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Dopaminergic substrates of reward in the caudate-putamen of the rat Carter, David Alexander 1975

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DOPAMINERGIC SUBSTRATES O F REWARD I N THE CAUBATE-PUTAtfEN OF THE RAT by DAVID ALEXANDER CARTER B . S c , U n i v e r s i t y o f T o r o n t o , 1973 A THESIS SUBMITTED I N PARTIAL FULFILLMENT OF THE REQUIREMENTS FOB THE DEGREE OF MASTER OF A^TS i n t h e De p a r t m e n t o f P s y c h o l o g y We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF B i U T I S H COLUMBIA S e p t e m b e r , 1975 In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree l y ava i l ab le for reference and study. I further agree that permission for extensive copying of th i s thesis for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i ca t ion of th is thes is for f i nanc i a l gain sha l l not be allowed without my writ ten permission. Department of P s v c h o l O S t V The Univers i ty of B r i t i s h Columbia 2075 Wesbrook P l a c e Vancouver, Canada V6T 1W5 i ABSTRACT An e x t e n s i v e mapping o f t h e c a u d a t e - p u t a m e n i n t h e r a t f o r i n t r a c r a n i a l s e l f - s t i m u l a t i o n (ICS) s i t e s » a s u n d e r t a k e n t o 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 t h e r o l e o f dopamine i n b r a i n s t i m u l a t i o n r e w a r d . E i g h t y - s e v e n p e r c e n t o f t h e p l a c e m e n t s i n t h e n e o s t r i a t u m s u p p o r t e d IC S , w i t h s e l f - s t i m u l a t i o n r a t e s g r e a t e r t h a n 250/15 min a t 56% o f t h e s i t e s . I n a s e c o n d e x p e r i m e n t , a n i m a l s were p r e p a r e d w i t h e l e c t r o d e s aimed a t t h e l a t e r a l c a u d a t e - p u t a m e n . Those s u b j e c t s d i s p l a y i n g ICS s u b s e q u e n t l y r e c e i v e d 6 -hydroxydopamine l e s i o n s t o t h e dopamine c e l l b o d i e s i n t h e s u b s t a n t i a n i g r a p a r s c o m pacta e i t h e r i p s i l a t e r a l o r c o n t r a l a t e r a l t o t h e e l e c t r o d e . The d e s t r u c t i o n o f t h e dopamine c e l l b o d i e s a t t e n u a t e d ICS i n b o t h g r o u p s d u r i n g t h e f i r s t p o s t - l e s i o n t e s t s e s s i o n s . However, t h e r a t e s i n t h e i p s i l a t e r a l g r o u p d e c l i n e d t o between 2-9% o f c o n t r o l s c o r e s , whereas t h e r a t e s i n t h e c o n t r a l a t e r a l g r o u p i m p r o v e d o v e r t e s t i n g t o 72% o f c o n t r o l v a l u e s , 28 days a f t e r t h e l e s i o n . On t h e b a s i s o f t h e s e d a t a , i t was c o n c l u d e d t h a t u n i l a t e r a l d e s t r u c t i o n o f t h e d o p a m i n e r g i c n i g r o - n e o s t r i a t a l (NSB) has two e f f e c t s on ICS b e h a v i o u r . F i r s t , u n i l a t e r a l r e d u c t i o n o f n e o s t r i a t a l dopamine i s a c c o m p a n i e d by a l o s s o f b r a i n s t i m u l a t i o n r e w a r d a t s i t e s n o r m a l l y i n n e r v a t e d by t h e NSB, s p e c i f i c a l l y t h e c a u d a t e - p u t a m e n . S e c o n d l y , l e s i o n s o f t h e NSB p r o d u c e a g e n e r a l d i s r u p t i o n i n b a r p r e s s i n g b e h a v i o u r , as e v i d e n c e d by t h e a t t e n u a t i o n o f ICS f o l l o w i n g c o n t r a l a t e r a l l e s i o n s . The p o s s i b l e r o l e o f t h e NSB i n n a t u r a l r e w a r d i s d i s c u s s e d . A. G. P h i l l i p i i i TABLE OF CONTENTS Page A b s t r a c t , . i G e n e r a l I n t r o d u c t i o n 1 P h a r m a c o l o g i c a l E v i d e n c e 1 A n a t o m i c a l A p p r o a c h e s 6 L e s i o n A pproach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 P u r p o s e o f t h e P r e s e n t E x p e r i m e n t 15 E x p e r i m e n t One . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 I n t r o d u c t i o n 16 Methods .. 16 R e s u l t s 18 D i s c u s s i o n 22 E x p e r i m e n t Two . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 I n t r o d u c t i o n 29 Methods 30 R e s u l t s 31 D i s c u s s i o n 38 G e n e r a l D i s c u s s i o n 41 R e f e r e n c e s 48 i v L I S T OF TABLES Page T a b l e I S i t e s S u p p o r t i n g ICS i n D i f f e r e n t D i v i s i o n s o f NA Systems ... . 7-8 T a b l e I I S i t e s S u p p o r t i n g ICS i n D i f f e r e n t D i v i s i o n s o f DA Systems . . 9 T a b l e I I I Maximum S e l f - s t i m u l a t i o n R a t e s / 1 5 min. C u r r e n t I n t e n s i t i e s , E l e c t r o d e P l a c e m e n t s , Days t o S p o n t a n e o u s S e l f - s t i m u l a t i o n , and S t i m u l a t i o n I n d u c e d Motor A r t i f a c t s , f o r I n d i v i d u a l R a t s D i s p l a y i n g S e l f - s t i m u l a t i o n .....20-21 T a b l e IV E f f e c t s o f U n i l a t e r a l 60HDA I n j e c t i o n s on I p s i l a t e r a l and C o n t r a l a t e r a l S t r i a t a l Dopamine L e v e l s and H y p o t h a l a m i c N o r e p i n e p h r i n e L e v e l s . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 V L I S T OF FIGURES Page F i g u r e 1 E l e c t r o d e P l a c e m e n t s D e p i c t e d on C o r o n a l S e c t i o n s o f t h e P e l l i g r i n o and Cushman (1967) a t l a s 19 F i g u r e 2 P h o t o m i c r o g r a p h D e p i c t i n g E l e c t r o d e T r a c t i n H e d i a l P o r t i o n o f A n t e r i o r CPU f r o m S u b j e c t CA1 22 F i g u r e 3 E f f e c t s o f U n i l a t e r a l 60HDA L e s i o n s o f t h e SNC on S e l f - s t i m u l a t i o n i n t h e I p s i l a t e r a l o r C o n t r a l a t e r a l CPU 33 F i g u r e 4 P h o t o m i c r o g r a p h s Showing t h e S i t e o f a 60HDA I n j e c t i o n i n t o t h e SNC . . . . . . . . . . . . . . . . . . . . . . . . . . 35 i v i ACKNOWLEDGEMENTS The a u t h o r w i s h e s t o thank S t e l l a Atmadja and S h e i l a B r o o k e f o r t h e i r e x c e l l e n t t e c h n i c a l a s s i s t a n c e , and C h r i s F i b i g e r f o r v a l u a b l e d i s c u s s i o n t h r o u g h o u t t h e e x e c u t i o n o f t h i s e x p e r i m e n t . S p e c i a l t h a n k s a r e due t o Tony P h i l l i p s , my s u p e r v i s o r , who a s s i s t e d t h r o u g h o u t . 1 GENERAL INTRODUCTION S i n c e t h e d i s c o v e r y o f i n t r a c r a n i a l s e l f - s t i m u l a t i o n (ICS) o v e r two d e c a d e s ago ( O l d s & M i l n e r , 1 9 5 4 ) , a c o n s i d e r a b l e amount of r e s e a r c h has been d i r e c t e d a t t h e n e u r a l s u b s t r a t e s o f t h i s ' phenomenon- C u r r e n t ICS t h e o r y c e n t r e s on t h e ' c a t e c h o l a m i n e h y p o t h e s i s * ( S t e i n , 1 9 6 2 ; Crow,1973; German 6 Bowden,1974) w h i c h p r o p o s e s t h a t s t i m u l a t i o n o f some c a t e c h o l a m i n e (CA) n e u r o n s l o c a t e d i n t h e c e n t r a l n e r v o u s s y s t e m (CNS), i s s u f f i c i e n t t o r e w a r d b e h a v i o u r . Key p h a r m a c o l o g i c a l , a n a t o m i c a l and l e s i o n d a t a which r e l a t e t o t h i s h y p o t h e s i s w i l l be r e v i e w e d below and a s t h i s d i s s e r t a t i o n i s p r i m a r i l y c o n c e r n e d w i t h t h e m e d i a t i o n of r e w a r d by dopamine n e u r o n s , e v i d e n c e r e l e v a n t t o t h i s c o n s i d e r a t i o n w i l l be e m p h a s i z e d . P h a r m a c o l o g i c a l E v i d e n c e The o r i g i n a l e v i d e n c e f o r CA m e d i a t i o n o f r e w a r d came f r o m p h a r m a c o l o g i c a l e x p e r i m e n t s , i n which d r u g e f f e c t s on ICS were o b s e r v e d . S t e i n (1962) o b s e r v e d t h a t c h l o r p r o m a z i n e and r e s e r p i n e r a i s e d t h e c u r r e n t t h r e s h o l d f o r I C S , whereas amphetamine l o w e r e d the t h r e s h o l d f o r ICS. As t h e r e was e v i d e n c e a t t h i s t i m e ( B r o d i e & Shore,1957) t h a t amphetamine p o t e n t i a t e d t h e CA m e d i a t e d c e n t r a l s y m p a t h e t i c r e s p o n s e whereas c h l o r p r o m a z i n e and r e s e r p i n e d e c r e a s e d t h i s same r e s p o n s e . S t e i n c o n c l u d e d t h a t ICS r e w a r d was m e d i a t e d by CA. T h i s r e l a t i o n s h i p between ICS and CA t r a n s m i s s i o n has been r e p l i c a t e d f r e q u e n t l y i n t h e i n t e r v e n i n g y e a r s (see German S Bowden,1974 f o r r e f e r e n c e s ) . 2 T h r e e d i s t i n c t t y p e s o f CA n e u r o n s have been d i s c o v e r e d i n t h e v e r t e b r a t e CHS, i e a d r e n a l i n (A) dopamine (DA) and n o r a d r e n a l i n (NA) ( H o k f e l t , F u x e , G o l d s t e i n & J o h a n s s o n , 1 9 7 4 ; O n g e r s t e d t , 1 9 7 1 ) . We may t h e r e f o r e ask whether t h e d r u g s u t i l i z e d i n t h e s e p h a r m a c o l o g i c a l s t u d i e s d i f f e r e n t i a t e between t h e s p e c i f i c CA s y s t e m s . O n f o r t u n a t e l y t h e r e i s e v i d e n c e t h a t t h e p a r t i c u l a r d r u g s used i n t h e s e s t u d i e s a f f e c t a l l t y p e s o f CA s y s t e m s (Anden, B u t c h e r , C o r r o d i , Fuxe 5 O n g e r s t e d t , 1970; U r e t s k y & I v e r s e n , 1 9 7 0 ; C a r l s s o n , 1964; F u x e , 1 9 7 5 ) . T h e r e f o r e , i f d r u g s a r e used t o i m p l i c a t e a g i v e n CA s y s t e m i n t h e m e d i a t i o n of r e w a r d , o n l y t h o s e which have s e l e c t i v e e f f e c t s s h o u l d be u t i l i z e d . E v i d e n c e s u g g e s t s t h a t NA may m e d i a t e r e w a r d . S t e i n and Wise (1969), u t i l i z i n g a push p u l l c a n n u l a , d e m o n s t r a t e d NA r e l e a s e i n t o c e r t a i n b r a i n r e g i o n s by r e w a r d i n g i n t r a c r a n i a l s t i m u l a t i o n , b ut n o t by n o n r e w a r d i n g i n t r a c r a n i a l s t i m u l a t i o n . S i m i l a r l y A r b u t h n o t t , F u x e , and O n g e r s t e d t , (1971) p r e s e n t e d h i s t o f l u o r e s c e n t e v i d e n c e t h a t NA r e l e a s e i n c r e a s e d o n l y a f t e r s t i m u l a t i o n a t r e w a r d p l a c e m e n t s . S t e i n (1975) and F r a n k l i n , S t e p h e n s and H e r b e r g (1975) have shown t h a t dopamine b e t a h y d r o x y l a s e i n h i b i t o r s , d r u g s which i n h i b i t t h e f o r m a t i o n o f NA can d i s r u p t I C S . T h e s e same d e f i c i t s c a n be r e v e r s e d by i n t r a v e n t r i c u l a r i n j e c t i o n s o f 1-NA ( S t e i n , 1975). F u r t h e r s u p p o r t f o r t h e r o l e o f NA i n r e w a r d comes f r o m t h e f i n d i n g t h a t a l p h a a d r e n e r g i c b l o c k e r s d i s r u p t ICS ( F r a n k l i n e t a l , 1 9 7 5 ; H a s t i n g s 8 S t u t z , 1 9 7 3 ) . However i t s h o u l d be remembered t h a t dopamine b e t a h y d r o x y l a s e i n h i b i t o r s and a l p h a a d r e n e r g i c 3 b l o c k e r s can d i s r u p t A t r a n s m i s s i o n as w e l l a s NA, and t h a t t h i s e f f e c t may be p a r t i a l l y r e s p o n s i b l e f o r t h e d r u g i n d u c e d s u p p r e s s i o n o f ICS ( Myers, J a w e t z & G o l d f i e n , 1 9 7 4 ) . C o n v i n c i n g e v i d e n c e t h a t NA may m e d i a t e r e w a r d i n a t l e a s t some b r a i n a r e a s was p r e s e n t e d by S t i n u s and T h i e r r y (1973). T h e s e a u t h o r s d e m o n s t r a t e d t h a t d