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Regional aspects of the delay of acquisition conditioned avoidance responding by chlorpromazine
REGIONAL ASPECTS OF THE DELAY OF ACQUISITION CONDITIONED AVOIDANCE RESPONDING BY CHLORPROMAZlNE Arnold
D. Sherman,
Frederick
Petty
and James L.
Sacquitne
Neurochemistry L a b o r a t o r y , Department of P s y c h i a t r y , U n i v e r s i t y of lowa and V e t e r a n s A d m i n i s t r a t i o n M e d i c a l C e n t e r , lowa C i t y , lowa arch 15, 1982)
(Received in fil
Summary C h l o r p r o m a z i n e i n j e c t e d i n t o t h e a m y g d a l a , septum, o r c a u d a t e d e l a y e d t h e a c q u i s i t i o n o f a one-way active avoidance response. Injections into nine other brain a r e a s were i n a c t i v e . F o l l o w i n g a s t a n d a r d dose o f c h l o r p r o m a z i n e a t i t s ED~ aying avoidance acquisition, tissue levelsb~ Iromazine from those animals displaying reduced ac ~n were s i g n i f i c a n t l y higher i n t h e c a u d a t e and amygdala than from ani mals not demons t r a t i n g a drug e f f e c t . A l t h o u g hh c h l o r p r o m a z i n e has a c h i e v e d wides despread c l i n i c a l use d u r i n g t h e 1 a s t 25 y e a r s , n e i t h e r i t s n e u r o a n a t o m i c l o c u s o f a c t i o n nor t h e neurochemi •o c h e m i c a l b a s i s o f i t s a n t i p s y c h o t i c a c i t i v i t y has been do " Ine n y pootthneessil s o oTf a h nyperac~ t i I v e n l"g r o - s t~r tl a r i~ at la l aopam~nerglc y s t e m in s c h i z o p h r e n i a l e d t o many s t u d i e s on t h e e f f e c t s o f a n t i ~ s y c h o t i c drugs on t h e r e l e a s e , m e t a b o l i s m , and b i n d i n g o f dopamine n the striatum. Several lines of evidence (1,2,3,4) suggested the a u d a t e as t h e l o c u s o f a c t i o n o f n e u r o l e p t i c s . S t u d i e s w i t h dopai n e m e t a b o l i t e s ( 5 , 6 , 7 ) have d e m o n s t r a t e d t h a t n e u r o l e p t i c s w i t h a i g h e r i n c i d e n c e o f e x t r a p y r a m i d a l s i d e e f f e c t s a f f e c t dopamine to g r e a t e r e x t e n t in the n i g r o - s t r i a t a l system than in t h e l i m b i c r cortical areas, while "atypical" n e u r o l e p t i c s a f f e c t dopamine ore in the l i m b i c a r e a s than the s t r i a t u m . f f e c t s i n d o p a m i n e - r i c h a r e a s have t h e r b r a i n areas are s e n s i t i v e to t r e x a m p l e , t h e c o r t e x has been impl pendent b i n d i n g s i t e s f o r n e u r o l e p t and t h a l a m u s , i n t r a p e r i t o n e a l l y ad~ not i m i p r a m i n e ) s i g n i f i c a n t l y eleva o acid neurotransmitters (9).
