dopamina acumbens autoadministração

7/27/2019 dopamina acumbens autoadministrao

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BRAINR E S E A R C HE L S E V I E R Brain Research 692 (1995) 47-56

R e s e a r c h r e p o r tE f f ec t s o f t h e d op am i n e D- 1 an t agon i s t S CH 23390 m i cro i n j ec t ed i n t o t h eaccumbens , amygdala or s tr ia tum on coca ine se l f -adminis trat ion in the rat

S . B a r a k C a i n e a , S t e p h e n C . H e i n r i c h s a , V i c k i L y n n C o f f i n b , G e o r g e F . K o o b a ,,D e p a r t m e n t o f N e u r o p h a r m a c o l o g y , T h e S c r i p p s R e s e a r c h I n s t i t u te , C V N - 7 , 1 0 6 6 6 N T o r r e v P i n e s R d ., L a J o ll a , C A 9 2 0 3 Z U S A

b S c h e r i n g - P l o u g h R e s e a r c h , K e n i l w o r t h . N J , U S AAccepted 2 May 1995

A b s t r a c tThis study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of theamygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effectsof self-administered cocaine. Microinjection of SCH 23390 (0-4.0 p.g total dose) into any of the three brain regions dose-dependentlyincreased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum,striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaineself-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent withthe rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regionalselectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in thenucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the'extended amygdala' may be an important substrate for the reinforcing actions of cocaine.

K e y w o r d s : Accumbens; Amygdala; Cocaine; Dopamine D-l; Reinforcement; SCH 23390; Self-administration; Striatum

1 . I n t r o d u c t i o nIt has been hypothesized that cocaine produces its rein-

forcing effects by inhibiting the reuptake of dopamine andthereby increasing the extracellular concentration ofdopamine in terminal regions of the mesocorticolimbicdopaminergic pathways [24,35,38]. Destruction ofdopaminergic elements in the nucleus accumbens or ven-tral tegmental area by infusion of the catecholaminergicneurotoxin 6-hydroxydopamine decreased cocaine self-ad-ministration [39-41], but not responding maintained byother reinforcers such as food or heroin [8,34]. In somecases this decrease in cocaine self-administration may havebeen indicative of an attenuation of the reinforcing proper-ties of cocaine, since some animals exhibited patterns ofbehavior resembling extinction, where a high rate of re-sponding was followed by cessation of responding [40].

* Corresponding author. Fax: (44) (1223) 333564.0006-8993/95/$09.50 1995 Elsevier Science B.V. All rights reservedS S D I 0006-8993(95)00598-6

Moreover, blockade of dopamine receptors by systemicadministration of dopamine receptor antagonists has beenshown to shift the cocaine self-administration dose-effectfunction to the right [5 ]. Thus blockade of dopaminereceptors increases or decreases cocaine self-administra-tion in a manner similar to reducing the dose of cocaineunder the dosage and scheduling conditions in effect[5,9,42,52,54]. The nucleus accumbens may be a criticalneuroanatomical substrate for these effects, since localadministration of dopamine receptor antagonists into thenucleus accumbens increased cocaine self-administrationunder dosage and scheduling conditions where such anincrease would be consistent with an attenuation of theeffects of cocaine [28,32,36].

More recently, the relative roles of dopamine receptorsin the amygdala and accumben s in cocaine self-administra-tion have been compared. Local administration of the D-1dopamine antagonist SCH 23390 into the amygdala in-creased the rate of cocaine (1.5 mg/kg) self-administrationunder a fixed-ratio schedule, an effect consistent with anattenuation of the effects of cocaine under those condi-


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48 S.B. Caine et al. / Brain Research 692 (1995) 47-56t i o n s , h o w e v e r t h e s a m e t r e a t m e n t f a i l e d t o a l t er t h e b r e a k -i n g p o i n t f o r t h i s d o s e o f c o c a i n e u n d e r a p r o g r e s s i v e - r a t i os c h e d u l e [3 2 ] . I n c o n t r a s t t o in t r a - a m y g d a l a S C H 2 3 3 9 0 ,i n t r a - a c c u m b e n s S C H 2 3 3 9 0 s i g n i f i c a n t l y d e c r e a s e d t h eb r e a k i n g p o i n t u n d e r t h e p r o g r e s s i v e - r a t i o s c h e d u l e , a ne f f e c t a l s o c o n s i s t e n t w i t h a n a t t e n u a t i o n o f t h e e f f e c t s o fc o c a i n e , b u t p r o d u c e d l e s s er e f f e c t s o n c o c a i n e s e l f -a d m i n -i s t r a t io n u n d e r th e f ix e d - ra t io s c h e d u l e [3 2 ] . B a s e d o nth e s e r e s u l t s , t h e a u th o r s p ro p o s e d d i f f e re n t ro l e s fo ra m y g d a l a a n d a c c u m b e n s i n c o c a i n e s e l f - a d m i n i s t r a t i o nb e h a v i o r , s u c h t h a t d o p a m i n e r e c e p t o r s i n t h e a m y g d a l am a y b e i n v o l v e d i n t h e i n t e r o c e p t i v e s t i m u l us p r o p e r t i e s o fc o c a i n e , w h i l e d o p a m i n e r e c e p t o r s i n t h e a c c u m b e n s a r ep r e f e r e n t i a l l y i n v o l v e d in t h e r e i n f o r c i n g e f f e c t s o f c o c a i n e[32].

T h o u g h i n t r i g u i n g , t h e b e h a v i o r a l e n d p o i n t s m e a s u r e di n t h a t s t u d y o f t e n o c c u r r e d o v e r s e v e r a l h o u r s f o l l o w i n gi n t r a c e r e b r a l a d m i n i s t r a t i o n . M o r e o v e r , i n j e c t i o n s o f S C H2 3 3 9 0 i n t o e i t h e r s i t e p r o d u c e d e q u i v a l e n t d e c r e a s e s i nl o c o m o t o r a c t i v i t y , a n d t h e r e w a s n o d e m o n s t r a t i o n o f an e u r o a n a t o m i c a l s i t e c o m p l e t e l y i n s e n s i t i v e t o t h e e f f e c t so f S C H 2 3 3 9 0 a d m in i s t r a t io n [3 2 ] . Th e s e i s s u e s r a i s ec o n c e r n a b o u t t h e r e g i o n a l s e l e c t i v i t y a n d t h e r e f o r e i n t e r -p r e t a t i o n o f t h e e f f e c t s o f i n t r a c e r e b ra l a d m i n i s t r a t io n o f ah i g h l y l i p o p h i l i c c o m p o u n d s u c h a s S C H 2 3 3 9 0 o n c o -c a i n e s e l f -a d m i n i s t r a t io n b e h a v i o r .

T h e p r e s e n t s t u d y t h e r e f o r e e x a m i n e d t h e e f f e c t s o fl o c a l a d m i n i s t r a t i o n o f S C H 2 3 3 9 0 i n t o t h e a c c u m b e n s ,a m y g d a l a o r d o r s a l s t r i at u m o n c o c a i n e s e l f - a dm i n i s t r a t io nu n d e r a f i x e d - r a t i o s c h e d u l e . T h e s h e l l o f t h e a c c u m b e n sa n d c e n t r a l n u c l e u s o f th e a m y g d a l a w e r e c h o s e n a s t a r g e t sfo r s e v e ra l r e a s o n s . F i r s t , t h e s e a re th e s u b re g io n s o fd e n s e s t d o p a m i n e r g i c i n n e r v a t i o n w i t h i n t h e s e s t r u c t u r e s[1 2 , 1 4 , 1 5 , 5 1 ] . S e c o n d , t h e a c c u m b e n s s h e l l h a s r e c e iv e dc o n s i d e r a b l e a t t e n t i o n w i t h r e g a r d t o c o n v e r g i n g a f f e r e n tin p u t s f ro m l im b ic s t ru c tu re s [1 7 , 2 1 , 2 2 , 4 5 ] a s w e l l a ss i g n i f i c an t e f f e r e n t c o n n e c t i o n s t o l i m b i c f o r e b r a i n r e g i o n s[1 8 ] a n d m e s e n c e p h a l i c d o p a m in e rg ic c e l l g ro u p s [4 ] . F i -n a l l y , i t h a s b e e n p r o p o s e d t h a t t h e a c c u m b e n s s h e l l a n dc e n t r a l a m y g d a l a r e p r e s e n t t h e b o r d e r s o f a l a r g e f o r e b r a i nc o n t i n u u m t e r m e d t h e e x t e n d e d a m y g d a l a [ 1 , 1 8 , 2 0 ] a n dt h a t t h e y m a y s h a r e , b y v i r t u e o f a n a t o m i c a l a n d n e u r o -c h e m ic a l s im i l a r i t i e s , fu n c t io n a l a t t r i b u te s .

