e headings, and i n a subsequent s e c t i o n , a reason why a c t i v e avoidance paradigms might not have been p a r t i c u l a r l y s u c c e s s f u l in demonstrating a r e l a t i o n s h i p between epinephrine l e v e l s and responding i n a v e r s i v e s i t u a t i o n s w i l l be p r o f e r r e d . E f f e c t of E p i n e p h r i n e I n j e c t i o n s on Human Behaviour P r i o r t o , and concomitant with, the e a r l y s t u d i e s of the r e l a t i o n s h i p between epinephrine and a v e r s i v e responding i n r a t s were a number of s t u d i e s examining the r e l a t i o n s h i p between epinephrine and emotional behaviour i n humans. The e a r l y r e s e a r c h e r s (e.g. C a n t r i l & Hunt, 1932; Landis & Hunt, 1932) found that accompanying the autonomic a r o u s a l produced by i n j e c t e d e p i n e p h r i n e were what Maranon (1924) l a b e l l e d " c o l d emotions". For the most p a r t , the human s u b j e c t s d i d not r e p o r t 55 f e e l i n g genuine emotions but s a i d , f o r example, t h a t they f e l t "as i f " they were a f r a i d or a n x i o u s . The o c c a s i o n a l s u b j e c t , however, d i d r e p o r t e x p e r i e n c i n g a genuine emotion when e p i n e p h r i n e was i n j e c t e d ( C a n t r i l & Hunt, 1932). S u b s e q u e n t l y , C a n t r i l (1934) found t h a t i f an e m o t i o n - p r o d u c i n g s t i m u l u s ( e . g . , a sudden l o u d n o i s e ) was a l s o a p p l i e d i n the e x p e r i m e n t a l s i t u a t i o n , the s u b j e c t s r e p o r t e d e x p e r i e n c i n g genuine e m o t i o n a l s t a t e s ( e . g . , f e a r ) more i n t e n s e than those e x p e r i e n c e d by c o n t r o l s u b j e c t s i n j e c t e d w i t h a p l a c e b o . In 1962, S c h a c h t e r and h i s a s s o c i a t e s ( S c h a c h t e r & S i n g e r , 1962; S c h a c h t e r _ Wheeler, 1962) performed a s e r i e s of e x p e r i m e n t s , the r e s u l t s of which appeared t o c l a r i f y and e x t e n d the f i n d i n g s of the e a r l i e r e x p e r i m e n t s ( L e s h n e r , 1978; S m i t h , 1973). S c h a c h t e r and h i s c o l l e a g u e s demonstrated t h a t i t was p o s s i b l e t o enhance the b e h a v i o u r r e f l e c t i n g e m o t i o n a l s t a t e s w i t h s y s t e m i c i n j e c t i o n s of e p i n e p h r i n e , p r o v i d e d t h a t the a p p r o p r i a t e e n v i r o n m e n t a l s t i m u l i were p r e s e n t . For example, i n j e c t e d e p i n e p h r i n e was found t o produce a t w o - f o l d i n c r e a s e i n the a n g e r - r e l a t e d b e h a v i o u r of male s t u d e n t s unaware of the n a t u r e of the i n j e c t i o n , when they were r e q u i r e d t o f i l l out an i r r i t a t i n g q u e s t i o n n a i r e and a n o t h e r person i n the same room was a c t i n g angry ( S c h a c h t e r & S i n g e r , 1962). In a d d i t i o n , S c h a c h t e r found t h a t the e n v i r o n m e n t a l m a n i p u l a t i o n s and not the i n j e c t e d e p i n e p h r i n e appeared t o d e t e r m i n e what type of emotion the s u b j e c t f e l t . For example, i n j e c t e d e p i n e p h r i n e was found t o a l s o i n c r e a s e t h e amount of amusement f e l t by s u b j e c t s w a t c h i n g a s l a p s t i c k comedy f i l m ( S c h a c h t e r & Wheeler, 1962). S c h a c h t e r c o n c l u d e d t h a t emotion i s a j o i n t p r o d u c t of p h y s i o l o g i c a l 56 a r o u s a l and s i t u a t i o n a l c u e s . S c h a c h t e r ' s h y p o t h e s i s has s i n c e been t e s t e