Using behavioral measures, other loci are suggested. For exmple, amphetamine-induced stereotypy has also been blocked by l e ions of the globus p a l l i d u s (10). I n t r a c r a n i a l i n j e c t i o n s of
0024-3205/82/211811-05503.00/0 Copyright
(e) 1982 Pergamon Press L
uroleptics have been d e m o n s t r a t e d t o b l o c k amphetamine a c t i o n s en made i n t o t h e n u c l e u s accumbens ( I i ) , c a u d a t e and septum ( 1 2 ) . h a n o l a m i n e (an i n h i b i t o r o f G A B A - t r a n s a m i n a s e ) a l s o reduced phetamine-induced hyperactivity when a d m i n i s t e r e d i n t o t h e nuCI eus accumbus ( 1 3 ) . Injections o f c h l o r p r o m a z i n e i n t o t h e hypothal alamus ( 1 4 ) a l s o a f f e c t e a t i n g b e h a v i o r , as does GABA a d m i n i stered ered t o t h e amygdala ( 1 5 ) . The e f f e c t s o f n e u r o l e p t i c s on avo i d a n c e a c q u i s i t i o n can a l s o be mimicked by a d m i n i s t r a t i o n of carbachol to the amygdala (16) or septum (15). Thus, i t can be seen t h a t , although the clearest associations can be made with the dopamine-rich areas of the brain, i t is l i k e l y that other loci and other neurotransmitters may be involved in the behavioral actions of neuro I~
L flUUS
General: Anlmals: Male S p r a g u e - D a w l e y r a t s ( 2 0 0 - 2 5 0 gm, B i o - L a b s , St. P a u l , MN) were used in a l l e x p e r i m e n t s . A l l were g r o u p - h o u s e d and had f r e e access t o food and w a t e r d u r i n g a l l phases o f t h e a 12 hour l i g h t / d a r k cycle with ~xperiments and were malnta I l g h t s on from 0600-1800 ho ed in a g r i d - f l o o r s h u t t l e box Behavioral: ~n~.,d,S Animals wuru ~usLuu w z. d Br,u. The grid :onstructed with one side 10 cm lower than the ,other. A f t e r a one-minute f a m i l i a r i f ] o o r sloped between the two l e v e l s . the t r i a l begun. nimal was placed on the lower grid and , {ation,. an anl tl lower g r i d , a I f , a f t e r 10 seconds, the animal was s t i l l on the animal escaped , 3.5 mA shock was i n i t i a t e d and continued u n t i l the level. A f t e r a 20 second i n t e r t r i ,al i n t e r v a l , the eplaced on the lower section of the grid and another Animals moving to the upper grid in less than 10 econds were not shocked, having performed an avoidance. Testing as continued u n t i l f i v e consecutive avoidances were performed. AnaIxtical: Brain regions were assayed for chlorpromazine by he method of Wiesel and Alfredsson (17). 0nly the parent compound as assayed since t h i s study reported that antidopaminergic e f f e c t s ould be a t t r i b u t e d p r i m a r i l y to i t rather than to metabolites. xperiment 1: of slx rats each were glven chlorpr( r saline (0.2 ~ l ) i n t r a c r a n i a l l y un( cts on avoidance a c q u i s i t i o n were a: tera] i n j e c t i o n s were made into the globus p a l l i d u s , nucleus accumbens bstantia nigra, entorhinal cortex, l a , septum, or caudate. Injections ic coordinates (18) which allowed F( sphere of less than 1 mm diameter w f the structure injected. S e v e r a l d r u g s , d y e s , and r a d i o l a b e l l e d e u r o t r a n s m i t ttet e r sr have been a d m i n i s t e r e d in 1 ~1 and a r e d e p o s i t e d i t h i n a s p h e r e o f 1 mm r a d i u s . C h l o r p r o m a z i n e was a d m i n i s t e r e d s the hydrochloride in s a l i n e o v e r t h e c o u r s e o f 1 m i n u t e .
periment 2: Twelve animals were i n j e c t e d i n t r a p e r i t o n e a l l y with chlorprozine at 2.5 mg/kg i . p . This dose represents the EDen f o r ocking avoidance a c q u i s i t i o n using the one-way avoidance procere described, as determined on animals receiving O, I , 2, 2.5, 3 dur, Dr 4 mg chlorpromazine/kg. A f t e r behavioral t e s t i n g 40 minutes t e r drug a d m i n i s t r a t i o n , the animals were k i l l e d and the leve] afte of chlorpromazine was determined in the septum, hippocampus, a n t e r i o r neocortex, p o s t e r i o r neocortex, amygdala, caudate, and hypothalamus. Animals r e q u i r i n g more than the control mean plus two standard deviations to establish an avoidance response were defined as demonstrating a drug response.