T h e d o r s a l s t r i a t u m w a s c h o s e n a s a n e u r o a n a t o m i c a lc o n t r o l e q u i d i s t a n t b e t w e e n t h e a c c u m b e n s s h e l l a n d c e n -t r a l a m y g d a l a , s in c e i t a l s o h a s a r i c h d o p a m in e rg ic in n e r -v a t io n [2 6 ] b u t h a s n o t b e e n im p l i c a t e d in th e r e in fo rc in gp ro p e r t i e s o f c o c a in e [2 8 , 3 6 , 4 1 ] . A f ix e d - ra t io s c h e d u l ew a s c h o s e n s o t h a t t h e t i m e c o u r s e o f a l t er a t i o n s in b e h a v -i o r m a i n t a i n e d u n d e r c o n s t a n t s c h e d u l e c o n d i t i o n s c o u l d b ee v a l u at e d . I n a d d i t io n t o c o m p a r i n g t h e e f f e c t s o f S C H2 3 3 9 0 in d i f f e re n t b ra in r e g io n s , t h e r e g io n a l s e l e c t iv i ty o fi n t r a c e r eb r a l S C H 2 3 3 9 0 a d m i n i s t r a t i o n w a s f u r t h e r e v a l u -a t e d b y m e a s u r i n g t h e t i m e c o u r s e o f d i f f u s i o n o f l o c a l l ya d m i n i s t e r e d S C H 2 3 3 9 0 u s i n g q u a n t i t a t i v e a u t o r a d i o -g r a p h i c m e t h o d s .

2 . M a t e r i a l s a n d m e t h o d s2.1. Subjects

T h i r t y m a l e a l b in o W i s t a r r a t s (C h a r l e s R i v e r , K i n g s t o n ,N Y ) w e i g h i n g 2 6 0 - 3 0 0 g u p o n a r r i v a l w e r e u s e d f o r t h i ss tu d y . E ig h te e n s u b j e c t s w e re u s e d to g e n e ra t e th e s e l f - a d -m in i s t r a t io n s tu d ie s p re s e n te d . A n a d d i t io n a l tw e l v e a n i -m a l s w e r e u s e d f o r q u a n t i t a t i v e a u t o r a d i o g r a p h y s t u d i e s .U p o n a r r i v a l a n i m a l s w e r e g r o u p - h o u s e d ( 2 - 3 ) , m a i n -t a i n e d i n a t e m p e r a t u r e - a n d l i g h t - c o n t r o ll e d e n v i r o n m e n t( 1 2 : 12 h L / D ) a n d h a n d l e d d a i ly . A l l b e h a v i o r a l t e s ti n go c c u r r e d d u r i n g t h e d a r k p h a s e o f t h e l i g h t / d a r k c y c l e .T h e r a t s h a d f r e e a c c e s s t o f o o d a n d w a t e r e x c e p t d u r i n gd a i l y 3 h t e s t s e s s io n s .2.2. Catheterization

O n e w e e k a f t e r a r r i v a l , r a t s w e r e a n e s t h e t i z e d w i t h ah a l o t h a n e - o x y g e n v a p o r m i x t u r e a n d i m p l a n t e d w i t hc h r o n i c i n t r a v e n o u s ( i . v .) j u g u la r c a t h e t e r s a s d e s c r i b e dp re v io u s l y [7 ] . B r i e f l y , t h e c a th e te r s c o n s i s t e d o f p o l y -e t h y l e n e t u b i n g g l u e d t o a g u i d e c a n n u l a b e n t a t a r i g h ta n g l e a n d e n c a s e d i n d e n t a l c e m e n t a n c h o r e d w i t h a 1 - in c hs q u a r e o f d u r a b l e m e s h . T h e t u b i n g w a s p a s s e d s u b c u t a -n e o u s l y f r o m t h e a n i m a l s ' s m i d - s c a p u l a r r e g i o n t o t h er ig h t e x te rn a l ju g u l a r v e in , w h e re i t w a s in s e r t e d a n ds e c u re d g e n t l y w i th s u tu re th re a d . A l l a n im a l s w e re a l -l o w e d t o r e c o v e r f o r a m i n i m u m o f 4 d a y s b e f o r e g i v e na c c e s s t o c o c a i n e . C a t h e t e r s w e r e f l u s h e d w i t h s a l in e c o n -t a i n i n g h e p a r i n ( 3 0 U S P U / m l ) d a i l y , a s w e l l a s b e f o r ea n d a f t e r s e l f - a d m in i s t r a t io n s e s s io n s . W h e n n o t i n u s e , at h r e a d e d s t y l e t c a p w a s a f f i x e d t o t h e g u i d e c a n n u l a . T h ei n t e g r i ty o f t h e c a t h e t e r w a s t e s t e d w h e n e v e r a n a n i m a l n o tr e c e i v i n g d r u g p r e t r e a t m e n t s d i s p l a y e d b e h a v i o r o u t s i d eb a s e l in e p a ra m e te r s . B r i e f l y , 0 . 1 m l o f t h e u l t r a s h o r t - a c t in gb a r b i t u r a t e a n e s t h e t i c B r e v i t a l S o d i u m ( 1 % m e t h o h e x i t a ls o d iu m , E l i L i l l y , I n d ia n a p o l i s , IN ) w a s a d m in i s t e re dt h r o u g h t h e c a t h e t e r . A n i m a l s w i t h p a t e n t c a t h e t e r s e x h i b i tp r o m i n e n t s i g n s o f a n e s t h e s i a ( p r o n o u n c e d l o s s o f m u s c l eto n e ) w i th in 3 s o f i . v . i n j e c t io n . A n im a l s w i th f a u l tyc a t h e t e r s w e r e r e c a t h e t e r i z e d o n t h e o p p o s i t e ju g u l a r v e i n .P r e t r e a t m e n t t e s t s w e r e r e p e a t e d w h e n r e c a t h e t e r i z a t i o nw a s n e c e s s a r y i n o r d e r t o r e i n s t a te b a s e l i n e b e h a v i o r a f t e ra p re t r e a tm e n t t e s t .2.3. Drugs

C o c a i n e H C 1 w a s o b t a i n e d f r o m S i g m a C h e m i c a l C o .( S t . L o u i s , M O ) a n d d i s s o lv e d i n sa l in e ( 2 .5 m g / m l ) . S C H2 3 3 9 0 m a l e a t e w a s s u p p l i e d b y S c h e r i n g - P l o u g h ( K e n i l -w o r th , N J) a n d d i s s o l v e d in m e th a n o l t o in s u re d i s s o l u t io n ,t h e n d i l u t e d w i t h s a l i n e t o a m i n i m u m 2 0 : 1s a l i n e / m e t h a n o l r a t i o . A 2 0 : 1 s a l i n e / m e t h a n o l s o l u t i o nw a s u s e d fo r v e h ic l e t r e a tm e n t s ( z e ro d o s e , F ig . 1 ) .


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S .B . C ai ne e t a l. / Bra i n R e se arc h 692 ( 1995) 47-56 49[ 3 H ] S C H 2 3 3 9 0 ( s p e c i f i c a c t i v i t y 7 2 . 8 C i / m m o l ) w a so b t a i n e d f r o m D u p o n t N E N P r o d u c t s ( B o s t o n , M A ) .2 . 4. S e l f - a d m i n i s t r a t i o n

T h e r a t s w e r e g i v e n a c c e s s to c o c a i n e ( 0 .2 5 m g / 0 . 1m l / 4 s ) u n d e r a f i x e d - ra t i o (F R ) 1 t i m e o u t ( T O ) 2 0 ss c h e d u l e f o r 3 h d a i l y . E a c h s e s s i o n w a s p r e c e d e d b y t h ea u t o m a t e d d e l i v e r y o f t w o r e i n f o r c e r s p r i o r t o a v a i l a b i l i t yo f t h e le v e r . T h e c o m p l e t i o n o f t h e F R r e q u i r e m e n t r e -s u i t e d i n a c t i v a t io n o f a w h i t e c u e l i g h t a b o v e t h e l e v e rw h i c h r e m a i n e d o n d u r i n g t h e 4 s i n f u s i o n a n d f o r th er e m a i n d e r o f t h e 2 0 s t i m e o u t p e r i o d , d u r i n g w h i c h r e -s p o n s e s w e r e r e c o r d e d b u t w e r e n o t r e i n f o r c e d . A n i m a l st h a t d i d n o t r e s p o n d a t l e a s t o n c e p e r h o u r w e r e g i v e n f o u rn o n c o n t i n g e n t i n j e c t io n s a t th e b e g i n n i n g o f e a c h h o u r o na l t e r n a t e d a y s d u r i n g t r a i n i n g . W h e n r e l i a b l e r e s p o n d i n gw a s o b s e r v e d , t h e f i x e d - r a t i o w a s i n c r e a s e d t o a v a l u e o f 5 .A f t e r b a s e l i n e l e v e l s o f s e l f - a d m i n i s t r a t i o n w e r e a c h i e v e du n d e r t h is s c h e d u l e (c r i t e r io n o f < 1 0 % d e v i a t i o n f r o m th em e a n o f t h e t o t a l re i n f o r c e r s e a r n e d i n t h r e e c o n s e c u t i v es e s s i o n s f o r e a c h r a t ) t h e a n i m a l s w e r e p r e p a r e d w i t hc h r o n i c i n d w e l l i n g i n t r a c e r e b r a l c a n n u l a e .2 . 5. l n t r a c e r e b r a l c a n n u l a t i o n s