d i n two o t h e r p u b l i s h e d e x p e r i m e n t s i n which e p i n e p h r i n e was a d m i n i s t e r e d s y s t e m i c a l l y . Rogers and Deckner (1975) f a i l e d t o c o n f i r m S c h a c h t e r ' s c o n c l u s i o n s . They found t h a t r e p o r t s of s u b j e c t i v e f e a r by p e o p l e who smoked c i g a r e t t e s were i n c r e a s e d by i n j e c t i n g e p i n e p h r i n e , w a t c h i n g a f i l m about c a n c e r , or a c o m b i n a t i o n of both t r e a t m e n t s ; however, the amount of s u b j e c t i v e f e a r r e p o r t e d by t h e s e d i f f e r e n t groups of s u b j e c t s d i d not d i f f e r s i g n i f i c a n t l y . A c c o r d i n g t o Gerdes (1979), i t i s p o s s i b l e t h a t the s u b j e c t s w a t c h i n g the f i l m had a s u f f i c i e n t l y h i g h l e v e l of endogenous e p i n e p h r i n e t o r e n d e r the i n j e c t e d e p i n e p h r i n e s u p e r f l u o u s . In 1979, Gerdes r e p o r t e d f i n d i n g s which were c o m p a t i b l e w i t h S c h a c h t e r ' s h y p o t h e s i s . She found t h a t s u b j e c t s i n j e c t e d w i t h e p i n e p h r i n e w h i l e they were w a i t i n g f o r o r a l s u r g e r y r e p o r t e d g r e a t e r f e a r than s u b j e c t s who were not g i v e n t h i s hormone, p r o v i d e d t h a t the s u b j e c t s i n j e c t e d w i t h e p i n e p h r i n e d i d not know t h a t e p i n e p h r i n e had been a d m i n i s t e r e d . I f t h e s e s u b j e c t s were informed t h a t they s h o u l d expect some symptoms of autonomic a r o u s a l , they d i d not r e p o r t more f e a r than d i d the s u b j e c t s not i n j e c t e d w i t h e p i n e p h r i n e . A l t h o u g h not c o n c l u s i v e , t h e s e s t u d i e s suggest t h a t e p i n e p h r i n e i n j e c t i o n s may enhance e m o t i o n a l b e h a v i o u r e x h i b i t e d by human s u b j e c t s i n e m o t i o n a l s i t u a t i o n s . Mowrer's Theory of Avoidance C o n d i t i o n i n g In the l a t e f o r t i e s , Mowrer (Mowrer, 1947; Mowrer & Lamoureaux, 1946) p o s t u l a t e d t h a t c o n d i t i o n e d f e a r i s a c r i t i c a l 57 f a c t o r i n the p r o d u c t i o n of avoidance responding. A c c o r d i n g to Mowrer, i t was the r e d u c t i o n of the f e a r c o n d i t i o n e d to the c o n d i t i o n e d stimulus that r e i n f o r c e d the avoidance response. Moreover, t h i s f ear s t a t e was supposedly mediated by the u n d e r l y i n g a c t i o n s of the autonomic nervous system. Thus, Mowrer him s e l f p r e d i c t e d that e p inephrine l e v e l s would i n f l u e n c e c o n d i t i o n e d a c t i v e avoidance behaviour (Smith, 1973). Because the experiments performed on humans had suggested that e p i n e p h r i n e might a f f e c t the emotions and emotional behaviour e x h i b i t e d i n a v e r s i v e s i t u a t i o n s and because Mowrer's t h e o r e t i c a l e x p l a n a t i o n of avoidance responding i m p l i c a t e d both e p i n e p h r i n e and an emotional response, i t i s not s u r p r i s i n g that many e a r l y i n v e s t i g a t o r s wishing to study the r e l a t i o n s h i p between epinephrine and behaviour would decide to u t i l i z e the c o n d i t i o n e d a c t i v e avoidance paradigm, the same paradigm used by Mowrer as a b a s i s f o r developing h i s theory. In many cases, more recent r e s e a r c h e r s seem to have used the same paradigm without c o n s i d e r i n g i t s m e r i t s . Why A c t i v e Avoidance Paradigms Have Not Been S u c c e s s f