Michela Marinelli et al- Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced sensitization of the locomotor response to cocaine

8/3/2019 Michela Marinelli et al- Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced

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BRAINRESEARCH

ELSEVIER Brain Research 724 (1996) 251-255

S h o r t c o m m u n i c a t i o nA c u t e p h a r m a c o l o g i c a l b l o c k a d e o f c o r t ic o s t er o n e s e c re t io n r e v e rs e s f o o d

r e s tr i c ti o n - in d u c e d s e n s i ti z a ti o n o f t h e l o c o m o t o r r e s p o n s e t o c o c a i n eM i c h e l a M a r i n el l i, M i c h e l L e M o a l , P ie r V i n c e n z o P i a z z a *

P s y c h o b i o l o g i e d e s C o m p o r t e m e n t s A d a p t a t i fs , I N S E R M U 2 5 9 , U n i u e r s it ~ d e B o r d e a u x 11 , D o m a i n e d e C a r r e i re , R u e C a m i l l e Sa i n t -S a ~n s , 3 3 0 7 7B o r d e a u x , F r a n c e

Accepted 5 March 1996

A b s t r a c t

Several data indicate that a blockade of s tress-induced corticosterone secretion prevents the development of the stress-inducedsensit ization of the behavioral effects of drugs of abuse. In this report we investigated if an acute blockade of corticosterone secretioncould reverse stress-induced sensitizat ion once it is already established. Food restrict ion (90% of init ial body weight) was used as stressor.Corticosterone secretion was blocked by the corticosterone synthesis inhibi tor metyrapone (100 mg/ kg). After 8 days of food restriction,animals received an injection of metyrapone and 3 h later they were tested either for the locomotor response to cocaine or for thecorticosterone secretion in response to stress (restraint, 30 min). Neither metyrapone nor food restriction had any effect on the locomotorresponse to a saline injection. In contrast, food-restricted animals, compared to ad libitum-fed controls, showed a higher locomotorresponse to cocaine and higher corticosterone levels. Treatment with metyrapone totally abolished these effects. Food-restricted animals,receiving a single injection of metyrapone, did not differ from ad libitum-fed controls for both locomotor response to cocaine andcorticosterone secretion. Metyrapone treatment also similarly reduced the response to cocaine and corticosterone secretion in adlibitum-fed controls. In conclus ion, this study provides further evidence that the enh ancement in drug effects produced by stress dependson an increase in corticosterone levels. Since stress-induced sensit ization is considered one of the condit ions predisposing to drug abuse,the present results might have implications for the treatment of addiction.K e y w o r d s : Corticosterone; Cocaine; Metyrapone; Stress-inducedsensitization;Food restriction; Locomotor response; Psychomotor effects

Life experiences, and in particular exposure to stressfulsituations, increase the sensitivity to the psychomo tor andreinforc ing properties of drugs of abuse (for review see[24,37,38,43]). In particular, different stressors enhanceboth the locomotor response to psychostimulant drugs andthe propensity to develop oral or intravenous self adminis-tration [1,3,11,13,14,18,20,26,33,36,44,51].

Recent studies suggest that the development of stress-induced enhancement of drug effects, a ph enomen on knownas behavioral sensitization, is mediated by stress-inducedcorticosterone secretion (for review see [38]). Treatmentprecluding stress-induced corticosterone secretion, as forexample adrenalectomy or a chronic treatment with thecorticosterone synthesis inhibitor metyrapone, blocks thedevelopment of the sensitization induced by several stres-

* Corresponding author. Fax: (33 ) 5696-6893; E-ma ih [email protected]/96/$15.00 1996 Elsevier Science B.V. All rights reservedP l l S0006-8993(96)00309-5

sors, such as restraint, social isolation and food restriction[12-15,40,48]. In parallel, in intact rats, repeated cortico-sterone admini strati on itself produces effects similar torepeated stress and thus induces the development of asensitization of the locomotor [16] and reinforcing effectsof psy chost imula nt drugs [39].

In this report the influence of corticosterone on stress-induced behavioral sensitization was further investigated.Specifically, we examined whether an a c u t e blockade ofcorticosterone synthesis could reverse stress-induced sensi-tization once its development had already occurred. Forthis purpose, we examined the effects of an acute treatmentwith metyrapone on the locomotor response to cocaine ofanimals in which behavioral sensitization had been in-duced by a period of food restriction. Food restriction wasused as a stressor because it powerfully increases bothcorticosterone secretion [4] and the psychomotor and rein-forcing effects of psychostimulants [6-8,10,12,14,34,48].The effects of metyrapone on corticosterone secretion werealso investigated.