A n i m a l s w e r e a n e s t h e t i z e d w i t h a h a l o t h a n e / o x y g e nv a p o r m i x t u r e a n d p la c e d i n a K o p f s te r e o t a x i c i n s t ru m e n tw i t h t h e i n c i s o r b a r s e t 3 . 3 m m b e l o w t h e i n t e r a u r a l l i n e( s k u ll f l at ) , a n d c o o r d i n a t e s w e r e c h o s e n w i t h t h e a i d o f as t a n d a r d b r a i n a t l a s [ 3 3 ] . S t a i n l e s s s t e e l 2 3 g a u g e i n t r a c e r e -b r a l c a n n u l a e 1 0 m m i n l e n g t h w e r e a i m e d 3 m m a b o v et h e t a r g e t s i t e s a n d i m p l a n t e d b i l a t e r a l l y u s i n g t h e f o l l o w -i n g c o o r d i n a t e s f r o m B r e g m a ( A P ) , m i d l i n e ( M L ) a n ds k u l l s u r f a c e ( D V ) : N u c l e u s a c c u m b e n s s h e l l , A P + 1 .7M L + 1.0 D V - 5 . 0 ; c e n t ra l n u c l e us o f t h e a m y g d a l a , A P+ 2 . 5 M L + 4 . 2 D V - 5 . 1 ; d o r sa l s tr ia t um , A P - 0 . 9 M L+ _4 .4 D V - 3 . 4 . I n t r a c e r e b r a l c a n n u l a e w e r e s e c u r e d tot h e s k u l l u s i n g d e n t a l c e m e n t a n c h o r e d w i t h f o u r s k u l ls c r ew s . R e m o v a b l e s t y l et w i r e ( 1 0 m m ) m a i n t a i n e d p a -t e n c y o f t h e i n t r a c e r e b r a l c a n n u l a e b e t w e e n i n j e c ti o n s .A f t e r 4 d a y s r e c o v e r y f r o m s u r g e r y , t h e a n i m a l s w e r ea g a i n g i v e n a c c e s s t o c o c a i n e 3 h d a i l y , b e g i n n i n g a p p r o x i -m a t e l y 1 - 2 h a f t e r t h e s t a rt o f th e d a r k p h a s e o f t h el i g h t / d a r k c y c l e .2 . 6 . I n t r a c e r e b r a l m i c r o i n j e c t i o n s

L o c a l a d m i n i s t r a t i o n s o f S C H 2 3 3 9 0 w e r e m a d e b yr e p l a c i n g t h e s t y l e t w i r e w i t h a 3 0 g a u g e n e e d l e f a s h i o n e dt o e x t e n d 3 m m b e y o n d t h e t i p o f th e i n t r a c e r e b r a l c a n n u l a .I n j e c t io n v o l u m e w a s 0 . 3 3 / x l p e r s i d e , i n f u s e d o v e r 2 8 su s i n g a H a m i l t o n m i c r o s y r i n g e c o n n e c t e d t o t h e n e e d l e v i ap o l y e t h y l e n e t u b i n g . N e e d l e s w e r e l e f t i n p l a c e f o r 3 0 sf o l l o w i n g t h e i n f u s i o n , a n d t h e n r e p l a c e d w i t h t h e w i r es t y l e t , a f t e r w h i c h t h e a n i m a l w a s i m m e d i a t e l y p l a c e d i n

t h e s e l f - a d m i n i s t r a t i o n c h a m b e r f o r t e s t i n g . A f t e r t h e i n -t r a c e r e b r a l c a n n u l a t io n s u r g e r y a n i m a l s w e r e r e - b a s e l i n e d( a t l e a s t t w o c o n s e c u t i v e d a y s _+ 1 0 % p r e - s u r g e r y b a s e l i n eo r t h r e e c o n s e c u t i v e d a y s + 1 0 % t o t a l r e i n f o r c e r s e a r n e dp e r s e s s i o n ) p r i o r t o p r e t r e a t m e n t t e s t s . T h e a n i m a l s w e r er e - t e s t e d i n t h i s f a s h i o n ( wi t h a r e t u r n t o b a s e l i n e o re s t a b l i s h m e n t o f a n e w b a s e l i n e c r i t e r i o n f o r a n e w p r e -t r e a t m e n t t e s t ) u n t il a ll d o s e s ( 0 , 0. 5 , 1 .0 , 2 . 0 / x g / s i d e = 0 ,1 .0 , 2 .0 , 4 .0 / z g t o t a l d o s e a d m i n i s t e r e d ) we r e t e s t e d i n aL a t i n s q u a r e w i t h i n - s u b j e c t s d e s i g n ( i . e . , e a c h s u b j e c t r e -c e i v e d e a c h d o s e o n c e ) .2 . 7. Q u a n t i t a ti ~ e a u t o r a d i o g r a p h y - - i n t r a c e r e b r a l[ 3 H ] S C H 2 3 3 9 0

E i g h t e e n a n i m a l s w e r e u s e d f o r q u a n t i t a t i v e a u t o r a d i o g -r a p h y . T e n a n i m a l s w i t h i n tr a c e r e b r a l c a n n u l a e a i m e d a tt h e c e n t ra l n u c l e u s o f th e a m y g d a l a w e r e u s e d 1 w e e k a f t e rt h e y h a d b e e n u s e d f o r a s e p a r a t e s t u d y w h e r e t h e y w e r ei n j e c t e d o n c e w i t h p u r i f i e d w a t e r ( 0 . 5 / x l / s i d e ) a n d t e s t e da s a c o n t r o l g r o u p i n a n a n x i o l y t i c e v a l u a t i o n b e h a v i o r a lp a r a d i g m . T h e s e a n i m a l s w e r e i n j e c te d w i t h 1 . 0 / x M[ 3 H ] S C H 2 3 3 9 0 ( 0 .3 3 / x l / s i d e ) a s d e s c r i b e d a b o v e , a n ds a c r i f i c e d a t 2 , 1 0 , 2 0 , 6 0 , 1 2 0 o r 1 8 0 m i n i n o r d e r t oe s t i m a t e t h e d i f f u s io n o f [ 3 H ] S C H 2 3 3 9 0 f r o m t h e i n j e c -t i o n s i t e b y q u a n t i t a t i v e a u t o r a d i o g r a p h y . B r i e f l y , t h e a n i -m a l s w e r e d e c a p i t a t e d a n d t h e b r a i n s r a p i d l y r e m o v e d a n df r e s h - f r o z e n i n p o w d e r e d d r y i c e . T h e y w e r e t h e n s t o r e d a t- 7 0 C u n t il s e c t i o n s ( 3 0 / . ~ m ) w e r e c u t o n a c r y o t o m e( - 1 6 C ) a n d th a w - m o u n t e d o n g e l a t in - c h r o m a t e c o a t e ds l i d e s . T h e s l i d e s w e r e a i r - d r i e d a n d a p p o s e d t o t r i t i u m -s e n s i t i v e f i l m ( A m e r s h a m , A r l i n g t o n H e i g h t s , I L ) a n dp l a c e d i n l i g h t - t i g h t c a s s e t t e s f o r 2 w e e k s , t h e n r e - a p p o s e dt o n e w f i l m f o r 3 m o n t h s . T h e a u t o r a d i o g r a p h s w e r ed e v e l o p e d w i t h s t a n d a r d c h e m i c a l s a n d t h e o p t i c a l d e n s i -t i e s a n a l y z e d u si n g a m i c r o c o m p u t e r b a s e d i m a g e a n a l y s i ss y s t e m .2 . 8. Q u a n t it a t i ~ ,e a u t o r a d i o g r a p h y - - i n t r a c e n o u s[ 3 H ] S C H 2 3 3 9 0

B e c a u s e t h e i n t r a c e r e b r a l l y a d m i n i s t e r e d [ 3 H ] S C H2 3 3 9 0 u s e d a b o v e f o r e s t i m a t i n g d i f f u s i o n w a s s i g n i f i -c a n t l y l o w e r i n c o n c e n t r a t i o n t h a n t h a t u s e d f o r t h e b e h a v -i o r a l s t u d ie s , a n a d d it i o n a l c o m p l e m e n t a r y a p p r o a c h w a se m p l o y e d t o m e a s u r e d i f f us i o n . I m m e d i a t e l y f o l lo w i n gi n t r a c e r e b r a l in j e c t io n o f S C H 2 3 3 9 0 ( 1 . 0 / x g / 0 . 3 3/ x l / s i d e ) i n t o t h e a c c u m b e n s s h e l l , c e n t r a l a m y g d a l a o rd o r s a l s tr i a t u m , 3 3 / z C i o f [3 H ] S C H 2 3 3 9 0 w a s a d m i n i s -t e r e d i . v . t o l a b e l D - 1 r e c e p t o r s i n v i v o . P r e v i o u s w o r k i nr a t s s u g g e s t e d t h a t t h e s p e c i f i c b i n d i n g o f t h e r a d i o l ig a n dw o u l d p e a k a t a p p r o x i m a t e l y 1 h p o s t - i n j e c t i o n [ 2 3 ] . T h u si n o r d e r t o e s t i m a t e t h e d i f f u s i o n o f i n t r a c e r e b r a l l y a d m i n -i s t e r e d S C H 2 3 3 9 0 v i a t h e lo c a l p r o t e c t i o n o f D -1 r e c e p -t o r s f r o m b i n d i n g i .v . [ 3 H ] S C H 2 3 3 9 0 , t h e d i f f u s i o n c o u l dn o t b e m e a s u r e d a t t i m e p o i n t s s h o r t e r t h a n 1 h .