Experiment I : When i n j e c t e d into the amygdala, caudate, or septum, (Table I ) chlorpromazine produced a behavioral e f f e c t s i m i l a r to that a f t e r i n t r a p e r i t o n e a l i n j e c t i o n , i . e . delayed a c q u i s i t i o n of the avoidance response. I n j e c t i o n s made into the other areas resulted in behavior which was not s i g n i f i c a n t l y d i f f e r e n t from e i t h e r unini~cted nr s ~a allii n e - i n i ~ c tted ~ d controls. ~nlnjected controls or No e f f e c t s on ~scape latency were observe E f f e ct of Regional I n j e c t i o n s of Chlorpr ~romazine on One-waX Avoidance A c q u i s i t i o n AREA A n t e r i o r neocortex Hippocampus Globus p a l l i d u s Nucleus accumbens Thalamus Hypothalamus Substantia nigra Entorhinal cortex Lateral geniculate Septum Caudate Amygdala
TRIALS 14 16 15 12 16 14 12 11 35 38 34
± ± ± ± ± ± ± ± ± ± ±
4 6 3 4 6 4 3 3 8* 12" 12"
resent mean ± standard deviation of t e r i o n of f i v e consecutive avoidanc ed controls or animals i n j e c t e d wit raged 11 ± 6 and 12 ± 4 t r i a l s resp f i c a n t l y higher than s a l i n e - i n j e c t e 0.05 by Randomization t e s t . xperlment z: Only in the caudate and amygdala (Table I f ) w a s there a sigi f i c a n t d i f f e r e n c e between drug ]evels of animals in which a drug f f e c t was observed and those which were unresponsive to drug at he ED.^ l e v e l . In both cases, more drug was present in the rainsb~f animals in which a behavioral drug e f f e c t was observed. his r e l a t i o n s h i p was not observed in any of the other areas
TABLE Chlorpromazine Levels in Showing a Drug E f f e c t o r Following Intraperitoneal
II Brain Areas of Animals Lack o f Drug E f f e c t Administration o f ED50
DRUG EFFECT PRESENT ABSENT 1.18 ± 0.11 1 . 0 ~ -+ 0 . 1 5 1.46 + 0 . 0 8 1 . 4 5 -+ 0 . 0 5 0 . 3 3 +- 0 . 0 3 0 . 3 4 ± 0.02 0 . 3 5 -+ 0 . 1 0 0 . 2 9 -+ 0 . 0 5 0 . 7 2 +- 0 . 0 4 " 0 . 6 4 -+ 0 . 0 4 0.06 0 . 8 7 +- 0 . 0 5 0.06" 0 . 2 3 -+ 0 . 0 9
AREA Septum Hippocampus Anterior neocortex Posterior neocortex Caudate Hypothalamus Amygdala
Data r e p r e s e n t mean ± s t a n d a r d d e v i a t i o n pg c h l o r p r o m a z i n e p e r gram o f t i s s u e . Metabolite levels were n o t i n c l u d e d . * Significantly h i g h e r t h a n i n a n i m a l s not demonstrating a drug e f f e c t , p
Thus, t h e data from E x p e r i m e n t 1 can be t a k e n as i n d i c a t i n g at a n e u r o l e p t i c e f f e c t can be p r o d u c e d by t h e i n j e c t i o n of l o r p r o m a z i n e i n t o t h e septum, c a u d a t e , o r amygdala. The f i n d i n g h i g h e r c h l o r p r o m a z i n e l e v e l s in t h e c a u d a t e and amygdala o f a n i m a l s r e s p o n d i n g to t h e EDr 0 o f c h l o r p r o m a z i n e (as compared to those ose not r e s p o n d i n g ) a g a i n ~ u g g e s t s t h a t t h e s e areas a r e t h e rell e v a n t ones in terms o f n e u r o l e p t i c action. In t h i s l i g h t , i t s h o u l d be remembered t h a t , at t h e EDen dose, o n l y h a l f o f t h e a n i m a l s a r e e x p e c t e d to show a drug ~ f e c t even though a l l r e c e i v e d t h e same dose o f d r u g . S i n c e o n l y c h l o r p r o m a z i n e was measured, t h e s e data do not r e l a t e to t h e q u e s t i o n o f which m e t a b o l i t e s m i g h t a l s o have b e h a v i o r a l a c t i v i t y in t h i s t e s t . Behavioral effects of these metabolites, p o s s i b l y a l s o in o t h e r brain regions are possible. F u r t h e r studi s t u d i e s desi d e s i g nre d to d e~termi termine neurotransmi tter volvement within the three "active" areas are in p r o g r e s s .