i s r u p t i o n o f ICS from s i t e s i n t h e v e n t r a l tegmentum by a l p h a m e t h y l p a r a t y r o s i n e c o u l d be r e v e r s e d by i n j e c t i o n s o f D L - t h r e o - 3 , 4 - d i h y d r o x y p h e n y l s e r i n e , a p r e c u r s o r o f NA. Complementary e v i d e n c e f o r NA s u b s t r a t e s o f r e w ard i n some b r a i n a r e a s was p r e s e n t e d by P h i l l i p s and F i b i g e r (1973), P h i l l i p s , B r o o k e and F i b i g e r , (1975), Liebman and B u t c h e r (1974), S t e p h e n s , F r a n k l i n and H e r b e r g (1975) and E l l m a n , Ackerman, Bodnar, J a c k l e r & S t e i n e r (1975). T h e s e a u t h o r s showed t h a t ICS f r o m b r a i n r e g i o n s c o n t a i n i n g h i g h c o n c e n t r a t i o n s o f NA n e u r o n s , i s more s e n s i t i v e t o t h e r a t e i n c r e a s i n g e f f e c t s o f d-amphetamine t h a n o f 1-araphetamine. As d-amphetamine i s a more e f f e c t i v e r e l e a s e r o f NA from s y n a p t o s o m e s t h a n i s 1-amphetamine ( Z i a n c e , A z z a r o & R u t l e d g e , 1 9 7 2 ) , t h e s e s t u d i e s r e p r e s e n t a d d i t i o n a l e v i d e n c e f o r t h e h y p o t h e s i s t h a t NA m e d i a t e s r e w a r d . P h a r m a c o l o g i c a l s t u d i e s have a l s o s u g g e s t e d t h a t DA may m e d i a t e r e w a r d . B r e e s e , Howard and L eahy (1971) had n o t e d t h a t i n t r a v e n t r i c u l a r i n j e c t i o n s o f 6-hydroxydopamine (60HDA), c a n d i s r u p t ICS. T h i s compound p r o d u c e s s e l e c t i v e d e p l e t i o n s o f b r a i n CA ( J a c k s , DeChamplain & Cordeau,1972). More r e c e n t l y C o o p e r , C o t t and B r e e s e (1974) and B r e e s e (1975) have shown t h a t t h i s d i s r u p t i o n i s c o r r e l a t e d w i t h b r a i n DA d e p l e t i o n b u t n o t 4 w i t h b r a i n NA d e p l e t i o n . In a n i m a l s p r e t r e a t e d w i t h d e s i p r a n t i n e , i n t r a v e n t r i c u l a r i n j e c t i o n s o f 60HDA r e d u c e b r a i n DA l e v e l s f a i r l y s e l e c t i v e l y . I n a n i m a l s t r e a t e d i n t h i s manner, ICS i s a c u t e l y d e p r e s s e d a f t e r t h e i n j e c t i o n , but r e c o v e r s t w e l v e d a y s l a t e r . Even when ICS had r e c o v e r e d i t c o u l d be d e p r e s s e d by d o s e s o f a l p h a m e t h y l p a r a t y r o s i n e , t h a t were t o o low t o have any e f f e c t on n o r m a l a n i m a l s . In c o n t r a s t n e i t h e r p r e f e r e n t i a l d e p l e t i o n o f NA (3x25 ug, 60HDA) o r s u b s e q u e n t t r e a t m e n t w i t h a l p h a methyl, p a r a t y r o s i n e had any e f f e c t on I C S . A n o t h e r method o f s e l e c t i v e l y a f f e c t i n g DA e mploys t h e use o f n e u r o l e p t i c d r u g s . T h e r e i s e v i d e n c e t h a t t h e s e d r u g s s e l e c t i v e l y a n t a g o n i z e DA t r a n s m i s s i o n (Anden e t a l , 1 9 7 0 ; Seeman 5 L e e , 1 9 7 5 ) . Wauguier and N i e m e g e e r s , (1 9 7 2 ) , Liebman and B u t c h e r , (1973), and P h i l l i p s , B r o o k e and F i b i g e r , (1975) r e p o r t t h a t n e u r o l e p t i c s can r e d u c e o r e v e n b l o c k ICS b e h a v i o u r . The d-and 1- amphetamine e f f e c t d e s c r i b e d above ( P h i l l i p s and F i b i g e r , 1 9 7 3 ) a l s o s u g g e s t s a r o l e f o r DA i n r e w a r d p r o c e s s e s . P h i l l i p s e t a l ( 1 9 7 5 ) , S t e p h e n s e t a l ( 1 9 7 5 ) , E l l m a n e t a l (1975) and Liebman and B u t c h e r (1974) have d e m o n s t r a t e d t h a t ICS f r o m r e g i o n s c o n t a i n i n g h i g h c o n c e n t r a t i o n s o f DA n e u r o n s i s e g u i s e n s i t i v e t o t h e r a t e i n c r e a s i n g e f f e c t s o f d- and 1-amphetamine. As d- and 1-amphetamine a r e r e p o r t e d t o be e q u a l i n f a c i l i t a t i n g r e l e a s e o f DA f r o m s y n a p t o s o m e s ( Z i a n c e e t a l , 1 9 7 2 ) , t h e h y p o t h e s i s t h a t DA m e d i a t e s r e w a r d i s s t r e n g t h e n e d . A l t h o u g h t h e s t u d i e s r e f e r r e d t o above s t r o n g l y s u g g e s t CA m e d i a t i o n o f r e w a r d , an a l t e r n a t i v e i n t e r p r e t a t i o n o f some of 5 t h e s e f i n d i n g s has r e c e n t l y been p r o p o s e d ( R o l l s , R o l l s , K e l l y , Shaw, Wood & D a l e , 1 9 7 4 ; F i b i g e r , C a r t e r & P h i l l i p s , 1 9 7 5 ) . N e u r o l e p t i c s and 60HDA can a f f e c t n o t o n l y ICS b u t a l s o a wide v a r i e t y o f o t h e r b e h a v i o u r s (Herz,1960; Wauguier & N i e m e g e e r s , 1 9 7 2 ; S t r i e k e r £ Zigmond,1974; C o o p e r , B r e e s e , G r a n t £' Howard, 1973; Malmnas, 1973) . These same d r u g s p r o d u c e a k i n e s i a and motor i m p a i r m e n t s ( S t r i e k e r & Zigmond,1974; S c h l e c h t e r S B u t c h e r , 1 9 7 2 ) . T h i s s u g g e s t s t h a t t h e wide r a n g i n g b e h a v i o u r a l d i s r u p t i o n s p r o d u c e d by a d m i n i s t r a t i o n o f t h e s e d r u g s may be due t o a 'motor i m p a i r m e n t * . R o l l s e t a l (1974) and F i b i g e r e t a l (1975) r e p o r t t h a t n e u r o l e p t i c s o r 60HDA d i s r u p t b a r p r e s s i n g f o r f o o d o r water w i t h o u t c o n c o m m i t a n t d e p r e s s i o n o f f r e e f e e d i n g o r d r i n k i n g b e h a v i o u r a t d r u g d o s e s shown t o d e p r e s s I C S . The r a t e i n c r e a s i n g e f f e c t s o f o t h e r d r u g s , s u c h as amphetamine, may r e s u l t f r o m a g e n e r a l f a c i l i t a t i o n of motor b e h a v i o u r . The f a c t t h a t amphetamine p r o d u c e s h y p e r a c t i v i t y and f a c i l i t a t e s a v a r i e t y o f b e h a v i o u r s ( K e l l e h e r & H o r s e , 1968) s u p p o r t s t h i s s u g g e s t i o n . T h e s e e x p e r i m e n t s do not d i s p r o v e CA m e d i a t i o n o f r e w a r d , b u t t h e y do a r g u e t h a t p h a r m a c o l o g i c a l e x p e r i m e n t s on ICS must c o n t r o l f o r t h e g e n e r a l motor e f f e c t s o f d r u g s i f t h e y a r e t o be used as e v i d e n c e f o r CA m e d i a t i o n o f r e w a r d . The d- and 1-amphetamine e f f e c t ( P h i l l i p s 5 F i b i g e r , 1 9 7 3 ) e s c a p e s t h e above c r i t i c i s m s . However i t r e l i e s on t h e r e l a t i o n s h i p s between b r a i n s i t e , d r u g a c t i o n and e f f e c t on ICS. As t h e s e r e l a t i o n s h i p s a r e n o t c l e a r ( F i b i g e r & P h i l l i p s , 1 9 7 4 ) t h e d- and 1-amphetamine e f f e c t c a n n o t be used as t h e s o l e e v i d e n c e f o r CA m e d i a t i o n o f r e w a r d . T h e r e f o r e , a l t h o u g h t h e 6 s t u d i e s r e v i e w e d a b o v e s u g g e s t CA m e d i a t i o n o f r e w a r d , d a t a d e r i v e d f r o m o t h e r methods w i l l be n e c e s s a r y t o c o n f i r m t h i s h y p o t h e s i s . A n a t o m i c a l A p p r o a c h e s O l d s (1956) p i o n e e r e d t h e a n a t o m i c a l a p p r o a c h t o t h e s t u d y o f ICS when he a t t e m p t e d t o c o r r e l a t e t h e d i s t r i b u t i o n o f p o s i t i v e ICS s i t e s w i t h c l a s s i c a l n euroanatomy. I n t h i s way i t was hoped t h a t pathways and n u c l e i s u b s e r v i n g r e w a r d c o u l d be i d e n t i f i e d . The d i s t r i b u t i o n o f p o s i t i v e s i t e s was s o w i d e s p r e a d ( O l d s , 1956; O l d s & P e r e t z , 1 9 6 0 ; O l d s , T r a v i s & S c h w i n g , 1960; O l d s S O l d s , 1 9 6 3 ) t h a t i t c o r r e l a t e d p o o r l y w i t h any n e u r a l s y s t e m . However, l a t e r i t was n o t e d t h a t t h e d i s t r i b u t i o n o f p o s i t i v e s i t e s d i d c o r r e l a t e w i t h b r a i n CA c o n c e n t r a t i o n s ( S t e i n , 1 9 6 2 ; P o s c h e l & N i netman,1963). With t h e a d v e n t o f t h e h i s t o f l u o r s c e n t t e c h n i q u e p r e c i s e l o c a l i z a t i o n o f CA n e u r o n s and t h e i r p r o c e s s e s became p o s s i b l e ( D a h l s t r o m & Fuxe,1964; O n g e r s t e d t , 1 9 7 1 ; L i n d v a l l & B j o r k l u n d , 1 9 7 4 ) . The d i s t r i b u t i o n o f p o s i t i v e ICS s i t e s c o r r e l a t e s c l o s e l y w i t h t h e l o c a t i o n of CA n e u r o n s . A d r e n a l i n n e u r o n s ( H o k f e l t e t a l , 1 9 7 4 ) have been i m p l i c a t e d i n t h e m e d i a t i o n o f r e w a r d by C a r t e r and P h i l l i p s ( 1 9 7 5 ) . These a u t h o r s d e m o n s t r a t e d ICS f r o m s i t e s l o c a t e d n e a r t h e A c e l l g r o u p C2 and a l o n g i t s r o s t r a l p r o j e c t i o n t h r o u g h t h e m e d u l l a o b l o n g a t a . Mapping s t u d i e s have a l s o s u g g e s t e d t h e i n v o l v e m e n t o f n o r a d r e n e r g i c n e u r o n s i n r e w a r d . A l i s t o f some o f t h e key TABLE I S i t e s S u p p o r t i n g ICS i n D i f f e r e n t D i v i s i o n s o f t h e NA S y s t e D o r s l N o r a d r e n e r g i c System N u c l e i o f O r i g i n l o c u s c o e r u l e u s Crow, S p e a r S A r b u t h n o t t (1972) E l l m a n , Ackerman, Bodnar, J a c k l e r & S t e i n e r (1975) E l l m a n , Ackerman, F a r b e r , M a t t i a c e & S t e i n e r (1974) R i t t e r S S t e i n (1973) R o u t t e n b e r g & M a l s b u r y (1969) D o r s a l N o r a d r e n e r g i c B u n d l e A r b u t h n o t t , Fuxe & O n g e r s t e d t (1971) Crow (1972) O l d s , T r a v i s & Schwing (1960) P h i l l i p s , B r o o k e 8 F i b i g e r (1975) R o u t t e n b e r g (1970) R o u t t e n b e r g 8 M a l s b u r y (1969) W o l f e , Mayer, C o r d e r & L i e b e s k i n d (1971) T e r m i n a l A r e a s s o l i t a r y n u c l e u s C a r t e r & P h i l l i p s (1975) c e r e b e l l u m B a l l , M i c c o & B e r n t s o n (1974) i n t e r s t i t i a l n u c l e u s o f s t r i a t e r m i n a l i s O l d s e t a l (1960) R o u t t e n b e r g (1971) o l f a c t o r y b u l b P h i l l i p s (1970) R o u t t e n b e r g (1971) septum O l d s S O l d s (196 3) R o u t t e n b e r g (1971) V a l e n s t e i n (1966) a n t e r i o r t h a l a m i c n u c l e i O l d s <1956) O l d s & O l d s (1963) O l d s e t a l (1960) hippocampus O l d s e t a l {1960) U r s i n , U r s i n S O l d s (1966) amygdala Wurtz & O l d s (1963) c o r t e x O l d s (1956) O l d s e t a l (1960) R o u t t e n b e r g (1971) R o u t t e n b e r g & S l o a n (197 2) Wurtz S O l d s (1963) - , C o n t i n u e d 8 TABLE I ( C o n t i n u e d ) S i t e s S u p p o r t i n g ICS i n D i f f e r e n t D i v i s i o n s o f t h e NA Systems V e n t r a l N o r a d r e n e r g i c System N u c l e i o f O r i g i n A2 C a r t e r S P h i l l i p s (1975) V e n t r a l N o r a d r e n e r g i c B u n d l e C a r t e r S P h i l l i p s (1975) Huang & R o u t t e n b e r g (1971) R i t t e r S S t e i n (1974) R o u t t e n b e r g & M a l s b u r y (1969) Wolf e e t a l (1971) T e r m i n a t i o n s c e n t r a l g r e y Liebman, Mayer & L i e b e s k i n d (1973) Mayer, H o l f e , A k i l , C o r d e r 5 L i e b e s k i n d (1971) R o u t t e n b e r g (1970) Wolf e e t a l (1971) b a s o l a t e r a l h y p o t h a l a m u s Huang & R o u t t e n b e r g (1971) Keene & C a s e y (197 0) O l d s 6 O l d s (1963) O l d s e t a l (1960) d o r s o m e d i a l h y p o t h a l a m u s C h r i s t e n s e n , F l e s h e r & H a l e y (1969) O l d s & O l d s (1963) p a r a v e n t r i c u l a r h y p o t h a l a m u s A t r e n s (1972) A t r e n s (1973) p r e o p t i c h y p o t h a l a m u s O l d s & O l d s (1963) O l d s e t a l (1960) P e r i v e n t r i c u l a r N o r a d r e n e r g i c System N u c l e i o f O r i g i n C o o p e r & T a y l o r (1967) E l l m a n e t a l (1974) Liebman e t a l (1973) Simon, Le Moal & C a r d o (1975) P e r i v e n t r i c u l a r B u n d l e Cooper & T a y l o r (1967) Liebman e t a l (1973) O l d s & O l d s (1963) R o u t t e n b e r g (197 0) T e r m i n a t i o n s m i d l i n e t h a l a m i c n u c l e i C o o p e r S T a y l o r (1967) p e r i v e n t r i c u l a r h y p o t h a l a m u s A t r e n s (1972) A t r e n s (1973) 9 TABLE I I S i t e s S u p p o r t i n g ICS i n D i f f e r e n t D i v i s i o n s o f t h e DA S y s t e m s N u c l e i o f O r i g i n s u b s t a n t i a n i g r a pa.rs com p a c t a Crow (1972) Liebman S B u t c h e r (1974) O l d s e t a l (1960) P h i l l i p s S F i b i g e r (1973) R o u t t e n b e r g (1970) R o u t t e n b e r g 8 M a l s b u r y (1969) v e n t r a l t e g m e n t a l a r e a A r b u t h n o t t e t a l (1971) Crow (1972) R o u t t e n b e r g (1970) R o u t t e n b e r g 8 M a l s b u r y (1969) Ward (1960) T e r m i n a t i o n s c e n t r a l a m y g d a l o i d n u c l e u s Wurtz 8 O l d s (1963) p y r i f o r m and J e n t o r h i n a l c o r t i c e s O l d s (1956) Wurtz 8 O l d s (1963) c i n g u l a t e c o r t e x O l d s (1956) S t e i n (1962) f r o n t a l c o r t e x C a r e y , G o o d a l l 8 L o r e n s (1975) R o l l s 8 C o o p e r (1974) R o u t t e n b e r g (1971) R o u t t e n b e r g 8 S l o a n (1972) l a t e r a l s e p t a l n u c l e u s O l d s 8 O l d s (1963) R o u t t e n b e r g (1971) n u c l e u s accumbens O l d s e t a l (1960) P h i l l i p s e t a l (1975) R o u t t e n b e r g (1971) R o u t t e n b e r g 8 S l o a n (1972) o l f a c t o r y t u b e r c l e O l d s e t a l (1960) P o s c h e l (1969) R o u t t e n b e r g (1971) CPD L e v i n e , F e r g u s o n , K r e i n i c l c , G u s t a f s o n 8 Schwartzbaum (1971) O l d s e t a l (1960) R o u t t e n b e r g (1971) Wurtz 8 O l d s (1963) 10 s t u d i e s i s presented i n Table I . anatomical approaches to ICS have i m p l i c a t e d Da neurons i n the mediation of reward as w e l l . Most DA neurons are l o c a t e d i n the v e n t r a l mesencephalon, i n t h e s u b s t a n t i a n i g r a pars compacta (SNC), and i n the adjacent v e n t r a l tegmental:area. The axons of these neurons p r o j e c t r o s t r a l l y through the medial f o r e b r a i n bundle and t erminate i n the caudata-putamen, nucleus accumbens, o l f a c t o r y t u b e r c l e , l a t e r a l septum, amygdala as w e l l as i n the f r o n t a l , c i n g u l a t e , p y r i f o r m and e c t o r h i n a l c o r t i c e s ( L i n d v a l l 6 Bjorklund,1974; Fuxe, H o k f e l t , Johansson, L i d b r i n k & Ljungdahl,1974). Crow (1972) observed t h a t ICS c o u l d be o b t a i n e d from the SNC or<» v e n t r a l tegmental area, a n i on t h i s b a s i s Crow suggested t h a t s t i m u l a t i o n of DA neurons c o u l d reward behaviour. T h i s i s confirmed by the f i n d i n g s t h a t ICS can be obtained along the r o s t r a l p r o j e c t i o n of the DA axons and i n most of the t e r m i n a l areas (see Table I I ) . However tha presence of ICS i n the most massive DA t e r m i n a l a r e a , the CPU, i s i n doubt as some i n v e s t i g a t o r s have r e p o r t e d p o s i t i v e (Levine, Ferguson, K r e i n i c k , Gustafson, & Schwartzbaum,1971; Routtenberg,1971; Wurtz & Olds, 1963) and others negative r e s u l t s (Olds 6 Olds,1963; P r a d o - A l c a l a , Kent 6 Reid,1975). A p a r t i c u l a r l y s t r i k i n g f i n d i n g i s t h a t of Prado-Alcala et a l (1975) who r e p o r t e d that 37 of 37 placements w i t h i n the CPU were n e g a t i v e f o r ICS. These authors concluded t h a t the CPU does not support ICS, and that ICS along the remainder of the n i g r o - s t r i a t a l bundle (NSB) c o u l d be due to s t i m u l a t i o n of a p a r a l l e l pathway. C l e a r l y t h i s u n c e r t a i n t y about CPU ICS r a i s e s problems f o r any suggestion t h a t the NSB mediates reward. C l a r i f i c a t i o n of t h i s 11 i s s u e provides the major r a t i o n a l e f o r the present study-L e s i o n Approach Hard (1960) was one of the f i r s t i n v e s t i g a t o r s to u t i l i z e the l e s i o n approach i n the study of ICS. This procedure c o n s i s t s of 1) h y p o t h e s i z i n g t h a t ICS from a given b r a i n s i t e i s mediated by a s p e c i f i c n e u r a l system, 2) l e s i o n i n g the r e l e v a n t system and a s s e s s i n g the e f f e c t s of the l e s i o n on ICS. I f the system i s i n v o l v e d i n t h e mediation of the reward then . the l e s i o n should a f f e c t the ICS (Routtenberg, 1971 )„ Many such l e s i o n s t u d i e s were re p o r t e d i n the mid and l a t e nineteen s i x t i e s (German & Bowden,1974), and the n e u r a l sytems t e s t e d f o r mediation o f reward were s e l e c t e d i n accordance w i t h the c l a s s i c a l neuroanatomy of the day (Olds & Olds, 1963; V a l e n s t e i n , 1966). Un f o r t u n a t e l y the r e s u l t s of these s t u d i e s were very d i f f i c u l t to i n t e r p r e t ( V a l e n s t e i n , 1966; Boyd & Gardner, 1967). I n v e s t i g a t o r s noted that very few CMS l e s i o n s were capable of d i s r u p t i n g ICS (Lorens, 1966; V a l e n s t e i n , 1966) . The l e s i o n s t h a t were e f f e c t i v e , u s u a l l y l o c a t e d i n the p o s t e r i o r diencephalon, ( S c h i f f , 1964; Boyd & Gardner, 1967; Olds & Olds,1969) c o r r e l a t e d p o o r l y with the systems hypothesized t o mediate the b r a i n s t i m u l a t i o n reward (Lorens, 1966; V a l e n s t e i n , 1966). With the development of the new • chemical neuroanatomy' (Dahlstrom & Fuxe,1964; Ungerstedt,1971), a r e i n t e r p r e t a t i o n of these l e s i o n s t u d i e s i n terms of CA systems was attempted (German 6 Bowden, 1974). These authors demonstrated t h a t the f i n d i n g s of the e a r l y l e s i o n s t u d i e s are c o n s i s t e n t with the CA 12 h y p o t h e s i s . The l e s i o n s which d i s r u p t e d ICS were l o c a t e d i n the p o s t e r i o r diancephalon where t h e CA systems run c l o s e t o one another. S e v e r a l systems c o u l d be completely destroyed by such a l e s i o n , whereas l e s i o n s were i n e f f e c t i v e i n more r o s t r a l b r a i n r e g i o n s where the CA systems are more d i f f u s a . U n f o r t u n a t e l y , these s t u d i e s have c e r t a i n drawbacks which preclude t h e i r p r o v i d i n g s t r o n g evidence f o r the CA h y p o t h e s i s . F i r s t the l e s i o n s were produced by e l e c t r o l y s i s or procaine i n j e c t i o n . These manipulations produce n o n s p e c i f i c n e u r a l d i s r u p t i o n , i n v o l v i n g many CA and non-ci systems. Second, these l e s i o n s may produce 'motor impairments' which c o u l d cause the depression of ICS (Hadryga S Albert,1971). Only two of t h e l e s i o n s t u d i e s (Hadryga & Albert,1971; Nakajima,1972) attempted to c o n t r o l f o r t h i s p o s s i b i l i t y . T h e r e f o r e i t remains d i f f i c u l t to draw any f i r m c o n c l u s i o n s from t h e m a j o r i t y of these s t u d i e s -T e c h n i c a l advances i n the l a t e nineteen s i x t i e s and e a r l y s e v e n t i e s permitted the development of a mora s p e c i f i c l e s i o n i n g technique, with which to t e s t the CA h y p o t h e s i s . F i r s t , t h e mapping of CA systems (Ungerstedt,1971) allowed f o r the p r e c i s e l o c a l i z a t i o n of e l e c t r o l y t i c l e s i o n s i n the a r e a of the r e l e v a n t CA system. T h i s technique i s e x e m p l i f i e d i n a study by C l a v i e r and fiouttenberg (1975). The CA hypothesis (Garman & Bowden,1974; Crow,1973) suggests t h a t ICS from s i t e s near the d o r s a l noradrenergic bundle (DNAB) i s due t o s t i m u l a t i o n of axons a r i s i n g from the l o c u s c o e r u l e u s (IC). To t e s t t h i s p o s s i b i l i t y C l a v i e r and Routtenberg (1975) assessed the e f f e c t s o f e l e c t r o l y t i c l e s i o n s of the LC on ICS from the r e g i o n of the 13 DNAB. Although the l e s i o n s decreased f o r e b r a i n NA they had no e f f e c t on 'DNAB' ICS- The i d e n t i t y of the system mediating •DNAB* ICS remains u n c l e a r . The second t e c h n i c a l advance developed from the d i s c o v e r y t h a t i n t r a v e n t r i c u l a r i n j e c t i o n s o f 60HDA reduced b r a i n CA c o n c e n t r a t i o n s and ICS {see p r e v i o u s d i s c u s s i o n ) . This l e d to a more s p e c i f i c l e s i o n technique i n which m i c r p l i t r e q u a n t i t i e s of 509 DA are i n j e c t e d i n t r a c e r e b r a l l y i n t o d i s c r e t e CA c o n t a i n i n g r e g i o n s o f the b r a i n (Ongerstedt, 1971) . Although there i s a small zone of n o n s p e c i f i c t i s s u e d e s t r u c t i o n at the cannula t i p , t h i s i s surrounded by a r e l a t i v e l y l a r g e area with s e l e c t i v e d e s t r u c t i o n of CA neurons (H o k f e l t & Ongerstedt,1973; S o t e l o , Javoy, Agid 6 Glowinski,1973; Agid, Javoy, Gl o w i n s k i , Bouvet & Sotelo,1973; Simon, Le Moal, Galey & Cardo, 1974) . I f p a r t i c u l a r CA systems are t o be s e l e c t i v e l y d e s t r o y e d , the i n j e c t i o n procedure i t s e l f i s c r i t i c a l . For example, i f the c o n c e n t r a t i o n of 60HDA i s above optimum ( H o k f e l t & Ongerstedt,1973) c o n s i d e r a b l e n o n s p e c i f i c t i s s u e d e s t r u c t i o n may r e s u l t (Butcher, East gate & Hodge, 1974). Th i s d i f f i c u l t y i s demonstrated i n the study toy B e l l u z i , R i t t e r , Wise and S t e i n (1975), who were attempting to provide evidence of NA involvement i n ICS from the r e g i o n of the SNC- These authors rep o r t e d a d i s r u p t i o n o f ICS f o l l o w i n g e i t h e r i n t r a c e r e b r a l i n j e c t i o n s o f 60HDA or t r a n s v e r s e k n i f e c u t s , c audal and i p s i l a t e r a l to the SNC e l e c t r o d e . I n j e c t i o n s or k n i f e c u t s caudal and c o n t r a l a t e r a l t o the SNC e l e c t r o d e had no e f f e c t on the SNC ICS. T h i s suggests t h a t ICS from the SNC r e g i o n may be due to s t i m u l a t i o n of a system p r o j e c t i n g through t h i s r e g i o n ( B e l l u z i et al,1975), however there i s no c o n c l u s i v e proof t h a t 1 4 a CA pathway i s i n v o l v e d because t h e i n j e c t i o n procedure o f B e l l u z i et a l (1975), ( i e . 10 ug 60HDA i n 1 u l of f l u i d ) i s l i k e l y t o have produced c o n s i d e r a b l e n o n s p e c i f i c damage- In f a c t the o b s e r v a t i o n t h a t ICS i n the SNC was not d i s r u p t e d by t h e s e l e c t i v e d e s t r u c t i o n of the ascending NA pathways with i n t r a c e r e b r a l ; i n j e c t i o n s o f 60HDA, ( P h i l l i p s , 1975) s t r o n g l y suggests the involvement of noa-rCA pathways i n the study o f B e l l u z i et a l (1975). 