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50 S . B . C a i n e e t a l. / B r a i n R e s e a r c h 6 9 2 ( 1 9 9 5 ) 4 7 - 5 6S i x o f t h e a n i m a l s u s e d f o r s e l f - a d m i n i s t r a t i o n ( t w o

f r o m e a c h b r a i n r e g i o n g r o u p ) w e r e s u b s e q u e n t l y u s e d f o re s t i m a t i n g t h e d i ff u s i o n o f in t r a c e r e b r a l S C H 2 3 3 9 0 f r o mt h e i n j e c t i o n s i te . A n i m a l s w e r e i n j e c t e d i n t r a c e r e b r a l l yw i t h S C H 2 3 3 90 ( 1 .0 / x g / 0 . 3 3 / x l / s i d e ) a s in t he b e h a v -i o r a l t es t s , a n d i m m e d i a t e l y t h e r e a f t e r i n j e c t e d i . v. w i t h 3 3/ x C i o f [ 3 H ] S C H 2 3 3 9 0 t o l a b e l D - 1 d o p a m i n e r e c e p t o r s i nv i v o a s p r e v i o u s l y d e s c r i b e d [ 2 ,3 , 23 ]. T w o a d d i t i o n a l a n i -m a l s w i t h s i m i l a r c o c a i n e s e l f - a d m i n i s t r a t i o n e x p e r i e n c e ,b u t l a c k i n g i n t r a c e r e b r a l c a n n u l a e , w e r e a l s o u s e d f o rc o n t r o l l a b e l i n g o f D - 1 r e c e p t o r s b y i . v . [3 H ] S C H 2 3 3 9 0a n d t o e v a l u a t e t h e e f f e c ts o f s .c . p r e t r e a t m e n t w i t h S C H2 3 39 0 ( 2 0 / z g / k g ) o n t h e in v iv o l a b e l in g o f D - 1 r e c e p t o r sb y i . v . [ 3 H ] S C H 2 3 3 9 0. A l l a n i m a l s u s e d f o r i n v i v ol a b e l i n g o f D - 1 r e c e p t o r s w i t h i .v . [ 3 H ] S C H 2 3 3 9 0 w e r es a c r i f i c e d 6 0 r a i n f o l l o w i n g r a d i o l i g a n d a d m i n i s t r a t i o n .T e n t r i t iu m s t a n d a r ds w e r e m a d e b y h o m o g e n i z i n g 0 . 6 m la l i q u o t s o f r a t b r a i n m a s h w i t h i n c r e a s i n g c o n c e n t r a t i o n so f t r i t iu m a n d f r e s h - f r e e z i n g t h e m a s h e s f o r s e c t i o n i n g a t

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Fig. 1 . A. Effects of SC H 23390 (0 , 0 .5 , 1 .0, 2 .0 p,g/0 .33 / .d /s ide = 0 ,1.0, 2.0, 4.0 total dose) microinjected into the accumb ens shell (AccS h),central amyg dala (CeA) or do rsal striatum (CPu) on cocain e self-adminis-tration (0.25 mg i.v.; FR 5 TO 20 sec) in separate groups of rats (valuesare group means and s tandard errors , n = 6/br a in region) . Top , effec ts onself-administration in the first 20 m in of th e session. Bo ttom, effects onself-administration over the entire 3 h session. Asterisks indicate signifi-cantly different f ro m vehicle injection (* p < 0.05; * * p < 0.01) byNeuman Keuls a posteriori test following significant main effect of doseby ANOV A. B. Top three panels, location of ventra l most extent of theinjector tracks in the animals used for the data in Fig. 1A. Bottom panel,nissl stained section showing the injector tracks (see arrows) and associ-a ted t issue dam age for a representa t ive anima l in the accumbens shellgroup.

Fig. 1 (continued).

3 0 / x m . A f t e r s c i n t i l l a t i o n c o u n t i n g o f t h e s e s a m p l e s , a ni m a g e a n a l y s i s s y s t e m w a s u s e d t o g e n e r a te a n o p t i c a ld e n s i t y - c o n c e n t r a t io n f u n c t io n f r o m t h e a u t o r a d i o g r a p h i ci m a g e s p r o d u c e d b y t h e s t a n d a r d s t h a t w e r e i n c l u d e d i ne a c h f i l m c a s s e t t e . O p t i c a l d e n s i t i e s o f a ll a u t o r a d i o g r a p h i ci m a g e s w e r e d e t e r m i n e d f r o m t h r ee m e a s u r e m e n t s o f e a c hi m a g e o n t h e i m a g e a n a l y s i s s y s t e m .


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S . B . C a i n e e t a l. / B r a i n R e s e a r c h 6 9 2 ( 1 9 9 5 ) 4 7 - 5 6 5 1

2.9 . His to logyA n i m a l s n o t u s e d f o r q u a n t i t a t iv e a u t o r a d i o g r a p h y w e r e

e u t h a n i z e d b y i . p . i n j e c t i o n o f p e n t o b a r b i t a l s o d i u m ( 1 0 0m g / k g ) f o l l o w e d b y i n t r a c ar d i ac i n f u si o n w i th 5 0 m l o f4 % f o r m a l i n . B r a i n s w e r e r e m o v e d a n d s t o r e d i n 4 %f o r m a l i n a n d s u b s e q u e n t l y s e c t i o n e d c o r o n a l l y ( 5 2 / z mt h i c k n e s s ) t o l o c a l i z e th e v e n t r a l m o s t e x t e n t o f t h e i n j e c t o rt r a c k s f o r r e c o r d i n g o n a b r a i n m a p ( F i g . 1 B ) .2 . 1 0 . A n a l y s e s

S e l f - a d m i n i s t r a t i o n d a t a f r o m p r e t r e a t m e n t t e s t s w e r ec a l c u l a t e d a s t h e p e r c e n t o f t h e i m m e d i a t e l y p r e c e d i n gb a s e l i n e r a t e o f c o c a i n e s e l f - a d m i n i s t r a t i o n , a n d e a c h e x -p e r i m e n t a l g r o u p ( a c c u m b e n s , a m y g d a l a , s t r i a t u m ) w a sa n a l y z e d u s i n g A N O V A w i t h r e p e a t e d m e a s u r e s o n d o s e( S C H 2 3 3 9 0) . F o l l o w i n g a s i g n i f i c a n t m a i n e f f e c t o f do s e ,i n d i v i d u a l c o m p a r i s o n s o f s i n g l e d o s e s w i t h t h e v e h i c l ew e r e p e r f o r m e d u s i n g N e u m a n - K e u l ' s a p o s t e r i o r i t e s t .P o t e n c y c o m p a r i s o n s f o r d i f f e r e n t r o u t e s o f a d m i n i s t r a t i o nw e r e c a l c u l a t e d u s i n g a c o m p u t e r p r o g r a m t h a t c a l c u l a t e sr e l a t iv e p o t e n c i e s a n d 9 5 % c o n f i d e n c e l i m i t s u s i n g a p a r a l -l e l li n e a s s a y o f t h e d o s e - e f f e c t f u n c t i o n s o f t h e i n d i v i d u a ld a ta p o in t s [4 9 ] . Q u a n t i t a t iv e a u to ra d io g ra p h ic d a ta (S e c -t i o n 3 . 3 ) w e r e a n a l y z e d b y t w o - w a y A N O V A o n i n t r a c e r e -b ra l i n j e c t io n s i t e a n d b ra in r e g io n m e a s u re d , a n d s ig n i f i -c a n t m a i n e f f e c t s w e r e f u r t h e r e x p l o r e d u s i n g D u n n e t t ' st e s t f o r c o m p a r i n g a ll t r e a t m e n t s w i t h a c o n t r o l .