in-
Acknowledgement T h i s r e s e a r c h was s u p p o r t e d t h r o u g h f u n d s from t h e D e p a r t m e n t of Psychiatry, University o f I o w a , and a V e t e r a n ' s A d m i n i s t r a t i o n Research Career Development o F. P e t t y . References 1. 2.
4. 5. 6. 7. 8.
N . E . ANDEN DEN and P. BEDARD, J. Pharmac. P Phar h a r m a c o l . 23 4 6 0 - 4 6 7 (1971). J. PERETT-CROUET, G.L. GHESSA, A. TAGLIAMON AMONTE and P. TAGI IAMONTF ONTE, Fed. Proc. 30 216 (1971). WERS and A. ROZITIS, J. Pharmac. Ph h a r m a c o l . 26 743-745 5. ~ARIHULLRL, HOLINI H. H. STADLER 31AULER and nd K.G. K.~. LLOYD LLUYU, CHOLINERGIC CHULINER~IC MECHA MECHANISMS p. 411, Raven P r e s s , New York ( 1 9 7 4 ) . N.E. ANDEN and G. STOCK, J. Pharmac. P h a r m a c o l . 25 346-354 (1973). B.H.C. WESTERINK and J. KORF, Eur. J. Pharmacol. 38 281-291 (1976). A. UZAN, N. LE FUR, M. MITRANI, M. KABOUCHE and A.M. DONADIEU, L i f e S c i . 23 2 6 1 - 2 7 4 ( 1 9 7 8 ) . 267-270G" LE FUR(~9~).GUILLOUX and A. UZAN, Biochem. P h a r m a c o l . __29 ONARD, Z. Naturforsch. 30 838-840 ( ALL and R.J. NAYLOR, Naunyn-Schmied ol. 278 117-133 (1973). PIJNENBERG, W.M.M. HONIG and J.M. V ol. 41 87-95 (1975). A. RANDRUP and H. PAKKENBERG, Psyc (1967). COCK and R.W. HORTON, Psychopharmac
4. 5. 6. 7.
(1976). S.F. LIEBOWITZ and N.E. MILLER, S c i e n c e 165 609-611 ( 1 9 6 9 ) . S.P. GROSSMAN, J. Comp. P h y s i o l . P s y c h o l . 58 194-200 ( 1 9 6 4 ) . J . D . BELLUZZl and S.P. GROSSMAN, P h y s i o l . a~d Behav. 4 371373 (1969). F.A. WIESEL and G. ALFREDSSON, Eur. J. Pharmacol. 40 263-272 (1976). Y and A.D. SHERMAN, L i f e Sci. 26 14
D. Sherman,
Frederick
Petty
and James L.