15 PURPOSE OF THE PRESENT EXPERIMENT A l t h o u g h t h e CA h y p o t h e s i s was p r o p o s e d o v e r a d e c a d e ago ( S t e i n , 1962) i t has seldom been s u b j e c t t o a d e f i n i t i v e t e s t b e c a u s e o f t h e d i f f i c u l t i e s i n h e r e n t i n t h e d i f f e r e n t m e t h o d o l o g i e s employed (see G e n e r a l I n t r o d u c t i o n ) . The p u r p o s e o f t h e p r e s e n t s t u d y i s t o u t i l i z e t h e a n a t o m i c a l and l e s i o n a p p r o a c h e s i n c o n c e r t as a r i g o r o u s t e s t o f t h e CA h y p o t h e s i s . To t h i s end, one s p e c i f i c CA s y s t e m , t h e NSB , was s e l e c t e d a s the f o c u s o f t h i s s t u d y . The NSB i s a l a r g e w e l l d e f i n e d CA s y s t e m ( U n g e r s t e d t , 1 9 7 1 ) and i t s t e r m i n a l r e g i o n i n t h e CPU i s w e l l i s o l a t e d f r o m o t h e r CA s y s t e m s ( U n g e r s t e d t , 1 9 7 1 ) . I t h a s a l s o been s t r o n g l y i m p l i c a t e d i n t h e m e d i a t i o n o f r e w a r d (German & Bowden,1974). To t e s t t h e h y p o t h e s i s t h a t t h e NSB m e d i a t e s r e w a r d , two e x p e r i m e n t s a r e p r o p o s e d . The f i r s t e x p e r i m e n t w i l l map t h e CPU f o r I CS. I f t h e CPU c a n be shown t o s u p p o r t ICS t h i s w i l l r e p r e s e n t f u r t h e r e v i d e n c e o f DA m e d i a t i o n o f r e w a r d . P o s i t i v e r e s u l t s w i l l j u s t i f y t h e s e c o n d e x p e r i m e n t i n wh i c h t h e e f f e c t o f 60HDA l e s i o n s o f t h e SNC w i l l be examined. T h i s s h o u l d p r o v i d e a d e f i n i t i v e t e s t o f whether DA f i b r e s m e d i a t e reward i n the CPU. 16 EXPERIMENT ONE I n t r o d u c t i o n Crow (1972) o r i g i n a l l y p r o p o s e d t h a t t h e NSB m e d i a t e s r e w a r d and t h a t s t i m u l a t i o n t h r o u g h o u t t h e t r a j e c t o r y o f t h i s s y s t e m r e i n f o r c e s b e h a v i o u r . W h i l e some s t u d i e s r e p o r t o b t a i n i n g ICS from t h e CPU ( L e v i n e e t a l , 1 9 7 1 ; R o u t t e n b e r g , 1 9 7 1 ) o t h e r i n v e s t i g a t o r s were u n a b l e t o o b t a i n ICS from t h i s s t r u c t u r e ( O l d s S O l d s , 1 9 6 3 ; P r a d o - A l c a l a e t a l , 1 9 7 5 ) . These d i v e r g e n t f i n d i n g s may be due t o m e t h o d o l o g i c a l d i f f e r e n c e s . Where c u r r e n t l e v e l s were s e t i n d i v i d u a l l y f o r e a c h a n i m a l (Wurtz S O l d s , 1963; L e v i n e e t a l , 1 9 7 1 ) CPU ICS was o b s e r v e d whereas when c u r r e n t l e v e l s were p r e d e t e r m i n e d ( O l d s & O l d s , 1 9 6 3 ; P r a d o - A l c a l a e t a l , 1 9 7 5 ) r e s u l t s were n e g a t i v e . C o n v e r s e l y w i t h e x t e n d e d t r a i n i n g p e r i o d s r e s u l t s were p o s i t i v e ( R o u t t e n b e r g , 1 9 7 1 ; L e v i n e e t a l , 1 9 7 1 ) , w i t h s h o r t e n e d p e r i o d s r e s u l t s were n e g a t i v e ( P r a d o - A l c a l a e t a l , 1 9 7 5 ) . T h e r e f o r e , i n t h e p r e s e n t s t u d y a n i m a l s w i t h e l e c t r o d e s aimed a t t h e CPU w i l l be g i v e n an e x t e n s i v e t r a i n i n g p e r i o d (14 d a y s ) , w i t h a c u r r e n t i n t e n s i t y s e t i n d i v i d u a l l y f o r e a c h a n i m a l t o maximize t h e p o s s i b i l i t y o f o b t a i n i n g I CS. Methods F i f t y - s i x male a d u l t W i s t a r r a t s (300-350 gin) were p r e p a r e d f o r s t e r e o t a x i c i m p l a n t a t i o n i n a c c o r d a n c e w i t h s t a n d a r d p r o c e d u r e ( S k i n n e r , 1 9 7 1 ) . A Kopf s t e r e o t a x i c i n s t r u m e n t was employed w i t h t h e mouthbar l o c a t e d 5.0 mm above t h e i n t r a o r a l 17 l i n e . In o r d e r t o e f f e c t i v e l y map t h e CPU, b i p o l a r e l e c t r o d e s ( P l a s t i c P r o d u c t s Co,, 0.008" d i a ) were s y s t e m a t i c a l l y i m p l a n t e d a t 1 mm i n t e r v a l s i n t h e a n t e r i o r p l a n e (4.0 mm a n t e r i o r - 1.0 mm p o s t e r i o r t o b r e g m a ) , l a t e r a l p l a n e (1.5-5.5 mm f r o m t h e m i d l i n e ) (4.2-7.5 mm below t h e c o r t e x ) . The m a j o r i t y o f a n i m a l s r e c e i v e d a s i n g l e i m p l a n t b u t 10 a n i m a l s were p r e p a r e d w i t h b i l a t e r a l e l e c t r o d e p l a c e m e n t s . A 5 day r e c o v e r y p e r i o d f o l l o w e d s u r g e r y . T e s t i n g f o r ICS was c o n d u c t e d i n f i v e i d e n t i c a l p l e x i g l a s s chambers (46 cm x 30 cm x 24 cm). D e p r e s s i o n o f a s m a l l 2.5 cm wide b a r a c t i v a t e d an a c c o n s t a n t c u r r e n t s t i m u l a t o r which d e l i v e r e d a v a r i a b l e i n t e n s i t y (1 - 200 ua) 60 Hz s i n e wave s t i m u l u s o f f i x e d d u r a t i o n (0.2 sec) t h r o u g h a f l e x i b l e c a b l e , t o t h e c h r o n i c e l e c t r o d e a s s e m b l y . On t h e f i r s t day o f s c r e e n i n g f o r I C S , s t i m u l a t i o n i n t e n s i t i e s were i n d i v i d u a l l y a d j u s t e d f o r e a c h a n i m a l t o t h e h i g h e s t l e v e l which e l i c i t e d an a p p r o a c h r e a c t i o n w i t h o u t s e r i o u s motor a r t i f a c t . E a c h a n i m a l was i n d i v i d u a l l y s h a p e d t o t h e l e v e r f o r 30 min p e r day u n t i l s p o n t a n e o u s ICS was o b s e r v e d . Those a n i m a l s w h i c h f a i l e d t o b a r p r e s s more t h a n 50 t i m e s i n 15 min a f t e r 14 d a y s o f s h a p i n g were c l a s s e d as h a v i n g n e u t r a l e l e c t r o d e p l a c e m e n t s . A 15 min t e s t s e s s i o n was g i v e n on t h e f i f t e e n t h t e s t day t o e s t a b l i s h t h e ICS r a t e f o r e ach a n i m a l w i t h a p o s i t i v e p l a c e m e n t . I m m e d i a t e l y f o l l o w i n g t h e l a s t ICS t e s t s e s s i o n , a l l a n i m a l s were s a c r i f i c e d , t h e i r b r a i n s removed and s t o r e d i n 10% b u f f e r e d f o r m a l i n . E ach b r a i n was f r o z e n and s e c t i o n e d a t 40u, and t h e s e c t i o n s c o n t a i n i n g t h e e l e c t r o d e t r a c t were mounted and 18 s t a i n e d w i t h c r e s y l v i o l e t - E l e c t r o d e p l a c e m e n t s were examined i n d e p e n d e n t l y by two o b s e r v e r s and l o c a t e d on c o r o n a l s e c t i o n s from t h e P e l l i g r i n o and Cushman (1967) s t e r e o t a x i c a t l a s . R e s u l t s F i f t y - n i n e o f t h e 66 e l e c t r o d e p l a c e m e n t s t e s t e d i n t h i s s t u d y were p o s i t i v e f o r ICS, and as can be s e e n f r o m an e x a m i n a t i o n o f F i g u r e 1, 48 o f t h e s e p l a c e m e n t s were l o c a t e d i n t h e CPU. A l t h o u g h one o f t h e most s t r i k i n g f e a t u r e s of t h e s e d a t a i s t h e homogeneous d i s t r i b u t i o n o f ICS s i t e s t h r o u g h o u t t h e CPU, i t a p p e a r s a s t h o u g h e l e c t r o d e s l o c a t e d i n t h e head o f t h i s s t r u c t u r e s u p p o r t t h e h i g h e s t r a t e s o f ICS. W i t h i n t h i s a n t e r i o r r e g i o n , two p l a c e m e n t s i n t h e v e n t r o m e d i a l q u a d r a n t y i e l d e d a mean r a t e o f 1136/15 min. A p h o t o m i c r o g r a p h d e p i c t i n g one o f t h e s e s i t e s i s shown i n F i g u r e 2. ICS r a t e s f r o m t h e d i f f e r e n t e l e c t r o d e s v e r i f i e d a s CPU p l a c e m e n t s , v a r i e d g r e a t l y from a low o f 55/15 min t o t h e h i g h d e s c r i b e d a b o v e . N e v e r t h e l e s s , 27 o f t h e s e p l a c e m e n t s s u s t a i n e d r a t e s g r e a t e r t h a n 250 p r e s s e s / 1 5 min. A d e t a i l e d d e s c r i p t i o n o f t h e ICS r a t e s , c u r r e n t i n t e n s i t i e s and e l e c t r o d e l o c i , i s c o n t a i n e d i n T a b l e I I I . The mean number o f d a y s t o s p o n t a n e o u s ICS f r o m a l l CPU p l a c e m e n t s was 7.7 + o r - 3.3 (SD). In a d d i t i o n t o I C S , e l e c t r i c a l s t i m u l a t i o n o f t h e CPU a l s o r e s u l t e d i n a number o f d i s t i n c t motor r e s p o n s e s (see T a b l e I I I ) . At a l l ICS p l a c e m e n t s s t i m u l a t i o n e l i c i t e d t h e commonly o b s e r v e d ' f o r w a r d l o c o m o t i o n - e x p l o r a t o r y ' r e a c t i o n w h i c h i s a t y p i c a l r e s p o n s e a t s i t e s i n t h e l a t e r a l h y p o t h a l a m u s f i v e 3-8 3-4 3-0 2-6 -0-6 F i g u r e 1 -lectrode placemoots d e p i c t e d on c o r o n a l s e c t i o n s or t h e P e l l i g r i n o and Cushman (1967) a t l a s . Legend f o r ICS rates/lb min: * 1000-1500; ^ 5 0 0 - 9 9 9 ; A 250-499; .100-249; . bO-99; O <50. TABLE I I I Maximum s e l f - s t i m u l a t i o n r a t e s / 1 5 min, c u r r e n t i n t e n s i t i e s , e l e c t r o d e p l a c e m e n t s , d a y s t o s p o n t a n e o u s s e l f - s t i m u l a t i o n , and s t i m u l a t i o n i n d u c e d motor a c t i v i t y , f o r i n d i v i d u a l r a t s d i s p l a y i n g s e l f - s t i m u l a t i o n . F r o n t a l * S u b j e c t C u r r e n t L o c a t i o n 1 " Days t o R a t e / M otor* S e c t i o n Number (ua) ICS 15 min Response 3.0 CA 1 60 CPU 5 1093 FLE 3.4 CA 3 70 CPU 3 1180 FLE 2. 6 CA5 100 CPU 2 250 FLE 3. 4 CA40 33 CPU 2 343 CR 3.0 CA42 42 CPU 9 756 HBT 3.0 CA43 30 CPU 6 702 CR NH CA44 45 8 753 HBT 3.4 CA47 50 CPU 11 822 HBT 3.4 CA48 40 CPU 6 607 CR 3.0 CA50 9 CPU 5 437 CR 3.8 CA51 100 FC 4 771 CR 2. 2 CA52 28 CPU 8 699 CR 3.8 CA53 6 CPU 2 112 CR 3.0 CA54 115 CPU 6 70 CR 2.2 CA55 80 CPU 12 245 HBT 2.6 CA56 180 CPU 14 55 HBT 1.8 CA57 130 poa 4 20 47 HBT 3.4 CA58 80 CPU 6 230 CR 2.6 CA59 13 CPU 8 173 CR 3.4 CA60 13 FC 6 124 CR 3.4 CA61 42 CPU 7 520 CR NH CA62 13 4 175 CR 3.4 CA64 11 FC 9 214 CR 3. 8 CA65 45 ACB 3 247 CR 3.4 CA66 45 CPU 5 247 CR 2. 6 CA68 60 SEP 8 2 87 CR 2.2 CA69 70 CPU 10 6 16 HBT 3.0 CA70.R 40 CPU 5 382 CR 2.2 CA71R 90 CPU 7 160 HBT 0.2 CA74R 30 CPU 8 420 CR -0. 2 CA75R 13 CPU 6 350 CR 1.0 CA76R 60 CPU 12 550 HBT -0.6 CA77R 30 CPU 7 80 CR -0.6 CA78R 50 CPU 10 120 CR -0.6 CA79R 25 CPU 5 290 CR 2. 2 CA80R 20 CPU 3 217 CR 1.0 CA81R 40 CPU 13 280 HBT 2.2 CA70L 60 CPU 12 60 HBT 1.8 CA71L 60 CPU 6 173 CR 3.0 CA72L 120 CPU 11 2 97 HBT 2.2 CA74L 100 CPU 4 805 F L E 2.2 CA75L 40 CPU 7 392 CR 1.0 CA76L 35 CPU 12 186 HBT . . . . C o n t i n u e d 21 TABLE I I I ( C o n t i n u e d ) Maximum s e l f - s t i m u l a t i o n r a t e s / 1 5 min, c u r r e n t i n t e n s i t i e s , e l e c t r o d e p l a c e m e n t s , d ays t o s p o n t a n e o u s s e l f - s t i m u l a t i o n , and s t i m u l a t i o n i n d u c e d motor a c t i v i t y , f o r i n d i v i d u a l r a t s d i s p l a y i n g s e l f - s t i m u l a t i o n . F r o n t a l S u b j e c t C u r r e n t L o c a t i o n Days t o R a t e / Motor S e c t i o n Number (ua) ICS 15 min Response 1.4 CA77L 50 CPO 7 420 FLE 1.0 CA79L 15 GP 10 241 HBT 1.4 CA81L 40 CPU 8 219 CR 0.6 CA82 25 CPU 13 155 CR -0.6 CA83 35 AMG 3 321 CR 0.2 CA84 70 CPU 4 310 CR 2.2 CA85 40 CPU 8 4 35 CR 1.0 CA86 70 CPU 6 372 CR 2. 2 CH87 14 ACB 12 147 CR 2. 6 CA88 20 CPU 10 216 CR 2.6 CA89 10 CPU 9 158 CR 3. 