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W h e n m i c r o i n j e c t e d in t o t h e a c c u m b e n s s h e l l o r c e n t r a la m y g d a l a , S C H 2 3 3 9 0 p r o d u c e d a d o s e - d e p e n d e n t i n c r e a s ei n c o c a i n e s e l f - a d m i n i s t r a t i o n ( 0 . 2 5 m g i . v . ) w h i c h w a so b s e rv a b l e w i th in th e f i r s t 2 0 m in o f t h e s e s s io n (F ig . 1 ,t o p : A c c u m b e n s , F3,15 = 1 1 . 3 , P < 0 . 0 0 1 ; a m y g d a l a , F3,15= 3 . 8 , P < 0 . 0 5 ) . I n c o n t r a s t , i n j e c t io n s in to th e d o r s a ls t r i a tu m fa i l e d to a l t e r c o c a in e s e l f - a d m in i s t r a t io n in th ef i rs t 20 ra in o f th e sess ion (F3 ,15 = 0 .9 , P > 0 .5) . In jec -t i o n s i n t o a l l t h r e e b r ai n r e g i o n s d o s e - d e p e n d e n t l y in -c r e a s e d t h e r a t e o f c o c a i n e s e l f - a d m i n i s t r a t i o n o v e r 3 h( F i g . 1 , b o t t o m : A c c u m b e n s , F 3 , t 5 = 1 4 .4 , P < 0 . 0 0 1 ;am ygd a la , F3 .L~ = 7 .0 , P < 0 .01; s t r ia tum , F3 ,15 = 8 .2 , P< 0 . 0 1 ) . H o w e v e r , a h i g h e r d o s e o f S C H 2 3 3 9 0 ( 4 . 0 k ~ g

t o t a l) w a s n e c e s s a r y t o p r o d u c e t h i s e f f e c t w h e n a d m i n i s -t e re d in to th e d o r s a l s t r i a tu m (4 . 0 / z g to t a l , P < 0 . 0 1 )c o m p a r e d w i t h t h e a c c u m b e n s o r a m y g d a l a ( 2 . 0 / x g to t a l,P < 0 . 0 5 ) . Th e l o c a l i z a t io n o f t h e v e n t r a l m o s t e x te n t o ft h e i n j e c t o r t r a c k s , a n d a p h o t o m i c r o g r a p h o f t h e t y p i c a le x t e n t o f t i s s u e d a m a g e p r o d u c e d d u r i n g t h e s t u d y a r es h o w n i n F i g . l B .

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F i g . 2 . A . Aut o r a d i og r a phs s howi ng d i f f us i on o f [3H ]S C H 23390 a td i f f e r e n t t i m e po i n t s f o l l owi ng i n t r a - a m ygda l a a dm i n i s t r a t i on (1 . 0 ~M,0 . 33 t x l / 28 s e c ) . No t e de t e c t i on o f t he r a d i o l i ga nd t h r oughou t t heposte r ior s t r ia tum 3 hr a f te r injec t ion (bot tom r ight ) . Shown ac tua l s ize .B . D i f f us i on ( r a m 3) a nd c onc e n t r a t ion o f [3H ]S C H 23390 ( ~M ) a tdi f f e rent t imepoints fol lowing int r a -amy gdala adminis t ra t ion Autoradio -g r a phs we r e a n a l yz e d us i ng a m i c r oc om put e r ba s e d i m a ge p r oc e s s o r a ndm ol a r va l ue s we r e c a l c u la t e d us i ng t r i ti um b r a i n m a s h s t a nda r ds i nc l udedin each f i lm casse t te . Other de ta i l s as in 2A.


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52 S.B. Ca ine et al. /Bra in Research 692 (1995) 47-563 . 2 . D i f f u s i o n o f i n t r a c e r e b r a l l y a d m i n i s t e r e d [ 3 H ] S C H2 3 3 9 0 m e a s u r e d b y q u a n t i t a t i v e a u t o r a d i o g r a p h y

I n t r a - a m y g d a l a i n j ec t i o n o f [ 3 H ] S C H 2 3 3 9 0 ( 1 . 0 / z M ,0 . 3 3 / z l / s i d e ) p r o d u c e d d i f f u s i o n fi e l ds t h a t i n c r e a se d i ns i z e a n d d e c r e a s e d i n c o n c e n t r a t i o n w i t h i n c r e a s i n g t i m ea f t e r i n t r a c e r e b r a l a d m i n i s t r a t i o n ( F i g . 2 A , B ) . T h e s h o r t e r( 2 w e e k s ) a u t o r a d i o g r a p h i c e x p o s u r e s a l l o w e d th e c o n c e n -t r a ti o n o f [ 3 H ] S C H 2 3 3 9 0 a t th e s i t e o f i n f u s i o n a t d if f e r -e n t t i m e s f o l l o w i n g i n j e c t i o n t o b e a c c u r a t e l y m e a s u r e d

14o12o ...................................................................................................1oo * .......................

8o * .

2O_z A c c S h C e A C P uI N T R A C E R E B R A L I NJ E C T IO N S I T E

D-1 DOPAMINE RECEPTOR BINDI NG IN VIVO60 MIN AFTER MICROINJECTION OF SCFI23390

A R E A M E A S U R E D :[ ] A c c S h[ ] C e A[ ] C P u

f r o m t h e c o n c e n t r a t i o n - o p t i c a l d e n s i t y f u n c ti o n g e n e r a t e db y t r i t iu m b r a i n m a s h s t a n d a r d s ( F i g . 2 A , B ) . T h e l o n g e r ( 3m o n t h s ) a u t o r a d i o g r a p h i c e x p o s u r e s a l l o w e d t h e s i z e o ft h e d i f f u s i o n f i e l d t o b e m e a s u r e d t o t h e li m i t s o f t h e f i lms a t u r a t i o n , a n d e v e n u n d e r t h e s e c o n d i t i o n s t h e b o r d e r s o ft h e i m a g e s w e r e w e l l d e f i n e d ( F i g . 2 A , r i g h t c o l u m n ) . T h er e s u lt s i n d i c a t e d a r a p i d d i f f us i o n o f [ 3 H ] S C H 2 3 3 9 0 s u c ht h a t b y 2 0 m i n . a f t e r i n t r a - a m y g d a l a i n j e c t i o n , d e t e c t a b l e[ 3 H ] S C H 2 3 3 9 0 h a d s p r e a d b e y o n d t h e b o r d e r s o f th ec e n t r a l n u c l e u s o f t h e a m y g d a l a , a n d t h e c o n c e n t r a t i o n o f[ 3 H ] S C H 2 3 3 9 0 a t th e s i te o f i n j e c t io n h a d d e c r e a s e d b y7 5 % .

T h e a c t u a l d e n s it y o f D - 1 r e c e p t o r s l a b e le d w i t h[ 3 H ] S C H 2 3 3 9 0 c a n n o t b e e v a l u a t e d u s i n g t h i s m e t h o d ,s i n c e t h e ti m e c o u r s e o f c le a r a n c e o f u n b o u n d [ 3 H ] S C H2 3 3 9 0 h a s n o t b e e n e v a l u a t e d f o l l o w i n g i n t r ac e r e b r a l a d -m i n i s t r a t i o n i n t o a b r a i n a r e a l a c k i n g D - 1 r e c e p t o r s ( s e eS e c t i o n 2 , t h i s s t u d y ; [ 2 , 3 , 2 3 ] ) . N e v e r t h e l e s s , i n c o n t r a s t t ot i m e p o i n t s o f 2 h o r l e s s in w h i c h t h e a u t o r a d i o g r a p h i ci m a g e s w e r e s p h e r o i d a l i n s h a p e , t h e b o r d e r s o f t h e a u to -r a d i o g r a p h i c i m a g e p r o d u c e d b y [ 3 H ] S C H 2 3 3 9 0 3 h a f t e ri n t r a - a m y g d a l a i n j e c t i o n ( F i g . 2 A , b o t t o m r i g h t ) m a t c h e dt h o s e o f t h e p o s t e r i o r s t r ia t u m f r o m t h e c o r r e s p o n d i n g n i s sls t a i n e d s e c t i o n ( n o t s h o w n ) . 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 tb y 3 h a f t er t h e i n t r a - a m y g d a l a i n j e c ti o n , u n b o u n d [ 3 H ] S C H2 3 3 9 0 h a d c l e a r e d f r o m t h e a r e a a r o u n d t h e i n j e c t i o n s i t ea n d b o u n d [ 3 H ] S C H 2 3 3 9 0 t o D - 1 r e c e p t o r s w a s d e -t e c t a b l e i n a f a i r l y l a r g e a r e a ( t h e e n t i r e i p s i l a t e r a l p o s t e -r i o r s t r i a t u m ) p r o x i m a l t o t h e i n j e c t i o n s i t e .3 .3 . D i ff u s io n o f i n t r a c e re b r a l ly a d m i n i s t e re d S C H 2 3 3 9 0m e a s u r e d b y i n c i v o l a b e l i n g o f D - 1 r e c e p t o r s w i t h i.~ ,.[ 3 H ] S C H 2 3 3 9 0