Sacquitne
Neurochemistry L a b o r a t o r y , Department of P s y c h i a t r y , U n i v e r s i t y of lowa and V e t e r a n s A d m i n i s t r a t i o n M e d i c a l C e n t e r , lowa C i t y , lowa arch 15, 1982)
(Received in fil
Summary C h l o r p r o m a z i n e i n j e c t e d i n t o t h e a m y g d a l a , septum, o r c a u d a t e d e l a y e d t h e a c q u i s i t i o n o f a one-way active avoidance response. Injections into nine other brain a r e a s were i n a c t i v e . F o l l o w i n g a s t a n d a r d dose o f c h l o r p r o m a z i n e a t i t s ED~ aying avoidance acquisition, tissue levelsb~ Iromazine from those animals displaying reduced ac ~n were s i g n i f i c a n t l y higher i n t h e c a u d a t e and amygdala than from ani mals not demons t r a t i n g a drug e f f e c t . A l t h o u g hh c h l o r p r o m a z i n e has a c h i e v e d wides despread c l i n i c a l use d u r i n g t h e 1 a s t 25 y e a r s , n e i t h e r i t s n e u r o a n a t o m i c l o c u s o f a c t i o n nor t h e neurochemi •o c h e m i c a l b a s i s o f i t s a n t i p s y c h o t i c a c i t i v i t y has been do " Ine n y pootthneessil s o oTf a h nyperac~ t i I v e n l"g r o - s t~r tl a r i~ at la l aopam~nerglc y s t e m in s c h i z o p h r e n i a l e d t o many s t u d i e s on t h e e f f e c t s o f a n t i ~ s y c h o t i c drugs on t h e r e l e a s e , m e t a b o l i s m , and b i n d i n g o f dopamine n the striatum. Several lines of evidence (1,2,3,4) suggested the a u d a t e as t h e l o c u s o f a c t i o n o f n e u r o l e p t i c s . S t u d i e s w i t h dopai n e m e t a b o l i t e s ( 5 , 6 , 7 ) have d e m o n s t r a t e d t h a t n e u r o l e p t i c s w i t h a i g h e r i n c i d e n c e o f e x t r a p y r a m i d a l s i d e e f f e c t s a f f e c t dopamine to g r e a t e r e x t e n t in the n i g r o - s t r i a t a l system than in t h e l i m b i c r cortical areas, while "atypical" n e u r o l e p t i c s a f f e c t dopamine ore in the l i m b i c a r e a s than the s t r i a t u m . f f e c t s i n d o p a m i n e - r i c h a r e a s have t h e r b r a i n areas are s e n s i t i v e to t r e x a m p l e , t h e c o r t e x has been impl pendent b i n d i n g s i t e s f o r n e u r o l e p t and t h a l a m u s , i n t r a p e r i t o n e a l l y ad~ not i m i p r a m i n e ) s i g n i f i c a n t l y eleva o acid neurotransmitters (9).
Using behavioral measures, other loci are suggested. For exmple, amphetamine-induced stereotypy has also been blocked by l e ions of the globus p a l l i d u s (10). I n t r a c r a n i a l i n j e c t i o n s of
0024-3205/82/211811-05503.00/0 Copyright
(e) 1982 Pergamon Press L
uroleptics have been d e m o n s t r a t e d t o b l o c k amphetamine a c t i o n s en made i n t o t h e n u c l e u s accumbens ( I i ) , c a u d a t e and septum ( 1 2 ) . h a n o l a m i n e (an i n h i b i t o r o f G A B A - t r a n s a m i n a s e ) a l s o reduced phetamine-induced hyperactivity when a d m i n i s t e r e d i n t o t h e nuCI eus accumbus ( 1 3 ) . Injections o f c h l o r p r o m a z i n e i n t o t h e hypothal alamus ( 1 4 ) a l s o a f f e c t e a t i n g b e h a v i o r , as does GABA a d m i n i stered ered t o t h e amygdala ( 1 5 ) . The e f f e c t s o f n e u r o l e p t i c s on avo i d a n c e a c q u i s i t i o n can a l s o be mimicked by a d m i n i s t r a t i o n of carbachol to the amygdala (16) or septum (15). Thus, i t can be seen t h a t , although the clearest associations can be made with the dopamine-rich areas of the brain, i t is l i k e l y that other loci and other neurotransmitters may be involved in the behavioral actions of neuro I~