0 CA90 40 CPU 7 180 CR 1.4 CA91 50 CPU 8 4 85 HBT 1.4 CA92 50 CPU 1 1 127 CR 2.6 CA94 70 CPU 14 72 HBT 2.6 CA95 36 CPU 11 737 HBT * s e c t i o n numbers from P e l l e g r i n o and Cushman (1967) NH; no h i s t o l o g y 1-CPU: c a u d a t e putamen, FC: f r o n t a l c o r t e x , POA: p r e o p t i c a r e a , ACB: n u c l e u s accumbens, SEP: septum, GP: g l o b u s p a l l i d u s , AMG: amygdala. * F L E : f o r w a r d l o c o m o t i o n - e x p l o r a t o r y , CR: c l o n u s r e a r i n g , HBT: head and body t u r n a n i m a l s d i s p l a y e d t h i s r e a c t i o n a l o n e . T w e n t y - n i n e o f t h e p l a c e m e n t s e l i c i t e d a ' c l o n u s - r e a r i n g ' r e s p o n s e , c h a r a c t e r i z e d by r a p i d r e a r i n g w i t h s u p e r i m p o s e d f o r e l i m b c l o n u s and f a c i a l t w i t c h e s . The i n t e n s i t y o f t h i s r e s p o n s e v a r i e d from b e i n g j u s t d e t e c t a b l e t o a v e r y p r o n o u n c e d form which i n t u r n would o c c a s i o n a l l y d e v e l o p i n t o a motor s e i z u r e . S t i m u l a t i o n a t t h e o t h e r 14 p l a c e m e n t s p r o d u c e d s t i m u l u s bound head t u r n i n g which 22 F i g u r e 2 P h o t o m i c r o g r a p h d e p i c t i n g e l e c t r o d e t r a c t i n m e d i a l p o r t i o n o f a n t e r i o r CPU f r o m s u b j e c t CA1 i n more s e v e r e c a s e s m a n i f e s t e d i t s e l f as a s t r o n g c o n t r a l a t e r a l body t u r n . T h i s c l a s s o f motor r e s p o n s e was termed 'head and body t u r n ' . D i s c u s s i o n The r e s u l t s o f t h e p r e s e n t mapping s t u d y show t h a t t h e m a j o r i t y o f p l a c e m e n t s i n t h e CPU w i l l s u p p o r t ICS ( i e 87% o f t h e e l e c t r o d e s t e s t e d . T h i s f i n d i n g c o n f i r m s p r e v i o u s 23 o b s e r v a t i o n s i n t h e r a t ( L e v i n e e t a l , 1971; R o u t t e n b e r g , 1971; Wurtz S O l d s , 1963), c a t ( J u s t e s e n , S h a r p & P o r t e r , 1963; O'Donohue & Hagamen, 1967) and monkey ( B u r s t e n & D e l g a d o , 1958; P l o t n i k , Mir & D e l g a d o , 1972) and c o n t r a d i c t s r e c e n t e v i d e n c e s u g g e s t i n g t h a t t h e n e o s t r i a t u m i n r a t d o e s n o t m a i n t a i n ICS ( P r a d o - A l c a l a e t a l , 1 9 7 5 ) . The r e p o r t e d f a i l u r e t o o b t a i n ICS from CPU e l e c t r o d e s i s b e s t a t t r i b u t e d t o p r o c e d u r a l d i f f e r e n c e s i n p a r t i c u l a r t o t h e s e l e c t i o n o f c u r r e n t i n t e n s i t i e s , and t o t h e number o f t e s t d a y s . Some o f t h e p r e v i o u s mapping s t u d i e s have employed a f i x e d c u r r e n t i n t e n s i t y f o r a l l a n i m a l s ( O l d s & O l d s , 1963; R o u t t e n b e r g , 1971), whereas t h e p r e s e n t p r o c e d u r e r e q u i r e d i n d i v i d u a l s e l e c t i o n of o p t i m a l c u r r e n t i n t e n s i t i e s which p r o d u c e d a c t i v a t i o n and s e a r c h i n g b e h a v i o u r , a l o n g w i t h a m i n i m a l amount o f d i s r u p t i v e motor a r t i f a c t . Once s e l e c t e d , t h e s e i n t e n s i t i e s were used t h r o u g h o u t t h e e x p e r i m e n t . P r a d o -A l c a l a e t a l (1975), v a r i e d t h e c u r r e n t i n t e n s i t y f r o m 30-90 uA, but t h e a n i m a l s were o n l y t e s t e d f o r 10 min p e r day a t a g i v e n i n t e n s i t y . F u r t h e r m o r e , t h e e x p e r i m e n t was t e r m i n a t e d a f t e r o n l y 5 c o n s e c u t i v e t e s t i n g d a y s . We d i d o b s e r v e ICS a t a number o f s i t e s a f t e r 2-5 d a i l y 30 min t e s t p e r i o d s , but t h e m a j o r i t y o f a n i m a l s r e q u i r e d a p p r o x i m a t e l y 8 days o f t r a i n i n g b e f o r e s p o n t a n e o u s ICS b e h a v i o u r was o b s e r v e d (see T a b l e I I I ) . I n f a c t , t h i s p r o l o n g e d l a t e n c y t o i n i t i a t i o n o f ICS s h o u l d n o t be s u r p r i s i n g i n view o f t h e r e p o r t s t h a t CPU s t i m u l a t i o n w i l l d i s r u p t t h e a c q u i s i t i o n o f new r e s p o n s e s {Wyers, Peeke> W i l l i s t o n & H e r z , 1968; Wyers S D e a d w y l e r , 1971) and i n c e r t a i n c a s e s , d i s r u p t o n g o i n g b e h a v i o u r (Delgado & B r a c c h i t t a , 1972). 24 On t h e c o n t r a r y , t h e s u c c e s s f u l e l i c i t i o n o f ICS i n s p i t e o f t h e s e p o t e n t i a l l y d i s r u p t i v e c o r r e l a t e s o f CPU s t i m u l a t i o n , may be t a k e n as f u r t h e r e v i d e n c e f o r t h e p r e s e n c e o f a p o w e r f u l • r e w a r d ' mechanism i n t h e n e o s t r i a t u m . J u s t e s e n e t a l (1963) s u g g e s t t h a t ICS i n t h e CPU of t h e c a t r e s u l t s f r o m s t i m u l a t i o n i n d u c e d h y p e r a c t i v i t y , which i n t u r n i n c r e a s e s o p e r a n t l e v e l s o f b a r p r e s s i n g . T h i s i s an u n l i k e l y e x p l a n a t i o n f o r t h e p r e s e n t f i n d i n g s f o r two major r e a s o n s . F i r s t l y , a l t h o u g h t h e bar p r e s s i n g r a t e s i n t h e J u s t e s e n e t a l (1963) s t u d y (mean e q u a l s s e v e n t y f i v e p r e s s e s i n f i f t e e n m i n utes) a r e c o m p a t i b l e w i t h ' s u c h a s u g g e s t i o n , t h e c o m b i n a t i o n o f h i g h r a t e s and m i n i m a l a r t i f a c t o b s e r v e d i n t h i s s t u d y make s u c h a p o s s i b i l i t y u n l i k e l y . S e c o n d l y , i t was o b s e r v e d t h a t a n i m a l s d i s p l a y i n g CPU ICS would e x t i n g u i s h when s t i m u l a t i o n s were d e l i v e r e d r e g u l a r l y and n o n c o n t i n g e n t l y , but a t t h e same a v e r a g e r a t e as t h e a n i m a l had p r e s s e d f o r p r e v i o u s l y . T h i s o b s e r v a t i o n s u g g e s t s t h a t CPU s t i m u l a t i o n f u n c t i o n s as a r e w a r d . W h i l e t h i s p a p e r i s p r i m a r i l y c o n c e r n e d w i t h t h e p o s s i b i l i t y o f NSB m e d i a t i o n o f ICS i n t h e CPU, a number o f o t h e r p o s s i b i l i t i e s must be c o n s i d e r e d . T h e s e i n c l u d e ; a f f e r e n t s from t h e c o r t e x , i n t r a l a m i n a r n u c l e i o f t h e t h a l a m u s and t h e v e n t r a l n o r a d r e n e r g i c b u n d l e and CPD e f f e r e n t s . I n t r a c r a n i a l s e l f - s t i m u l a t i o n f r o m a v a r i e t y o f b r a i n s i t e s , i s d e p e n d e n t upon t h e p r e f r o n t a l c o r t e x and a c t i v a t e s s i n g l e u n i t s i n t h i s r e g i o n ( R o l l s & C o o p e r , 1 9 7 3 ; R o l l s 6 C o o p e r , 1 9 7 4 ) . As ICS c a n be o b t a i n e d from t h e s e p r e f r o n t a l s i t e s , R o l l s and C o o p e r (1974) 25 s u g g e s t e d t h a t t h e p r e f r o n t a l c o r t e x m o d u l a t e s a c t i v i t y a t o t h e r ICS s i t e s . Most p r e f r o n t a l a f f e r e n t s and e f f e r e n t s p r o j e c t i n t o o r t h r o u g h t h e head o f t h e CPU and c o u l d m e d i a t e t h e ICS f r o m t h a t r e g i o n . I n a s i m i l a r v e i n , R o u t t e n b e r g (1971) mapped c e r t a i n a s p e c t s o f t h e CPU f o r ICS and e m p h a s i z e d t h a t •a p r e p o n d e r a n c e o f p o s i t i v e p l a c e m e n t s were l o c a t e d a l o n g t h e m e d i a l edge o f t h e n u c l e u s . As l e s i o n s a t ICS s i t e s i n t h e m e d i a l p r e f r o n t a l c o r t e x were a c c o m p a n i e d by d e g e n e r a t i o n t h r o u g h t h e v e n t r o m e d i a l a s p e c t o f t h e c a u d a t e - p u t a m e n which i n t u r n a p p e a r e d t o i n t e r d i g i t a t e w i t h f a s c i c l e s i n t h e l a t e r a l a s p e c t o f t h e m e d i a l f o r e b r a i n b u n d l e , R o u t t e n b e r g (1971) s u g g e s t e d t h a t ICS a l o n g t h i s t r a j e c t o r y may i n v o l v e p a r t o f a d e s c e n d i n g c o r t i c a l p r o j e c t i o n . Webster (1961) has d e m o n s t r a t e d t h a t t h e e n t i r e c e r e b r a l c o r t e x p r o j e c t s t o p o g r a p h i c a l l y t o t h e CPU. As t h e e n t o r h i n a l , p y r i f o r m , c i n g u l a t e and p r e f r o n t a l c o r t i c e s have been shown t o s u p p o r t I C S , f i b r e s f r o m a l l o f t h e s e r e g i o n s p r o j e c t i n g t o c o r r e s p o n d i n g r e g i o n s o f t h e CPU may m e d i a t e CPU ICS. As w e l l , C o o p e r and T a y l o r (1967) r e p o r t t h a t ICS c a n be o b t a i n e d f r o m ' c l a s s i c a l * t h a l a m i c i n t r a l a m i n a r n u c l e i . R ecent d e v e l o p m e n t s i n t h a l a m i c neuroanatomy have b r o a d e n e d t h e d e f i n i t i o n o f t h e i n t r a l a m i n a r n u c l e i t o i n c l u d e t h e p o s t e r i o r complex (Heath S J o n e s , 1 9 7 1 ; J o n e s & P o w e l l , 1 9 7 1 ) , a r e g i o n f r o m w h i c h ICS had p r e v i o u s l y been r e p o r t e d ( O l d s 6 O l d s , 1 9 6 3 ) . As t h e i n t r a l a m i n a r n u c l e i p r o j e c t t o t h e e n t i r e CPU (Kemp & P o w e l l , 1 9 7 1 c ; K i l l a c k e y & Ruygo,1975) i t i s p o s s i b l e t h a t t h e s e f i b r e s c o u l d m e d i a t e CPU ICS. L i n d v a l l and B j o r k l u n d (1974) r e c e n t l y t r a c e d a m i n o r component o f t h e v e n t r a l n o r a d r e n e r g i c 26 b u n d l e f i b r e s i n t o t h e CPU, which c o n c e i v a b l y c o u l d be m e d i a t i n g CPU I C S . and f i n a l l y , e f f e r e n t p r o j e c t i o n s must a l s o be c o n s i d e r e d as pathways f r o m t h e CPU p r o j e c t t o t h e g l o b u s p a l l i c u s and s u b s t a n t i a n i g r a ( S z a b o , 1 9 6 2 ) . The o b s e r v a t i o n o f ICS t h r o u g h o u t t h i s p r o j e c t i o n s y s t e m ( P r a d o - A l c a l a e t a l , 1 9 7 5 ; O l d s & Olds,1963) must be t a k e n i n t o a c c o u n t i n any e x p l a n a t i o n o f CPU ICS. D e s p i t e t h e p o s s i b l e c o n t r i b u t i o n s o f t h e s y s t e m s d e s c r i b e d above, t h e major s u b s t r a t e f o r ICS i n t h e CPU would a p p e a r t o be t h e NSB. B i o c h e m i c a l (Koslow, B a c a g n i & C o s t a , 1 9 7 4 ; Von V o i g t l a n d e r & Moore, 1971) and h i s t o c h e m i c a l (Fuxe, 1965; U n g e r s t e d t , 1 9 7 1 ) s t u d i e s have p r o v i d e d e v i d e n c e f o r h i g h c o n c e n t r a t i o n s o f DA i n t h e CPU. I n t h i s r e g a r d , i t i s i m p o r t a n t t o n o t e t h a t t h e h i g h e s t r a t e s o f ICS were o b t a i n e d i n t h e a n t e r i o r p o r t i o n o f t h e CPU, and t h i s o b s e r v a t i o n i s i n a c c o r d w i t h d a t a f r o m a p r e v i o u s s t u d y on monkeys ( P l o t n i k e t a.1, 1972). T h i s r e l a t e s t o t h e r e c e n t o b s e r v a t i o n t h a t t h e h i g h e s t c o n c e n t r a t i o n s o f DA a r e f o u n d i n t h e r o s t r a l a s p e c t o f t h e CPU (Koslow e t a l , 1 9 7 4 ) . The c e l l b o d i e s o f t h i s DA s y s t e m r e s i d e i n t h e SNC and t h e p r o j e c t i o n s o f t h e NSB has been t r a c e d by h i s t o c h e m i c a l f l u o r e s c e n c e ( U n g e r s t e d t , 1 9 7 1 ) . Of r e l e v a n c e t o t h e p r e s e n t d i s c u s s i o n i s t h e h i g h i n c i d e n c e o f ICS a l o n g t h e t r a j e c t o r y o f t h i s DA s y s t e m , f r o m i t s o r i g i n s i n t h e SNC, t h r o u g h t h e l a t e r a l h y p o t h a l a m u s and e n t o p e d u n c u l a r n u c l e u s , t o i t s t e r m i n a l r e g i o n i n t h e CPU ( f o r r e v i e w s e e German & Bowden,1974). T h i s p o s i t i v e c o r r e l a t i o n between ICS p l a c e m e n t s and t h e t r a j e c t o r y o f t h e NSB gave r i s e t o t h e h y p o t h e s i s t h a t ICS i n t h e CPU i s s u b s e r v e d by DA n e u r o n s . 