B

C

T h e e f f e c t s o f lo c a l l y a d m i n i s te r e d S C H 2 3 3 9 0 o n t h el a b e l in g o f D - 1 r e c e p t o r s b y i . v. [ 3 H ] S C H 2 3 3 9 0 a r es h o w n i n F i g . 3. T h e i n t r a c e re b r a l s i t e o f S C H 2 3 3 9 0i n j e c t i o n d i d n o t s i g n i f i c a n t l y a f f e c t t h e o v e r a l l r e d u c t i o ni n [ 3 H ] S C H 2 3 3 9 0 b i n d i n g a c r o s s b r a i n r e g i o n s m e a s u r e d ,b u t t h e r e w a s a n e f f e c t o f b r a i n r e g i o n m e a s u r e d a n d a ni n j e c t i o n s i t e x r e g i o n m e a s u r e d i n t e r a c t i o n ( i n t r a c e r e b r a li n j e c t i o n s i t e , F 2 , 6 = 1 . 0 6 , n o t s i g n i f i c a n t ; b r a i n r e g i o n

Fig. 3. A. Regional in vivo b inding of i .v. [3H]SCH 23390 60 min aftermicroinjection of SCH 23390 (1.0 /xg/side, 2.0 / .Lg total) into theaccumben s shell, central amy gdala or d orsal striatum. Va lues are meansand standard errors. Dotted lines indicate 4-1 SD fro m the mea n ofcontrol binding. Asterisks indicate significantly different from control byDunnett ' s test fol lowing main effect by ANOV A. Other details as in 2B.B. Representative autoradiographs of in vivo binding o f [3H]SCH 2339060 min after i.v. administration. A, c ontrol. B, SC H 2339 0 (1.0 /xg/0.33/xl/side) microinjected into the a ccumbe ns shell immediately prior to i.v.administration of [3H]-SCH 23390. C, SCH 23390 (20.0 /xg/kg) admin-istered subcutaneously 20 min prior to i .v. administration of [3H]SCH23390. Note that the effe cts of SCH 23390 on coc aine self-administrationare similar wh en administered intra-accumbe ns (1.0 /~g/0.33 /xl/side;Fig. 1A) as in B o r subcutaneously (20.0 ~g /kg ; [9]) as in C.


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S . B . C a i n e e t a l. / B r a i n R e s e a r c h 6 9 2 ( 1 9 9 5 ) 4 7 - 5 6 53

m e a s u r e d , F2, 6 = 6 . 2 3 , P < 0 . 0 1 ; i n j e c t io n s i t e r e g io nm e a s u re d in t e ra c t io n , F 4 ,1 2 = 7 2 . 0 9 , P < 0 . 0 0 1 ) . Mo re -o v e r , t h e b i n d i n g o f i .v . a d m i n i s t e r e d [ 3 H ] S C H 2 3 3 9 0 w a ss e l e c t iv e l y p r o t e c t e d i n t h e r e g i o n i n j e c t e d w i t h o u t a l t e r in gra d io l a b e l in g in th e o th e r r e g io n s ( s e e F ig . 3 A , a s t e r i s k si n d i c at e s i g n i f i c a n t ly d i f f e r e n t f r o m c o n t r o l b y i n d e p e n d e n tc o m p a r i s o n , P < 0 . 0 5 ) .

T h e d i f f u s io n o f i n t ra c e re b r a l S C H 2 3 3 90 ( 1 . 0 / x g / 0 . 3 3/ x l / s i d e ) 1 h f o l l o w i n g i n j e c t io n ( 2 . 2 _+ 0 . 5 m m 3 / s i d e )w a s s im i l a r t o th a t e s t im a te d u s in g in t r a c e re b ra l a d m in i s -t r a t io n o f [3 H ]S C H 2 3 3 9 0 ( s e e S e c t io n 3 . 2 ) . I t i s n o ta b l et h a t t h e d i f f u s i o n o f S C H 2 3 3 9 0 1 h a f t e r i n t r a c e r e b r a la d m i n i s t r a t i o n i s m a r k e d l y r e s t r i c t e d c o m p a r e d w i t h t h ee f f e c t o f s .c . p r e t r e a t m e n t w i t h S C H 2 3 3 9 0 ( 2 0 / x g / k g ) o nt h e i n v i v o b i n d i n g o f i . v. [ 3 H ] S C H 2 3 3 9 0 ( F i g . 3 B ) , g i v e nt h a t t h e se t w o t r e a t m e n t s p r o d u c e c o m p a r a b l e e f f e c t s o nc o c a in e s e l f - a d m in i s t r a t io n (F ig . 1 , t h i s s tu d y ; [9 ] ) .3 .4 . R e l a t i v e p o t e n c y o f S C H 2 3 3 9 0 b y i n t r a c e r eb r a l a d -m i n i s t r a t i o n t ,e r s u s s u b c u t a n e o u s a d m i n i s t r a ti o n

T h e d o s e - e f f e c t d a t a f o r S C H 2 3 3 9 0 a d m i n i s t e r e d in t ot h e t h r e e b r a i n r e g i o n s w a s c o m p a r e d t o p r e v i o u s l y r e -p o r t e d d a t a o n t h e e f f e c t s o f S C H 2 3 3 9 0 a d m i n i s t e r e ds u b c u t a n e o u s l y o n c o c a i n e s e l f - a d m i n i s t r a t i o n u n d e r i d e n -t i c a l c o n d i t io n s (0 . 2 5 m g i . v . ; F R 5 TO 2 0 s e c ) [9 ] . Th el i n e a r r e g r e s s i o n p l o t s f o r t h e d o s e - e f f e c t d a t a b y e a c hro u te o f a d m in i s t r a t io n w e re s u b j e c t e d to a p a ra l l e l l i n ea s s a y a n d r e l a t iv e p o te n c y v a l u e s w e re c a l c u l a t e d [4 9 ] . Th ep o t e n c y o f S C H 2 3 3 9 0 a d m i n i s t e r e d s . c. [ 9] w a s a s s i g n e d ar e l a t i v e p o t e n c y v a l u e o f 1 . 0 , a g a i n s t w h i c h t h e o t h e rr o u t e s o f a d m i n i s t r a t i o n w e r e c o m p a r e d . T h e r e l a t i v e p o -t e n c y v a l u e s i n T a b l e 1 t h e r e f o r e r e f l e c t t h e r a t i o o f t h ea m o u n t o f S C H 2 3 3 9 0 b y e a c h r o u t e o f a d m i n i s t r a t i o nr e q u i r e d t o p r o d u c e a n e q u i v a l e n t e f f e c t t o t h a t o f a d o s eg i v e n b y s u b c u t a n e o u s a d m i n i s t r a t i o n o v e r t h e e n t i r e 3 hs e s si o n . I n t r a - a c c u m b e n s o r i n t r a - a m y g d a l a b u t n o t i n t r a -s t ri a t al a d m i n i s t ra t i o n s w e r e s i g n i f i c a n tl y m o r e p o t e n t t h a ns u b c u t a n e o u s a d m i n i s t r a ti o n ( P < 0 . 0 5 ) , a lt h o u g h t h e m a x -i m u m d i f f e r e n c e (a c c u m b e n s v e r s u s s u b c u t a n e o u s ) r e p r e-s e n t e d o n l y a n a p p r o x i m a t e t w o f o l d i n c r e a s e i n p o t e n c y .

Table 1Regional potency of intracerebral SCH 23390 relative to subcuta neousadministration aRegion Potency ratio Significan ceAccum bens shell 0.45 P < 0.05Central amygdala 0.69 P < 0.05Caudate -putamen 0.96 P > 0.1a The potency ratio shown refers to the ratio of the amount of drugnecessary to produce an equivalent effect to som e standard assigned avalue of unity [49]. Thus 0.45 /~g in the accumbe ns shell or 0.69 p,g inthe central a mygdala produces an effect equivalent to that produced by1.0 ,u,g administ ered subcutan eously.

Th u s in t r a - a c c u m b e n s a d m in i s t r a t io n o f 4 . 0 / z g to ta l (2 . 0/ z g / s i d e ) o f S C H 2 3 3 9 0 p r o d u c e d a n e f f e c t i d e n t i c a l t ot h a t o b s e r v e d a f t e r a d m i n i s t r a ti o n o f 2 0 . 0 / z g / k g s .c . ( 8 .0/ x g t o t a l f o r t h e a v e r a g e b o d y w e i g h t o f 0 . 4 k g / s u b j e c t ) .