u l At a s u p e r f i c i a l l e v e l i n v e s t i g a t o r s using c o n d i t i o n e d a c t i v e avoidance paradigms were merely t r y i n g to answer the f o l l o w i n g q u e s t i o n : What i s the r e l a t i o n s h i p between epinephrine and fear-mediated behaviour? In doing so, however, they were making q u e s t i o n a b l e assumptions. F i r s t they assumed, that ^Mowrer's t h e o r e t i c a l i n t e r p r e t a t i o n of c o n d i t i o n e d avoidance was c o r r e c t ; t hat i s , that avoidance l e a r n i n g i s dependent upon an emotional response being e l i c i t e d by the c o n d i t i o n e d a v e r s i v e s t i m u l u s . Second, they assumed that an i n c r e a s e i n the i n t e n s i t y 58 of t h i s emotional response would f a c i l i t a t e avoidance c o n d i t i o n i n g ( c f . Moyer & B u n n e l l , 1958). Even i f the c o n t r o v e r s i a l f i r s t assumption ( H e r r n s t e i n , 1969; Mackintosh, 1974; Tarpy, 1975) were accepted, a number of reasons can be generated f o r q u e s t i o n i n g the second assumption (Moran, Ahmad, & Meagher, 1970). For example, i n c r e a s i n g shock i n t e n s i t y has been found to r e s u l t i n i n c r e a s e d e p i n e p h r i n e r e l e a s e from the a d r e n a l medulla (Frankenhaeuser, 1971; Frankenhaeuser, Frohber, & M e l l i s , 1965/66), yet shocks of h i g h i n t e n s i t i e s have been found to i n t e r f e r e with the a c q u i s i t i o n of two-way a c t i v e avoidance responses (Mackintosh, 1974; Tarpy, 1975). In the two-way a c t i v e avoidance paradigm crouching and f r e e z i n g are, i n i t i a l l y at l e a s t , the prepotent responses (e.g., Anisman & Walhsten, 1974). I t has been suggested by many authors (e.g., Moyer & Korn, 1964; Mackintosh, 1974; Tarpy, 1975; Theios, Lynch, & Lowe, 1966) that high shock l e v e l s r e t a r d two-way a c t i v e avoidance performance by enhancing these c r o u c h i n g and f r e e z i n g responses that compete with the r e q u i r e d avoidance response. I t i s p o s s i b l e that e p i n e p h r i n e i t s e l f c o u l d be one of the f a c t o r s mediating the d i s r u p t i v e e f f e c t of h i g h shock l e v e l s . Increased shock i n t e n s i t y c o u l d i n c r e a s e endogenous ep i n e p h r i n e l e v e l s which i n turn c o u l d enhance crouching and f r e e z i n g . Thus, i n some s i t u a t i o n s one might expect a d i s r u p t i o n , r a t h e r than a f a c i l i t a t i o n of a c t i v e avoidance i n response to i n c r e a s i n g l e v e l s of e m o t i o n a l i t y . C o n c l u s i o n The p o i n t made in the preceding s e c t i o n i s merely a reason why i n j e c t i o n s of e p i n e p h r i n e might not n e c e s s a r i l y be expected 59 to enhance c o n d i t i o n e d a c t i v e avoidance responses and not a c l a i m t h at systemic e p i n e p h r i n e does not enhance l e a r n e d responding i n a v e r s i v e s i t u a t i o n s . Although many s t u d i e s have examined the e f f e c t of a l t e r i n g p e r i p h e r a l epinephrine l e v e l s on le a r n e d responses to a v e r s i v e s t i m u l a t i o n , the r e s u l t s of these s t u d i e s have been so i n c o n s i s t e n t that i t i s impossible to t e l l whether systemic epinephrine enhances l e a r n e d reponding or not. The r e s u l t s of the present s t u d i e s , however, c l e a r l y c o n f i r m the hy p o t h e s i s that systemic e p i n e p h r i n e enhances innate responding i n a v e r s i v e s i t u a t i o n s . 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