27 The motor r e s p o n s e s which a c c o m p a n i e d CPU ICS a r e s i m i l a r t o t h o s e d e s c r i b e d i n p r e v i o u s s t u d i e s ( L e v i n e e t a l , 1 9 7 1 ; P r a d o - A l c a l a e t a l , 1 9 7 5 ) . I n p a r t i c u l a r t h e 'head and body t u r n ' i s s i m i l a r t o t h e r e s p o n s e r e p o r t e d by P r a d o - A l c a l a e t a l (1975 ) , whereas t h e • c l o n u s - r e a r i n g ' r e s p o n s e i n t h e p r e s e n t s t u d y i s s i m i l a r t o t h e ' f l o p p i n g ' r e s p o n s e a l s o d e s c r i b e d by t h e f o r m e r g r o u p . The q u e s t i o n a r i s e s as t o whether t h e s e motor r e s p o n s e s a r e due t o d i r e c t s t i m u l a t i o n o f n e u r a l e l e m e n t s o f the CPU o r t h e i n t e r n a l c a p s u l e . I n t h e c a t , where t h e i n t e r n a l c a p s u l e and CPU a r e s e p e r a t e , t h e l o w e s t t h r e s h o l d f o r e l i c i t a t i o n o f t h e 'body t u r n ' was i n t h e CPU ( L a u r s e n , 1 9 6 3 ) . The same r e s p o n s e s , 'body t u r n ' , ' c l o n u s ' and ' e x p l o r a t o r y ' were r e p r o d u c e d when DA a g o n i s t s were i n j e c t e d i n t r a c e r e b r a l l y i n t o t h e CPU ( U n g e r s t e d t , B u t c h e r , B u t c h e r , Anden S Fuxe, 1969; C o o l s , 1 9 7 3 ; C o o l s , H e n d r i k s , S K o r t e n , 1 9 7 5 ) . T h e s e r e s u l t s i m p l y t h a t CPU n e u r a l e l e m e n t s , i n p a r t i c u l a r t h o s e w i t h DA s u b s t r a t e can m e d i a t e t h e o b s e r v e d motor r e s p o n s e s . The motor s e i z u r e s t h a t o c c a s i o n a l l y f o l l o w e d CPU s t i m u l a t i o n a r e s i m i l a r t o t h e r e s p o n s e s d e s c r i b e d by G o d d a r d , M c l n t y r e and L e e c h (1969), and c o n f i r m t h a t s e i z u r e s o f t e n r e s u l t from ICS ( P o r t e r , C o n r a d S B r a d y , 1 9 5 9 ) . However i t i s u n l i k e l y t h a t t h i s s e i z u r e a c t i v i t y i s d i r e c t l y r e l a t e d t o I C S . A n t i c o n v u l s a n t d r u g s a r e r e p o r t e d t o i n c r e a s e ICS (Mogenson, 1964) , and i t has been o b s e r v e d ( P o r t e r e t a.1, 1959; P l o t n i k e t a l , 1 9 7 2 ) t h a t ICS i s not a c c o m p a n i e d by s e i z u r e a c t i v i t y a t some s i t e s . T h i s f i n d i n g was c o n f i r m e d w i t h CPU ICS. E l e c t r o g r a p h i c r e c o r d i n g s o f t h e CPU were made f r o m t h e ICS I 28 e l e c t r o d e . A f t e r s t i m u l a t i o n a t ICS c u r r e n t l e v e l s , 3 a n i m a l s w i t h ' c l o n u s - r e a r i n g ' a r t i f a c t , d i s p l a y e d r h y t h m i c a l s p i k i n g a c t i v i t y , and upon r e p e a t e d s t i m u l a t i o n t h e s e a n i m a l s c o u l d be i n d u c e d t o s e i z u r e . I n c o n t r a s t , even a f t e r r e p e a t e d s t i m u l a t i o n no s p i k i n g o r s e i z u r e b e h a v i o u r was o b s e r v e d i n 2 a n i m a l s e x h i b i t i n g a ' f o r w a r d l o c o m o t i o n - e x p l o r a t o r y ' r e s p o n s e . 29 EXPERIMENT THO Introduction Experiment I has c l e a r l y demonstrated that the CPU supports ICS. This complements the r e s u l t s of other mapping studies which have shown that ICS can be obtained throughout the remainder of the NSB (see General Introduction). This, in turn, suggests that stimulation of DA neurons can reinforce behaviour. ;However, the p o s s i b i l i t y remains that other systems in these regions mediate the reinforcement. For example, Routtenberg (1971) and Ro l l s and Cooper (1974) have proposed that descending projections from the prefrontal cortex may mediate reinforcement. .As- these f i b r e s would pass through the CPU and median forebrain bundle (Routtenberg, 19171), ICS in these areas could be due t o stimulation of these c o r t i c o f u g a l fibres.. Fortunately, s e l e c t i v e destruction of the SNC by i n t r a c r a n i a l i n j e c t i o n s of 60HDA allows t h i s and other s i m i l a r p o s s i b i l i t i e s to be tested. To ensure that nearby NA axons are not disrupted animals in tha following experiment were pretreated with desipramine, a compound which i n h i b i t s the uptake of 6 OH DA by NA neurons. To control for the • motor impairoents* resulting from an SNC l e s i o n , ICS i n a group of animals with i p s i l a t e r a l SNC lesions w i l l ba compared to ICS i n a group with cont r a l a t e r a l SNC lesions. As the SNC innervates the i p s i l a t e r a l CPU (Ungerstedt,1971) , a greater depression of CPU ICS following i p s i l a t e r a l lesions would constitute evidence of DA mediation of reward in the CPU. 30 Methods The mapping study i d e n t i f i e d a zone in; the l a t e r a l caudate nucleus from which r e l i a b l e ICS c o u l d be e l i c i t e d and t h e r e f o r e 20 animals (300 - 350 g) sere prepared with c h r o n i c b i p o l a r e l e c t r o d e s aimed at t h i s s i t e . With the mouth-bar l o c a t e d 4.2 mm below the i n t e r a u r a l l i n e , the c o - o r d i n a t e s were a n t e r i o r 0.5 mm to bregma, 3.0 mm from the m i d l i n e , and 5.0 mm below the d o r s a l s u r f a c e of the c o r t e x . Upon recovery from s u r g e r y , the s u b j e c t s were screened f o r ICS, i n accordance with the procedure o u t l i n e d i n Experiment I . Those animals d i s p l a y i n g r e l i a b l e ICS behaviour were given 3 days of a d d i t i o n a l p r e - l e s i o n t r a i n i n g , and the average ICS r a t e over these t h r e e 15 min s e s s i o n s served as the p r e - l e s i o n b a s e l i n e . To ensure the s e l e c t i v e d e s t r u c t i o n of the DA c e l l b o d i es i n the SNC, the 15 s u b j e c t s e x h i b i t i n g ICS were p r e t r e a t e d with desipramine (25 ag/kg), a compound which i n h i b i t s the uptake o f 6-OHDfi by NA neurons i n the v i c i n i t y of - the i n j e c t i o n s i t e . T h i r t y minutes l a t e r , a l l animals were a n e s t h e t i z e d with i halothane and placed i n t h e s t e r e o t a x i c instrument f o r the acute i n s e r t i o n of a f i n e 34 gauge cannula i n t o the SNC. C o - o r d i n a t e s , with mouth bar a t 4.2 mm belowv the i n t e r a u r a l l i n e , were a n t e r i o r +3.2 mm, l a t e r a l +2.1 mm, and d o r s a l / v e n t r a l -2. 1 mm, from s t e r e o t a x i c z e r o . With the cannula i n p l a c e , 8 ug o f 6-OHDA (dosage expressed as the f r e e base) i n 4 u l o f v e h i c l e , prepared a c c o r d i n g to a standard procedure, was i n j e c t e d i n t o the SNC a t a r a t e of 1 ul/min. E i g h t animals r e c e i v e d n e u r o t o x i c l e s i o n s of the i p s i l a t e r a l SNC and 7 animals with c o n t r a l a t e r a l l e s i o n s 31 served as c o n t r o l s . A 7 day recovery p e r i o d preceded the resumption of t e s t i n g f o r ICS. The p o s t - l e s i o n t e s t s were i d e n t i c a l t o the p r e - l e s i o n s e s s i o n s , with the e x c e p t i o n t h a t a 5 min •priming' p e r i o d preceded the 15 min ICS t e s t . T e s t i n g continued f o r 21 days. Upon completion of t e s t i n g , 28 days a f t e r the l e s i o n , each animal was s a c r i f i c e d by c e r v i c a l f r a c t u r e , the b r a i n removed and d i s s e c t e d on i c e . NA was measured i n the hypothalamus, while DA was measured i n the l e f t and r i g h t CP (McGeer & ScGeer, 196 2) . The b r a i n stem of each animal was f i x e d i n 10% b u f f e r e d f o r m a l i n , f r o z e n and s e c t i o n e d a t 40u. S e c t i o n s c o n t a i n i n g the i n j e c t i o n s i t e were mounted and s t a i n e d with c r e s y l v i o l e t . R e s u l t s The r e s u l t s o f t h i s experiment c l e a r l y support the hypothesis t h a t ICS i n the CPO i s dependent upon DA i n n e r v a t i o n of t h i s s t r u c t u r e s Neurotoxic l e s i o n s of the DA c e l l bodies i n SNC produced a s u s t a i n e d decrease i n ICS r a t e t o l e s s than 10;S of p r e - l e s i o n c o n t r o l s c o r e s , at s i t e s i n the i p s i l a t e r a l CPO*. These e f f e c t s p e r s i s t e d f o r 28 days f o l l o w i n g the l e s i o n , a t which time t e s t i n g was terminated. I d e n t i c a l but c o n t r a l a t e r a l SNC l e s i o n s r e s u l t e d i n a temporary d i s r u p t i o n of ICS. The ICS r a t e dropped t o 2H% of the p r e - l e s i o n score over the f i r s t t h r e e days of p o s t - o p e r a t i v e t e s t i n g but had r e t u r n e d t o 72% of the c o n t r o l value dur i n g the l a s t t hree days of t e s t i n g (see F i g . 3). 32 F i g u r e 3 E f f e c t s o f u n i l a t e r a l 60HDA l e s i o n s o f t h e SNC on s e l f -s t i m u l a t i o n i n t h e • • i p s i l a t e r a l o r c o n t r a l a t e r a l * — C P U . D a t a r e p r e s e n t s means +or-SEH. 5 0 0 - 3 - -1 " 1 - 3 4 - 6 7 - 9 1 0 - 1 2 1 3 - 1 5 16 -18 1 9 - 2 1 time (days) 34 F i g u r e 4 P h o t o m i c r o g r a p h s s h o w i n g t h e s i t e o f 60HDA i n j e c t i o n i n t o t h e SNC. P h o t o m i c r o g r a p h A i s a low power (10X) r e p r o d u c t i o n o f t h e s e c t i o n c o n t a i n i n g t h e i n j e c t i o n s i t e . P h o t o m i c r o g r a p h s B and C r e p r e s e n t m a g n i f i c a t i o n s (12X) o f t h e a r e a s b o x e d i n p h o t o m i c r o g r a p h A. P h o t o m i c r o g r a p h B shows t h e l e s i o n e d a r e a o f the SNC now i n v e s t e d by g l i a l c e l l s . P h o t o m i c r o g r a p h C shows t h e same r e g i o n o f t h e c o n t r a l a t e r a l c o n t r o l SNC (see t e x t f o r f u r t h e r e x p l a n a t i o n ) . 36 TABLE IV E f f e c t s of U n i l a t e r a l 60HDA I n j e c t i o n s oa I p s i l a t e r a l and C o n t r a l a t e r a l S t r i a t a l Dopamine L e v e l s and Hypothalamic Noradrenaline L e v e l s DA (ug/gmj Group I p s i l a t e r a l SNC 6OHDA C o n t r a l a t e r a l SNC 60HDA C o n t r o l L e f t CPU 10.60+or-0.76 (108%) + 0.68+or-0.24 (7%) 9.60+or-0.68 (100%) Righ t CPU 0.52+or-0.17* 12.50+or^1.32 (109%) 11.43+or-0.53 (100%) NA (ug/gm) Hypothalamus 1.89+or-0. 19 (85%) 2.18+or-0.12 (98%) 2-23+or-0.09 (100%) *mean+or- (SEN) tpercentage o f c o n t r o l value * s i g n i f i c a n t l y d i f f e r e n t from l e f t CPU, p<-01 * * s i g n i f i c a n t l y d i f f e r e n t from r i g h t CPU, p<.01 **no s i g n i f i c a n t d i f f e r e n c e from c o n t r o l , p>.05 For s t a t i s t i c a l a n a l y s i s , the pre- and p o s t - l e s i o n ICS r a t e s f o r both groups were averaged over 3-day b l o c k s , which i n t u r n were analyzed f o r between group d i f f e r e n c e s by a n a l y s i s o f v a r i a n c e with repeated measures over t e s t d a y s . •; T h i s a n a l y s i s r e v e a l e d a s i g n i f i c a n t d i f f e r e n c e between the groups, F (1,13) = 28.93, p < .001. Subsequent t e s t s f o r simple main e f f e c t s ( i . e . Group d i f f e r e n c e on a given block o f t e s t s ) followed the procedure d e s c r i b e d by Hiner (1971). There were no s i g n i f i c a n t d i f f e r e n c e s between the p r e - l e s i o n ICS r a t e s of the i p s i l a t e r a l and c o n t r a l a t e r a l l e s i o n groups (F( 1,53) - 1. 