4 . D i s c u s s i o nI n t r a - a c c u m b e n s o r i n t r a - a m y g d a l a a d m i n i s tr a t i o n o f t h e

D - 1 a n t a g o n i s t S C H 2 3 3 9 0 p r o d u c e d a r a p i d i n c r e a s e i nt h e r a t e o f c o c a i n e s e l f - a d m i n i s t r a t i o n w i t h a p o t e n c ys l ig h t l y b u t s ig n i f i c a n t l y g re a t e r t h a n s y s t e m ic a d m in i s t r a -t io n . In c o n t r a s t , i n t r a - s t r i a t a l S C H 2 3 3 9 0 d id n o t i n c re a s ec o c a i n e s e l f - a d m i n i s t r a t i o n w i t h i n t h e f i r s t 2 0 m i n o f t h es e s s i o n , a n d t h e p o t e n c y o f i n t r a - s t r i a t a l S C H 2 3 3 9 0 w a se q u i v a l e n t t o s u b c u t a n e o u s a d m i n i s t r a t i o n o f t h e a n t a g o -n i s t . I n a d d i t io n to th e b e h a v io ra l d a t a , a u to ra d io g ra p h icm e a s u re s in d ic a t e d th a t t h e r e g io n a l s e l e c t iv i ty o f D -1r e c e p t o r b l o c k a d e f o l l o w i n g i n t r a c e r e b r a l a d m i n i s tr a t i o n o fS C H 2 3 3 9 0 i s t i m e - d e p e n d e n t ( e .g . , e x c e e d i n g t h e b o r d e r so f t h e c e n t r a l a m y g d a l a w i t h i n 2 0 m i n ) . T a k e n t o g e t h e r ,t h e s e d a ta s u p p o r t t h e h y p o th e s i s t h a t i . v . c o c a in e s e l f - a d -m in i s t r a t io n in th e r a t c a n b e m o d u l a t e d th ro u g h D -1d o p a m i n e r e c e p t o r s i n t h e n u c l e u s a c c u m b e n s o r a m y g -da la .

I n c r e a s e d c o c a i n e s e l f - a d m i n i s t r a t i o n a f t e r i n t r a - a c c u -m b e n s o r i n t r a - a m y g d a l a a d m i n i s t r a t i o n o f a d o p a m i n ea n ta g o n i s t h a v e b e e n o b s e rv e d p re v io u s l y [2 8 , 3 2 , 3 6 ] . S u c ha n in c re a s e in s e l f - a d m in i s t r a t io n r a t e i s c o n s i s t e n t w i th as h i f t t o t h e r i g h t o f t h e c o c a i n e d o s e - e f f e c t f u n c t i o n u n d e rth e s e c o n d i t io n s [9 , 2 5 ] . I n d e e d a s h i f t t o t h e r ig h t i n th ee n t i r e c o c a i n e s e l f - a d m i n i s t r a t i o n d o s e - e f f e c t f u n c t i o n h a sb e e n d e m o n s t r a t e d f o l l o w i n g s y s t e m i c a d m i n i s t r a t i o n o fS C H 2 3 3 9 0 [5 , 1 0 ] . N e v e r th e l e s s i t r e m a in s to b e c o n c l u -s i v e l y d e t e r m i n e d t h a t b l o c k a d e o f D - 1 r e c e p t o r s i n t h ea c c u m b e n s o r a m y g d a l a p r o d u c e s a s u r m o u n t a b l e a n t a g o -n i s m o f t h e e f f e c t s o f s e l f - a d m i n i s t e r e d c o c a i n e u s i n g ar a n g e o f c o c a i n e d o s e s . S u c h a d e m o n s t r a t i o n m a y b ep a r t i c u l a r l y im p o r t a n t , s in c e l e s io n s tu d ie s o f s p e c i f i c t e r -m i n a l r e g i o n s o f t h e m e s o c o r t i c o l i m b i c d o p a m i n e p a t h -w a y s , s u c h a s 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 a n d t h e a m y g -d a l a , h a v e id e n t i f i e d e f f e c t s o n c o c a in e s e l f - a d m in i s t r a t io no n l y a t l o w e r o r h i g h e r d o s e s o f c o c a i n e , r e s p e c t i v e l y[29,31 ,44] .

I t a ls o r e m a i n s t o b e d e t e r m i n e d t h a t c h a n g e s i n c o c a i n es e l f - a d m i n i s t r a t i o n u n d e r r a t e - d e p e n d e n t s c h e d u l e s r e f l e c tc h a n g e s s p e c i f i c a l l y i n t h e r e i n f o r c i n g e f f e c t s o f c o c a i n e .C o c a i n e p r o d u c e s c h a n g e s i n s c h e d u l e - c o n t r o l l e d b e h a v i o rm a i n t a i n e d b y o t h e r r e i n f o r c e r s [4 8 ,5 3 ], a n d s u c h c h a n g e sa r e r e v e r s e d b y d o p a m i n e r e c e p t o r a n t a g o n i s t s [ 46 ]. M o r e -o v e r , a n d o f p a r t i c u l a r r e l e v a n c e t o t h e p r e s e n t s t u d y ,o t h e r s h a v e p r o p o s e d t h a t d o p a m i n e r g i c r e c e p t o r b l o c k a d ein th e a m y g d a l a a l t e r s t h e r a t e o f c o c a in e s e l f - a d m in i s t r a -t io n b y a l t e r in g th e in t e ro c e p t iv e s t im u l u s , b u t n o t t h er e i n f o r c i n g , e f f e c t s o f c o c a i n e [ 32 ].

S e v e ra l a d d i t io n a l i s s u e s w a r ra n t fu r th e r c o n s id e ra t io n


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54 S . B . C a i n e e t a l. / B r a i n R e s e a r c h 6 9 2 ( 1 9 9 5 ) 4 7 - 5 6r e g a rd in g in t e rp re t a t io n o f t h e p re s e n t d a t a . F i r s t, i t isp e r h a p s s u r p r i s i n g t h a t i n t r a c e r e b r a l S C H 2 3 3 9 0 i n t h i ss t u d y h a d a m a x i m u m p o t e n c y o n l y t w o f o l d g r e a t e r t h a nt h a t o f s u b c u t a n e o u s l y a d m i n i s t e r e d S C H 2 3 3 9 0 . O n e p o s -s ib l e e x p l a n a t io n i s t h a t t h e c r i t i c a l n e u ro a n a to m ic a l l o c if o r t h e e f f e c t s o f S C H 2 3 3 9 0 o n c o c a i n e s e l f - a d m i n i s t r a -t i o n h a v e y e t t o b e i d e n t i fi e d . A n a l t e r n a ti v e e x p l a n a t i o n i st h a t m u l t i p l e n e u r o a n a t o m i c a l l o c i o f D - 1 r e c e p t o r s a r ein v o l v e d in c o c a in e s e l f - a d m in i s t r a t io n , a n d th a t t h e s im u l -t a n e o u s b l o c k a d e o f t h e s e s i t e s b y s y s t e m i c a d m i n i s t r a ti o no f S C H 2 3 3 9 0 c o n t r i b u t e s t o a t t e n u a t e t h e b e h a v i o r a le f f e c t s o f c o c a i n e a t r e l a t i v e l y l o w d o s e s o f t h e s y s t e m i -c a l l y a d m in i s t e re d a n ta g o n i s t . A th i rd p o s s ib i l i t y c o m e sf r o m p r e v i o u s w o r k d e m o n s t r a t i n g a m u t u a l a n t a g o n i s mb e t w e e n d o p a m i n e ( i n d i r e c t l y i n c r e a s e d b y c o c a i n e ) a n dd o p a m i n e r e c e p t o r a n t a g o n i s t s i n c o c a i n e s e l f - a d m i n i s t r a -t io n [5 , 1 0 ] a s w e l l a s i n o th e r b e h a v io ra l a s s a y s[1 9 , 4 6 ,4 7 , 5 0 ] . Th u s i t i s p o s s ib l e th a t s ig n i f i c a n t c o n c e n t r a -t i o n s o f S C H 2 3 3 9 0 , e v e n l o c a l l y , m a y b e n e c e s s a r y t oc o m p e t e w i t h t h e e f f e c t s o f c o c a i n e t o i n d i r e c t l y a c t i v a t eD -1 r e c e p to r s . I t s h o u l d b e n o te d th a t t h e d o s e - re l a t e de f f e c t s o f i n t r a c e r e b r a l S C H 2 3 3 9 0 o b s e r v e d h e r e a r e i ng o o d a g r e e m e n t w i t h p r e v i o u s s t u d i e s [ 2 8, 32 ] .