L flUUS
General: Anlmals: Male S p r a g u e - D a w l e y r a t s ( 2 0 0 - 2 5 0 gm, B i o - L a b s , St. P a u l , MN) were used in a l l e x p e r i m e n t s . A l l were g r o u p - h o u s e d and had f r e e access t o food and w a t e r d u r i n g a l l phases o f t h e a 12 hour l i g h t / d a r k cycle with ~xperiments and were malnta I l g h t s on from 0600-1800 ho ed in a g r i d - f l o o r s h u t t l e box Behavioral: ~n~.,d,S Animals wuru ~usLuu w z. d Br,u. The grid :onstructed with one side 10 cm lower than the ,other. A f t e r a one-minute f a m i l i a r i f ] o o r sloped between the two l e v e l s . the t r i a l begun. nimal was placed on the lower grid and , {ation,. an anl tl lower g r i d , a I f , a f t e r 10 seconds, the animal was s t i l l on the animal escaped , 3.5 mA shock was i n i t i a t e d and continued u n t i l the level. A f t e r a 20 second i n t e r t r i ,al i n t e r v a l , the eplaced on the lower section of the grid and another Animals moving to the upper grid in less than 10 econds were not shocked, having performed an avoidance. Testing as continued u n t i l f i v e consecutive avoidances were performed. AnaIxtical: Brain regions were assayed for chlorpromazine by he method of Wiesel and Alfredsson (17). 0nly the parent compound as assayed since t h i s study reported that antidopaminergic e f f e c t s ould be a t t r i b u t e d p r i m a r i l y to i t rather than to metabolites. xperiment 1: of slx rats each were glven chlorpr( r saline (0.2 ~ l ) i n t r a c r a n i a l l y un( cts on avoidance a c q u i s i t i o n were a: tera] i n j e c t i o n s were made into the globus p a l l i d u s , nucleus accumbens bstantia nigra, entorhinal cortex, l a , septum, or caudate. Injections ic coordinates (18) which allowed F( sphere of less than 1 mm diameter w f the structure injected. S e v e r a l d r u g s , d y e s , and r a d i o l a b e l l e d e u r o t r a n s m i t ttet e r sr have been a d m i n i s t e r e d in 1 ~1 and a r e d e p o s i t e d i t h i n a s p h e r e o f 1 mm r a d i u s . C h l o r p r o m a z i n e was a d m i n i s t e r e d s the hydrochloride in s a l i n e o v e r t h e c o u r s e o f 1 m i n u t e .
periment 2: Twelve animals were i n j e c t e d i n t r a p e r i t o n e a l l y with chlorprozine at 2.5 mg/kg i . p . This dose represents the EDen f o r ocking avoidance a c q u i s i t i o n using the one-way avoidance procere described, as determined on animals receiving O, I , 2, 2.5, 3 dur, Dr 4 mg chlorpromazine/kg. A f t e r behavioral t e s t i n g 40 minutes t e r drug a d m i n i s t r a t i o n , the animals were k i l l e d and the leve] afte of chlorpromazine was determined in the septum, hippocampus, a n t e r i o r neocortex, p o s t e r i o r neocortex, amygdala, caudate, and hypothalamus. Animals r e q u i r i n g more than the control mean plus two standard deviations to establish an avoidance response were defined as demonstrating a drug response.