20, p > .05) , nor were s i g n i f i c a n t d i f f e r e n c e s observed during the f i r s t 3 days o f p o s t - o p e r a t i v e t e s t i n g (F (1,53 = 0.96, p > .05). However, s i g n i f i c a n t d i f f e r e n c e s i n ICS r a t e were found f o r each of the subsequent p o s t - l e s i o n t e s t p e r i o d s . S p e c i f i c a l l y , f o r pos t -o p e r a t i v e days 4-6, F (1,53) = 8.50, p < .01; days 7-9, F(1,53) = 37 1 3 . 4 0 , p < . 0 1 ; days 1 0 - 1 2 , F ( 1 , 5 3 ) = 1 5 . 4 0 , p < . 0 1 ; days 1 3 -1 5 , F ( 1 , 5 3 ) = 1 4 . 8 0 , p < . 0 1 ; days 1 6 - 1 8 , F (1 , 5 3 ) = 2 0 . 7 0 , p < . 0 1 ; and days 1 9 - 2 1 , F ( 1 , 5 3 ) = 3 3 . 9 0 , p < . 0 1 . Although not s u b j e c t e d to a d e t a i l e d a n a l y s i s , i t should be noted that the s t i m u l a t i o n induced motor responses were t o p o g r a p h i c a l l y s i m i l a r p o s t - l e s i o n , while the frequency o f s e i z u r e s i n c r e a s e d . P r i o r to the l e s i o n no s e i z u r e s were observed whereas p o s t - l e s i o n 5 7 $ c of the c o n t r a l a t e r a l l e s i o n group d i s p l a y e d s e i z u r e s and 3 7 % of the i p s i l a t e r a l l e s i o n group d i s p 1 a y ed S e i z u re s . H i s t o l o g i c a l ^ a n a l y s i s of the i n j e c t i o n s i t e (Figure 4) r e v e a l e d d e s t r u c t i o n of the SNC (shown on t h e l e f t s i d e of the f i g u r e - compare with normal SNC on the c o n t r a l a t e r a l side) while non-DA neurons of the s u b s t a n t i a n i g r a pars r e t i c u l a t a immediately a d j a c e n t t o the i n j e c t i o n s i t e appear normal. The r e s u l t s of the b i o c h e m i c a l assays are shown i n T a b l e IV. U n i l a t e r a l i n j e c t i o n s of 6-OHDA i n t o the SNC reduced s t r i a t a l DA l e v e l s i n the i p s i l a t e r a l and c o n t r a l a t e r a l groups to a mean of 41 and 71 of c o n t r o l , r e s p e c t i v e l y . / S t r i a t a l DA l e v e l s on the s i d e c o n t r a l a t e r a l t o the l e s i o n d i d not d i f f e r s i g n i f i c a n t l y from l e v e l s i n unlesioned s u b j e c t s (p > - 0 5 ) . I t i s a l s o important t o note t h a t pre-treatment with desipramine p r o t e c t e d adjacent NA neurones from damage, as evidenced by normal NA l e v e l s i n the hypothalami of both l e s i o n groups. 38 D i s c u s s i o n The h y p o t h e s i s t h a t ICS from the CPU i s mediated by t h e NSB, was confirmed i n the present; experiment by the almost complete d i s r u p t i o n of CPU ICS f o l l o w i n g 60HDA l e s i o n s of the DA c e l l bodies i n the SNC. U n i l a t e r a l 60HD& l e s i o n s of the SNC, produced a s i g n i f i c a n t r e d u c t i o n i n ICS d u r i n g the i n i t i a l phases of post l e s i o n t e s t i n g , r e g a r d l e s s of whether the l e s i o n was i p s i l a t e r a l o r c o n t r a l a t e r a l to the e l e c t r o d e . These i n i t i a l d e f i c i t s are best a s c r i b e d to a ; * motorimpairment',? which had a ge n e r a l d e p r e s s i v e e f f e c t upon the bar p r e s s i n g response. T h i s i s c o n s i s t e n t with p r e v i o u s r e p o r t s of d i s r u p t i o n of bar p r e s s i n g f o r ICS, food or water f o l l o w i n g ; pretreatment with n e u r o l e p t i c s , i n t r a v e n t r i c u l a r i n j e c t i o n s of 60HDA ( F i b i g e r e t al*19.75; R o l l s e t a l , 1974) or d i s r u p t i o n o f the NSB (Kent S Grossman,1973), and with the view that the NSB subserves important motor f u n c t i o n s (Ungerstedt,1974). However, i t i s important t o emphasize t h a t animals i n both groups d i s p l a y e d above operant bar p r e s s i n g behaviour f o l l o w i n g the l e s i o n , thereby demonstrating t h e i r a b i l i t y t o perform the a p p r o p r i a t e response. In subsequent t e s t s , the response r a t e of the i p s i l a t e r a l r l e s i o n group d e c l i n e d t o a l e v e l t h a t ranged between 2% - S%of t h e i r p r e o p e r a t i v e s c o r e s , a l e v e l t h a t i s comparable to a f r e e operant r a t e i n these t e s t chambers. In c o n t r a s t , the response r a t e of the animals i n the c o n t r a l a t e r a l group e x h i b i t e d a s i g n i f i c a n t improvement t o a l e v e l t h a t was 72% o f p r e l e s i o n c o n t r o l s c o r e s . I t i s proposed t h a t the; d e c l i n e and v i r t u a l c e s s a t i o n o f ICS i n the i p s i l a t e r a l - l e s i o n group i s ' d u e t o the l o s s of the r e i n f o r c i n g e f f e c t s of CPO s t i m u l a t i o n . But b e f o r e t h i s can be accepted a l t e r n a t i v e e x p l a n a t i o n s must be c o n s i d e r e d . There i s l i t t l e p o s s i b i l i t y t h a t the hypophagia and sensori-motor impairment caused by SNC l e s i o n s ( M a r s h a l l ; Richardson & Teitelbaum,19 74) are r e s p o n s i b l e f o r the e f f e c t of an i p s i l a t e r a l l e s i o n on ICS. The c o n t r a l a t e r a l - l e s i o n group should s u f f e r these same b e h a v i o u r a l d e f i c i t s , - a n d y e t they r e c o v e r ICS behaviour. SNC l e s i o n s r e s u l t e d i n an i n c r e a s e i n s t i m u l a t i o n induced motor s e i z u r e s . Could t h i s d i s r u p t i v e i n f l u e n c e be the cause of the d e c l i n e i n ICS? As the c o n t r a l a t e r a l - l e s i o n group tended to d i s p l a y more s e i z u r e s than the i p s i l a t e r a l group a f t e r the l e s i o n , t h i s a l s o seems an u n l i k e l y e x p l a n a t i o n of the ICS d e c l i n e . Two f u r t h e r arguments s t r o n g l y suggest t h a t the ICS d e c l i n e i s due to a l o s s of r e i n f o r c e m e n t . F i r s t l y P h i l l i p s , C a r t e r and F i b i g e r (1975) demonstrated t h a t SNC l e s i o n s d i s r u p t e d ICS from s i t e s i n the d o r s a l l a t e r a l hypothalamus, near the NSB, but not from s i t e s i n the v e n t r o - l a t e r a l hypothalamus,. This suggests t h a t the e f f e c t o f an SNC l e s i o n on ICS i s very s p e c i f i c and may be c o n f i n e d t o dopaminergic regions of the b r a i n . Secondly, any type of general d i s r u p t i v e e f f e c t on ICS should be e v i d e n t on the f i r s t day of p o s t - o p e r a t i v e t e s t i n g . . There i s l i t t l e reason to suppose that a g e n e r a l d i s r u p t i v e e f f e c t would decrease ICS g r a d u a l l y , over the course of three days. On the other hand th e l o s s o f the r e i n f o r c i n g e f f e c t s of CPO s t i m u l a t i o n would produce a gradual d e c l i n e i n responding.; Anatomical (Hokfelt & Ungerstedt,1973) and b i o c h e m i c a l (HcGeer, F i b i g e r , McGeer & 40 Brooke,1973) evidence suggest t h a t degenerating but p a r t i a l l y f u n c t i o n a l DA t e r m a i n a l s e x i s t i n the CPU 7 days o f t e r a 60HDA SNC l e s i o n . During the f i r s t 3 days of ICS t e s t i n g s t i m u l a t i o n may r e l e a s e DA from these t e r m i n a l s and r e i n f o r c e behaviour. As degeneration proceeds t h i s c a p a b i l i t y would be g r a d u a l l y l o s t , thus e x p l a i n i n g the g r a d u a l d e c l i n e i n *. responding of animals with i p s i l a t e r a l SNC l e s i o n s . In c o n t r a s t to e f f e c t s on ICS, motor beh a v i o u r s e l i c i t e d by the s t i m u l a t i o n , were e s s e n t i a l l y u n a l t e r e d by the SNC l e s i o n s . T h i s i n d i c a t e s t h a t while the r e l e a s e of DA may be s u f f i c i e n t t o e l i c i t a p a r t i c u l a r motor response (Ungerstedt e t al,1969) i t i s not necessary. I t i s apparent > t h a t u n i l a t e r a l DA d e n e r v a t i o n has two e f f e c t s on ICS behaviour. 1. Seduction o f DA l e v e l s i s accompanied by a l o s s of b r a i n s t i m u l a t i o n reward at s i t e s n ormally i n n e r v a t e d by the NSB, namely the CPU. 2. L e s i o n s o f the NSB produce a general d i s r u p t i o n i n bar p r e s s i n g behaviour, as evidenced by the a t t e n u a t i o n of ICS f o l l o w i n g c o n t r a l a t e r a l l e s i o n s i n t h e present experiment. T h i s i s i n agreement with t h e o r e t i c a l treatments o f the NSB > which ^suggest both motor and reinforcement f u n c t i o n s f o r t h i s system (Crow^1973). 41 GENERAL DISCUSSION Crow (1972) obtained ICS from s i t e s i n the DA n u c l e i of the v e n t r a l mesencephalon, and on t h i s b a s i s hypothesized t h a t s t i m u l a t i o n o f DA neurons could r e i n f o r c e behaviour. The demonstration of ICS alo n g the NSB and i n t h e globus p a l l i d u s (see General I n t r o d u c t i o n ) were c o n s i s t e n t with t h i s s u g g e s t i o n , but the f a i l u r e s to observe ICS i n the CPU c a s t doubt upon Crow's hypothesis.. T h i s discrepancy /was r e s o l v e d by Experiment I which c l e a r l y demonstrated that the CPU supports ICS, and i t was suggested t h a t previous f a i l u r e s to o b t a i n CPU ICS were due t o methodological i n s u f f i c i e n c i e s . T h i s evidence suggested DA involvement i n reward, and t h e r e f o r e i n Experiment I I the SNC was l e s i o n e d with 6-OHDA. The r e s u l t s confirmed the hy p o t h e s i s t h a t DA mediated CPU b r a i n s t i m u l a t i o n reward. When the l e s i o n was i p s i l a t e r a l t o the e l e c t r o d e ICS was v i r t u a l l y a b o l i s h e d , while c o n t r a l a t e r a l l e s i o n s produced only a p a r t i a l d i s r u p t i o n o f ICS, which probably r e f l e c t s a n o n s p e c i f i c d i s r u p t i o n of bar p r e s s i n g . These r e s u l t s suggested two r o l e s f o r the NSB; motor c o n t r o l and re i n f o r c e m e n t , and provide the f i r s t s t r o n g evidence f o r the mediation of reward by a s p e c i f i c n e u r a l system* I t i s g r a t i f y i n g t o note t h a t N e i l l , Parker and Gold (1975) have very r e c e n t l y r e p o r t e d experiments which coroborate the f i n d i n g s and c o n c l u s i o n s o f t h e present s t u d y . I n t r a s t r i a t a l i n j e c t i o n s of 6-OHDA d i s r u p t e d l a t e r a l hypothalamic ICS, d e s p i t e the normal performance of the same animals i n oth e r b e h a v i o u r a l s i t u a t i o n s . As i n t r a s t r i a t a l i n j e c t i o n s of dopamine re v e r s e d the ICS d e f i c i t i t i s c l e a r t h a t the ICS decrement was due to the 4 2 d i s r u p t i o n of DA t r a n s m i s s i o n i n the CPU. The f i n d i n g s of the present study have i d e n t i f i e d the NSB as a s u b s t r a t e of ICS, but other systems are undoubtedly i n v o l v e d i n b r a i n s t i m u l a t i o n reward as' wellw The DA p r o j e c t i o n s to the mesolimbic r e g i o n and to c e r t a i n c o r t i c a l areas are l i k e l y candidates because ICS can be obtained throughout t h e i r t r a j e c t o r y (see G e n e r a l I n t r o d u c t i o n ) and t h e i r n u c l e i o f o r i g i n are i n t e r m i n g l e d or a d j a c e n t to the c e l l s which g i v e r i s e to the NSB ( L i n d v a i l & Bjorklund,1974; Fuxe