A f u r t h e r c o n s i d e r a t i o n r e g a r d s t h e m e a s u r e m e n t o fd i f f u s i o n o f S C H 2 3 3 9 0 b y t h e a u t o r a d i o g r a p h i c m e t h o d se m p l o y e d h e r e . A l t h o u g h t h e t i m e - r e l a t e d d i f f u s i o n o f[ 3 H ] S C H 2 3 3 9 0 f o l l o w i n g d i r e c t i n t r a c e r e b r a l a d m i n i s t r a -t i o n s u g g e s t e d a l o c a l a c t i o n ( < 2 . 0 m m 3 ) o f S C H 2 3 3 9 0i n t h e f i r s t h o u r f o l l o w i n g m i c r o i n j e c t i o n s o f t h e a n t a g o -n i s t, t h e r a d i o l i g a n d c o n c e n t r a t i o n w a s s i g n i f i c a n t l y l o w e rt h a n t h a t u s e d i n t h e b e h a v i o r a l s t u d i e s . H o w e v e r , w h e nt h e a p p r o p r i a t e c o n c e n t r a t i o n o f S C H 2 3 3 9 0 w a s m i c r o i n -j e c t e d l o c a l l y , a r e g i o n a l l y s e l e c t i v e b l o c k a d e o f t h e b i n d -i n g o f i . v . [ 3 H ] S C H 2 3 3 9 0 i n v i v o w a s o b s e r v e d a t 1 hp o s t - i n j e c ti o n w i t h a s i m i l a r d i f f u s i o n a r e a ( a p p r o x i m a t e l y2 . 0 m m 3 ) . T a k e n t o g e t h e r , t h e s e d a t a m i g h t s u g g e s t t h a ti n t r a c e r e b r a l S C H 2 3 3 9 0 p r o d u c e s r a p i d r e g i o n a l l y s e l e c -t i v e e f f e c t s w i t h i n a d i s ta n c e o f a p p r o x i m a t e l y 2 . 0 m m 3 i nth e f i r s t h o u r . N e v e r th e l e s s , g iv e n th e r a p id d e c re a s e in th ec o n c e n t r a t i o n o f [ 3 H ] S C H 2 3 3 9 0 a t t h e s i t e o f i n j e c t i o nfo l l o w in g in t r a c e re b ra l a d m in i s t r a t io n , c a u t io n i s s t i l l w a r -r a n t e d i n i n t e r p r e t i n g r e s u l t s w i t h o u t a d e q u a t e n e u -r o a n a t o m i c a l c o n t r o l s . S u c h c a u t i o n m u s t a l s o b e t a k e n i nd r a w i n g c o n c l u s i o n s f r o m t h e p r e s e n t r e s u l t s a b o u t t h ei n v o l v e m e n t o f D - 1 r e c e p t o r s i n s u b r e g i o n s o f t h e a c c u m -b e n s ( i . e . , s h e l l v s . c o re ) o r s p e c i f i c n u c l e i o f t h e a m y g d a l a( i . e . , c e n t r a l ) i n c o c a in e s e l f - a d m in i s t r a t io n .

F i n a l l y , t h e s e r e s u l t s s u g g e s t a r o l e f o r d o p a m i n e r g i cm e c h a n i s m s i n t h e a m y g d a l a i n c o c a i n e s e l f - a d m i n i s t r a -t i o n , b u t th e p r o c e s s b y w h i c h D - 1 r e c e p t o r b l o c k a d e i n t h ea m y g d a l a m i g h t m o d u l a t e c o c a i n e s e l f - a d m i n i s t r a t i o n i su n c l e a r . I t h a s b e e n s u g g e s t e d t h a t , b y v i r t u e o f c o m m o nn e u r o c h e m i c a l a n d a n a t o m i c a l c h a r a c t e r i s t i c s , t h e c e n t r a ln u c l e u s o f t h e a m y g d a l a a n d n u c l e u s a c c u m b e n s s h e l la d j o in a f o r e b r a i n c o n t i n u u m t e r m e d t h e e x t e n d e d a m y g -d a l a , a n d th u s m a y s h a re fu n c t io n a l a t t r i b u te s [1 , 1 8 ] . S u p -

p o r t f o r a r o l e f o r t h e e x t e n d e d a m y g d a l a i n c o c a i n es e l f -a d m i n i s t r a t io n c o m e s f r o m t h e o b s e r v a t i o n t h a t l e s i o n so f p r o j e c t i o n a r e a s f r o m t h e s h e l l o f t h e a c c u m b e n s t o t h es u b l e n t i c u l a r e x t e n d e d a m y g d a l a p r o d u c e m o r e r o b u s t e f -f e c t s o n c o c a i n e s e l f - a d m i n i s t r a t i o n t h a n d o l e s i o n s o fp r o j e c t i o n a r e as f r o m t h e c o r e r e g i o n o f t h e a c c u m b e n s t oth e s u b c o m m is s u ra l v e n t r a l p a l l id u m [4 3 ] .

O t h e r e v i d e n c e o f a m y g d a l a i n v o l v e m e n t i n t h e b e h a v -i o r a l e f f e c t s o f c o c a i n e i s p r o v i d e d b y o b s e r v a t i o n s t h a tb l o c k a d e o f D - 1 r e c e p t o r s i n t h e a m y g d a l a a t t e n u a t e s t h ed i s c r im in a t iv e s t im u l u s p ro p e r t i e s o f c o c a in e [1 1 ] , a n d th a tc o m b i n e d 6 - h y d r o x y d o p a m i n e l e s i o n s o f t h e a m y g d a l a a n da c c u m b e n s m o r e e f f e c t i v e l y d i s r u p t c o c a i n e s e l f -a d m i n i s -t r a t io n th a n a c c u m b e n s l e s io n s a l o n e (K o o b e t a l . , u n p u b -l i sh e d o b s e r v a t i o n s ) . N e v e r t h e l e s s , r e m o v a l o f d o p a m i n e r -g i c t e r m i n a l s i n t h e a m y g d a l a w i t h 6 - h y d r o x y d o p a m i n ed o e s n o t p r o d u c e r o b u s t e f f e c t s o n c o c a i n e s e l f -a d m i n i s tr a -t io n (K o o b e t a l . , u n p u b l i s h e d o b s e rv a t io n s ; [3 1 ] ) e x c e p tf o r h i g h d o s e s o f c o c a i n e [ 3 1 ] . M o r e o v e r , d o p a m i n e r g i ca c t iv a t io n in th e n u c l e u s a c c u m b e n s i s m o d u l a t e d b yd o p a m in e rg ic a c t iv i ty in th e a m y g d a l a [2 7 , 3 1 ] , a n d th i se f f e c t m a y b e r e s p o n s i b l e f o r t h e f a c i l i t a te d a c q u i s it i o n o fs e l f -a d m i n i s t r a ti o n o f l o w d o s e s o f a m p h e t a m i n e o b s e r v e df o l l o w i n g 6 - h y d r o x y d o p a m i n e l e s io n s o f t h e a m y g d a l a [ 1 3] .T h u s i t m a y b e t h a t , a s h a s b e e n p r o p o s e d f o r t h e m e d i a lp re f ro n ta l c o r t e x [1 6 , 3 7 ] , d o p a m in e rg ic m e c h a n i s m s in th ea m y g d a l a a r e i n v o l v e d i n c o c a i n e s e l f - a d m i n i s t r a t i o n b yv i r t u e o f t h e i r i n f l u e n c e o n d o p a m i n e r g i c t o n e i n t h en u c l e u s a c c u m b e n s .

T h e p r e c i s e n u c l e i w i t h i n t h e a m y g d a l a t h a t m a y p l a y aro l e in c o c a in e s e l f - a d m in i s t r a t io n r e m a in u n c l e a r . Th ec e n t r a l n u c l e u s o f t h e a m y g d a l a c o n t a i n s a s i g n i f i c a n ta m o u n t o f d o p a m i n e a n d i s a s s o c i a t e d w i t h t h e e x t e n d e da m y g d a l a . T h e b a s o l a t e r a l n u c l e u s p r o v i d e s t h e m a j o re f f e r e n t p a t h w a y f r o m t h e a m y g d a l a t o t h e a c c u m b e n s[2 2 ] , a n d c o n ta in s a d e n s i ty o f D -1 r e c e p to r s c o m p a ra b l e toth a t o f t h e c e n t r a l n u c l e u s [6 ] . I n a d d i t io n , w i th in th ea m y g a l a i n f o r m a t i o n f l o w s f r o m t h e b a s o l a t e r a l n u c l e u s toth e c e n t r a l n u c l e u s w i th o u t a r e c ip ro c a l i n n e rv a t io n [3 0 ] .D e s p i t e t h e r e g i o n a l s e l e c t i v i t y o f e f f e c t s p r o d u c e d b yi n t r a c e r e b r a l S C H 2 3 3 9 0 o b s e r v e d h e r e , i d e n t i f y i n g t h ei n v o l v e m e n t o f s p e c i f i c a m y g d a l a n u c l e i i n t h e b e h a v i o r a le f f e c t s o f s e l f - a d m i n i s t e r e d co c a i n e , a s w e l l a s t h e r o l e o fa c c u m b e n s d o p a m i n e r g i c a c t i v i t y i n t h e s e e f f e c t s , m a yr e q u i r e m a n i p u l a t i o n s m o r e r e g i o n a l l y s e l ec t i v e t h a n t h o s ee m p l o y e d i n t h e p r e s e n t s t u d y .

AcknowledgementsT h i s w o r k w a s s u p p o r t e d b y g r a n t s D A 0 5 2 7 8 , D A 0 4 3 9 8

a n d D A 0 7 3 5 2 f r o m t h e N a t i o n a l I n s t i t u t e o n D r u g A b u s e .T h e a u t h o r s t h a n k B o b L i n t z f o r a s s i s t a n c e w i t h h a r d w a r ea n d s o f tw a re , a n d C l a i r e E . W i l l i a m s fo r h e r v a l u a b l ec o n t r ib u t io n to th e s e s tu d ie s . Th i s i s p u b l i c a t io n 8 9 9 3 -N Pf r o m T h e S c r i p p s R e s e a r c h I n s t i tu t e .


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