Experiment I : When i n j e c t e d into the amygdala, caudate, or septum, (Table I ) chlorpromazine produced a behavioral e f f e c t s i m i l a r to that a f t e r i n t r a p e r i t o n e a l i n j e c t i o n , i . e . delayed a c q u i s i t i o n of the avoidance response. I n j e c t i o n s made into the other areas resulted in behavior which was not s i g n i f i c a n t l y d i f f e r e n t from e i t h e r unini~cted nr s ~a allii n e - i n i ~ c tted ~ d controls. ~nlnjected controls or No e f f e c t s on ~scape latency were observe E f f e ct of Regional I n j e c t i o n s of Chlorpr ~romazine on One-waX Avoidance A c q u i s i t i o n AREA A n t e r i o r neocortex Hippocampus Globus p a l l i d u s Nucleus accumbens Thalamus Hypothalamus Substantia nigra Entorhinal cortex Lateral geniculate Septum Caudate Amygdala
TRIALS 14 16 15 12 16 14 12 11 35 38 34
± ± ± ± ± ± ± ± ± ± ±
4 6 3 4 6 4 3 3 8* 12" 12"
resent mean ± standard deviation of t e r i o n of f i v e consecutive avoidanc ed controls or animals i n j e c t e d wit raged 11 ± 6 and 12 ± 4 t r i a l s resp f i c a n t l y higher than s a l i n e - i n j e c t e 0.05 by Randomization t e s t . xperlment z: Only in the caudate and amygdala (Table I f ) w a s there a sigi f i c a n t d i f f e r e n c e between drug ]evels of animals in which a drug f f e c t was observed and those which were unresponsive to drug at he ED.^ l e v e l . In both cases, more drug was present in the rainsb~f animals in which a behavioral drug e f f e c t was observed. his r e l a t i o n s h i p was not observed in any of the other areas
TABLE Chlorpromazine Levels in Showing a Drug E f f e c t o r Following Intraperitoneal
II Brain Areas of Animals Lack o f Drug E f f e c t Administration o f ED50
DRUG EFFECT PRESENT ABSENT 1.18 ± 0.11 1 . 0 ~ -+ 0 . 1 5 1.46 + 0 . 0 8 1 . 4 5 -+ 0 . 0 5 0 . 3 3 +- 0 . 0 3 0 . 3 4 ± 0.02 0 . 3 5 -+ 0 . 1 0 0 . 2 9 -+ 0 . 0 5 0 . 7 2 +- 0 . 0 4 " 0 . 6 4 -+ 0 . 0 4 0.06 0 . 8 7 +- 0 . 0 5 0.06" 0 . 2 3 -+ 0 . 0 9
AREA Septum Hippocampus Anterior neocortex Posterior neocortex Caudate Hypothalamus Amygdala
Data r e p r e s e n t mean ± s t a n d a r d d e v i a t i o n pg c h l o r p r o m a z i n e p e r gram o f t i s s u e . Metabolite levels were n o t i n c l u d e d . * Significantly h i g h e r t h a n i n a n i m a l s not demonstrating a drug e f f e c t , p
Thus, t h e data from E x p e r i m e n t 1 can be t a k e n as i n d i c a t i n g at a n e u r o l e p t i c e f f e c t can be p r o d u c e d by t h e i n j e c t i o n of l o r p r o m a z i n e i n t o t h e septum, c a u d a t e , o r amygdala. The f i n d i n g h i g h e r c h l o r p r o m a z i n e l e v e l s in t h e c a u d a t e and amygdala o f a n i m a l s r e s p o n d i n g to t h e EDr 0 o f c h l o r p r o m a z i n e (as compared to those ose not r e s p o n d i n g ) a g a i n ~ u g g e s t s t h a t t h e s e areas a r e t h e rell e v a n t ones in terms o f n e u r o l e p t i c action. In t h i s l i g h t , i t s h o u l d be remembered t h a t , at t h e EDen dose, o n l y h a l f o f t h e a n i m a l s a r e e x p e c t e d to show a drug ~ f e c t even though a l l r e c e i v e d t h e same dose o f d r u g . S i n c e o n l y c h l o r p r o m a z i n e was measured, t h e s e data do not r e l a t e to t h e q u e s t i o n o f which m e t a b o l i t e s m i g h t a l s o have b e h a v i o r a l a c t i v i t y in t h i s t e s t . Behavioral effects of these metabolites, p o s s i b l y a l s o in o t h e r brain regions are possible. F u r t h e r studi s t u d i e s desi d e s i g nre d to d e~termi termine neurotransmi tter volvement within the three "active" areas are in p r o g r e s s .
in-
Acknowledgement T h i s r e s e a r c h was s u p p o r t e d t h r o u g h f u n d s from t h e D e p a r t m e n t of Psychiatry, University o f I o w a , and a V e t e r a n ' s A d m i n i s t r a t i o n Research Career Development o F. P e t t y . References 1. 2.
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