et al,1974>. , T h i s c o n j e c t u r e c o u l d be t e s t e d with a technique s i m i l a r to the one used i n the present study. ICS can a l s o be o b t a i n e d from b r a i n r e g i o n s , such, as the hippocampus which r e c e i v e e x t e n s i v e NA i n n e r v a t i o n but almost no DA i n n e r v a t i o n . , As t h i s r e g i o n supports ICS (Ursin et al,1966) a l e s i o n o f the DNAB would i n d i c a t e i f NA f i b r e s mediate hippocampal b r a i n s t i m u l a t i o n reward. He a r e now i n a p o s i t i o n to d i s c u s s t h r e e major i s s u e s concerned with the r o l e of the NSB i n reward. Host t h e o r e t i c a l treatments of ICS suggest t h a t i n t r a c r a n i a l s t i m u l a t i o n r e i n f o r c e s behaviour by i n f l u e n c i n g pathways e x c i t e d by n a t u r a l rewards (Olds, 1962; Crow, 1973; Mogehson & P h i l l i p s , 1975) . I f t h i s i s t r u e t h e n i s should be p o s s i b l e to i d e n t i f y SNC a f f e r e n t s which r e l a y the consequences of n a t u r a l rewards. The SNC r e c e i v e s f i b r e s from th e b a s a l g a n g l i a but few o t h e r i n p u t s are known. Crow (1973) hy p o t h e s i z e d t h a t the SNC r e c e i v e s an o l f a c t o r y pathway v i a the habenula which produces the approach behaviours and operant reinforcement c h a r a c t e r i s t i c of i n c e n t i v e m o t i v a t i o n . However Heimer (1972) 43 has shown t h a t the o l f a c t o r y c o r t e x does not p r o j e c t to the habenula as p r e v i o u s l y thought. Thus Crow's suggested pathway i s i n q u e s t i o n . Future i n v e s t i g a t i o n s may i d e n t i f y the c r i t i c a l a f f e r e n t s t o the SNC. For example, F i b i g e r and C a r t e r (unpublished observations) u s i n g r e t r o g r a d e t r a n s p o r t of p r o t e i n (La V a i l & La V a i l , 197 2) have demonstrated l a b e l l e d c e l l s i n the p e r i a c q u e d u c t a l grey a f t e r i n j e c t i o n s of horse r a d i s h p e r o x i d a s e i n t o the s u b s t a n t i a n i g r a . Evidenca suggests t h a t t h i s r e g i o n r e c e i v e s s e x u a l l y r e l a t e d sensory s t i m u l i ( P f a f f , Diakow, Zigmond, Lee-Ming Kow,1974) , and supports ICS (Liebman e t a l 1973). S i n g l e u n i t s t u d i e s of t h e SNC would be f r u i t f u l f o r i d e n t i f y i n g the b e h a v i o u r a l r e i n f o r c e r s a f f e c t i n g the f i r i n g r a t e of SNC c e l l s . although the i n p u t s which a f f e c t the SNC are unknown t h e r e i s c o n s i d e r a b l e d a t a d e s c r i b i n g the e f f e c t of the NSB on the f u n c t i o n of the CPU. The NSB, as w e l l as o t h e r CPU a f f e r e n t s , terminate on d e n d r i t i c s p i n e s i n the CPU (Kemp & Powell,1971b; Bak, Choi, S a s s i e r , Usun S Hagner, 1975) . One type of CPU neuron (spiny neuron) accounts f o r almost a l l of the d e n d r i t i c s p i n e s i n the CPU (Kemp 6 P o w e l l , 1971a) . This i n d i c a t e s t h a t the NSB terminates almost e x c l u s i v e l y on the spiny neurons. There i s evidence t h a t these c e l l s form i n h i b i t o r y c h o l i n e r g i c synapses on nearby CPU output neurons (Kemp & Powell,1971a; McGeer, McGeer, G r e w a l l & S i n g h , 1 9 7 5 ) . T h i s presumed DA i n n e r v a t i o n o f Ach interneurGns was confirmed by ( H a t t o r i , McGeer, Singh, McGeer, and F i b i g e r , 1 9 7 5 ) , who demonstrated DA t e r m i n a l s synapsing d i r e c t l y on c h o l i n e a c e t y l t r a n s f e r a s e p o s i t i v e c e l l s i n the CPU. U n f o r t u n a t e l y , because of the s m a l l s i z e of these 44 c e l l s , there i s no e l e c t r o p h y s i o l o g i c a l data on the nature o f t h i s synapse, t h e r e f o r e we must r e l y on b i o c h e m i c a l evidence which suggests that the NSB i n h i b i t s Ach i n t e r n e u r o n s . Dopamine, t r a n s m i s s i o n i s d i r e c t l y r e l a t e d t o Ach l e v e l s , and i n v e r s e l y r e l a t e d t o Ach turnover (Guyenet, Javoy, Agid, Beaujouan 6 Glowinski,1975; Rommelspacher S Kuhar,1975; T r a b u c c h i , Cheney; Racagni S Costa,1975)- Furthermore, pharmacological agents which decrease DA t r a n s m i s s i o n a c t u a l l y i n c r e a s e Ach r e l e a s e i n the CPO, whereas DA a g o n i s t s reverse t h i s e f f e c t ( S t a d l e r , L l o y d , Gaedea-Ciria & Bartholini>1973; S t a d l e r , L l o y d 6 B a r t h o l i n i , 1 9 7 4 ) . E l e c t r i c a l s t i m u l a t i o n of the CPO causes DA r e l e a s e (Von V o i g t l a n d e r S Moore, 1971). Hence i t i s hypothesized t h a t CPO s t i m u l a t i o n i s rewarding because of i t s a b i l i t y t o i n h i b i t Ach i n t e r n e u r o n s . Before c o n s i d e r i n g the q u e s t i o n of CPO e f f e r e n t s , the b e h a v i o u r a l e f f e c t s of DA r e l e a s e onto CPO i n t e r n e u r o n s w i l l be b r i e f l y d e s c r i b e d . F i r s t l y , as shown by the present study, DA r e l e a s e i s capable of r e i n f o r c i n g behaviour. Secondly, i t can produce v a r i o u s motor behaviours i n c l u d i n g motor a r t i f a c t s and e x p l o r a t o r y and consummatory behaviours. These can be produced by e l e c t r i c a l s t i m u l a t i o n of the NSB r e g i o n (Crow,1972; York,1973; C h r i s t o p h e r & B u t t e r , 1968; Glickman S Schiff,1967) o r by d i r e c t a p p l i c a t i o n of DA a g o n i s t s to the CPO (Cools,1973; Cools et a l , 1975) . Although no consummatory behaviours were observed a f t e r e l e c t r i c a l s t i m u l a t i o n of the CPO ( C a r t e r , unpublished o b s e r v a t i o n s ; Levine et al,1971), t h i s c o u l d be due to the n o n s p e c i f i c nature o f e l e c t r i c a l s t i m u l a t i o n . T h i s i s c o n s i s t e n t with C o o l s , Hendriks and. Korten»s (1975) o b s e r v a t i o n 45 t h a t a p p l i c a t i o n of DA a g o n i s t s t o the CPU r e s u l t s i n a h i g h frequency of a wide v a r i e t y of b e h a v i o u r s , i n c l u d i n g consummatory behaviours. C o n v e r s e l y , NSB degeneration decreases the occurrence of s t i m u l a t i o n induced consummatory and e x p l o r a t o r y behaviours ( P h i l l i p s & F i b i g e r , 1975), as w e l l as producing a k i n e s i a ( S t r i e k e r & Zigmond ,197 4) . Although both reward and motor behaviours accompany NSB a c t i v a t i o n t h e s e e f f e c t s appear to depend on d i f f e r e n t systems. Evidence f o r t h i s statement comes from the f a c t t h a t e l e c t r i c a l s t i m u l a t i o n of the CPU a f t e r denervation-of; the NSB s t i l l e l i c i t s motor responses but reward i s no l o n g e r present. The nature o f t h i s d i s s o c i a t i o n w i l l become c l e a r e r as the a c t i o n of the NSB on CPU e f f e r e n t s i s c o n s i d e r e d . Any attempt to d e f i n e the way i n which a c t i v a t i o n of the NSB could r e i n f o r c e behaviour must focus on the e f f e r e n t p r o j e c t i o n s from the CPU. The main p r o j e c t i o n goes to the globus p a l l i d a s and from t h e r e to e i t h e r the c o r t e x v i a the thalamus (Kemp 6 Powell,1971c) or c a u d a l l y t o the nucleus tegmenti pedunculopontis (Nauta S Mehler,1966). These CPU e f f e r e n t s are normally i n h i b i t e d by the spiny i n t e r n e u r o n , d i s c u s s e d e a r l i e r , but play an important r o l e i n the c o n t r o l of motor responses, when a c t i v e . S p e c i f i c a l l y , c o r t i c a l f i b r e s p r i m a r i l y from a s s o c i a t i o n c o r t e x , p r o j e c t t o the CPU which i n t u r n e x e r t s an e x c i t a t o r y i n f l u e n c e on the motor c o r t e x . T h i s e x c i t a t o r y l o o p appears to be e s s e n t i a l f o r the i n i t i a t i o n of s p e c i f i c behaviours and i t s a c t i v i t y i s c o n t r o l l e d i n p a r t by the NSB (Kornhuber, 1974; Hatthysse, 1974; H u l l , Buchwald & Te ith/196-7; L i l e s , 1974} * To r e i t e r a t e , a c t i v a t i o n of the NSB would i n c r e a s e 46 the flow of i n f o r m a t i o n from a s s o c i a t i o n c o r t e x t o motor c o r t e x v i a the CPO, thereby e n s u r i n g the e l i c i t a t i o n o f an a p p r o p r i a t e response i n the presence of a s p e c i f i c s t i m u l u s s i t u a t i o n . During l e a r n i n g , a c t i v a t i o n of the MSB by consumption of a g o a l o b j e c t would f a c i l i t a t e the a s s o c i a t i o n o f sensory and motor i n f o r m a t i o n c u r r e n t l y being processed i n the c o r t e x . As the CPO r e l a y between a s s o c i a t i o n and motor c o r t i c e s i s strengthened over repeated t r i a l s , the s t i m u l u s s i t u a t i o n alone should e v e n t u a l l y e l i c i t the motor response p r e v i o u s l y e l i c i t e d by t h e g o a l o b j e c t . T h i s would account f o r the d i s s o c i a t i o n between the motor responses and r e i n f o r c e m e n t . While s t i m u l a t i o n of the NSB a c t u a l l y r e i n f o r c e s n e u r a l p a t t e r n s o f behaviour i n the CPO s t i m u l a t i o n o f a denervated CPO would o n l y a c t i v a t e motor behaviour v i a the output neurons without l i n k i n g t h i s t o a s t i m u l u s s i t u a t i o n . The present f i n d i n g s are a l s o r e l e v a n t to c l i n i c a l a b n o r m a l i t i e s , such as s c h i z o p h r e n i a and Parkinson's d i s e a s e which may be due to m a l f u n c t i o n i n g of the NSB (Hatthysse, 1974; Hornykiewicz, 1973)... Because of tha high c o r r e l a t i o n between the c l i n i c a l e f f e c t i v e n e s s of n e u r o l e p t i c s i n the treatment o f s c h i z o p h r e n i a , and the a b i l i t y of these drugs t o impair DA t r a n s m i s s i o n , i t has been proposed t h a t s c h i z o p h r e n i a r e s u l t s from o v e r a c t i v e DA neurons. (Seeman & Lee, 1975; Snyder, 1974) . As the CPO was t r a d i t i o n a l l y thought to c o n t r o l motor f u n c t i o n (Laursen,1963), i t was d i f f i c u l t t o see how a d i s o r d e r i n t h i s s t r u c t u r e c o u l d produce s c h i z o p h r e n i a . .However, i n view of the above d i s c u s s i o n i t i s c l e a r t h a t an o v e r a c t i v e NSB c o u l d be c h a r a c t e r i z e d as an »open gate* a l l o w i n g e x c e s s i v e c o r t i c a l 47 a c t i v i t y , which i s normally i n h i b i t e d , to f i n d e x p r e s s i o n i n behaviour. The r e s u l t i n g exaggerated behaviour (Hatthysse,1974) would be unresponsive t o environmental c o n t i n g e n c i e s as a l l behaviours would be r e i n f o r c e d by the h y p e r a c t i v e DA system, l e a d i n g t o the r i g i d i t y c h a r a c t e r i s t i c of s c h i z o p h r e n i c behaviour (Matthysse,1974). Parkinson's d i s e a s e on the other hand, appears t o r e s u l t from degeneration of the NSB (Foix,1921; Hornykiewicz,1973). The r e s u l t a n t a k i n e s i a i s understandable i f t h i s system i s e s s e n t i a l f o r t he i n i t i a t i o n of behaviour (Ungerstedt, 1974), but the i n t e l l e c t u a l impairment which accompanies t h i s d i s e a s e i s d i f f i c u l t to e x p l a i n i n terms of a motor d e f i c i e n c y (Loranger, G o o d e l l , McDowell, Lee 6 Sweet, 1973) . 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