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252 M. Marinelli et al ./ Brain Research 724 (1996) 251 255

M a l e S p r a g u e - D a w l e y r at s ( If f a -C r e d o , L y o n , F r a n c e )w e i g h i n g 2 8 0 - 3 0 0 g w e r e u se d . A n i m a l s w e re i n d i v i d u a l lyh o u s e d w i t h a d l i b i t u m a c c e s s to f o o d a n d w a t e r u n l e s so t h e r w i s e s p e c i f ie d . A 1 2 : 12 l i g h t - d a r k c y c l e ( li g h t s o f f at1 2 p m ) w a s m a i n t a i n e d i n t h e a n i m a l r o o m , a n d t e m p e r a -t u r e ( 2 2 C ) a n d h u m i d i t y ( 6 0 % ) w e r e k e p t c o n s ta n t . A n i -m a l s w e r e a l l o w e d a t l ea s t o n e w e e k t o a c c l i m a t i z e to t h ea n i m a l r o o m b e f o r e s t a r t i n g a n y m a n i p u l a t i o n .M e t y r a p o n e ( S i g m a ) w a s d i s s o l v e d i n a s o lu t i o n o fd i s t i ll e d w a t e r c o n t a i n i n g 7 % o f T w e e n 8 0 w h i c h w a s a l s ou s e d a s v e h i c l e s o l u t i o n . M e t y r a p o n e w a s a d m i n i s t e r e d s . c .a t a d o s e o f 10 0 m g / k g i n a 2 m l / k g v o l u m e . T h i s d o s ew a s u s e d b e c a u s e w e h a v e s h o w n p r e v i o u s l y t h a t a s im i l a rt r e a tm e n t s i g n i f i c a n t l y d e c r e a s e s s t r e s s - i n d u c e d c o r t i c o -s t e r o n e s e c r e t i o n [4 0 ]. C o c a i n e H C 1 ( C o o p E r a t i o n P h a r m a -c e u t i q u e F r a n ~ a i s e , F r a n c e ) w a s d i s s o l v e d i n 0 .9 % N a C 1s o l u t i o n a n d i n j e c te d i. p . at a d o s e o f 1 0 m g / k g i n av o l u m e o f 1 m l / k g .

L o c o m o t o r a c t i v i t y w a s m e a s u r e d i n c i r c u l a r c o r r i d o r s( 1 0 c m w i d e a n d 7 0 c m i n d i a m e t e r ) e q u i p p e d w i t h f o u re q u a l l y - s p a c e d p h o t o e l e c t r i c b e a m s l o c a t e d a l o n g t h e p e r -p e n d i c u l a r a x is o f th e a p p a r a t u s . S i n c e t h e lo c o m o t o rr e s p o n s e t o n o v e l t y a n d s e n s i t i v i t y t o th e p s y c h o m o t o re f f e ct s o f p s y c h o s t i m u l a n t s a r e c o r r e l a t e d [2 1 , 3 5] , w e e n -s u r e d a h o m o g e n e o u s d i s t r i b u t io n o f t h i s f a c t o r t h r o u g h o u tt h e d i f fe r e n t e x p e r i m e n t a l g r o u p s . F o r th i s p u r p o s e , o n ew e e k p r i o r to a n y o t h e r e x p e r i m e n t a l m a n i p u l a t i o n , a l la n i m a l s w e r e t e s t e d fo r t h e i r l o c o m o t o r r e s p o n s e t o n o v -e l t y o v e r 2 h . R a t s w e r e t h e n e v e n l y d i s t r i b u t e d a m o n g t h ed i f f e r e n t e x p e r i m e n t a l g r o u p s a c c o r d i n g t o t h e i r a c t iv i t ys c o r e .

A n i m a l s u n d e r g o i n g t h e f o o d r e s tr i c ti o n p r o c e d u r e w e r er e d u c e d t o 9 0 % o f th e i r b o d y w e i g h t u s i n g t h e f o l l o w i n gp r o c e d u r e : o n t h e f i r s t d a y o f f o o d r e s t r i c t i o n a l l r a t sr e c e i v e d 8 g o f f o o d a n d o n e a c h o f th e f o l l o w i n g d a y s t h ed a i l y r a ti o n w a s i n d i v i d u a l l y a d a p t e d a c c o r d i n g t o t h ea t t a in e d b o d y w e i g h t s o a s t o r e a c h 9 0 % o f t h e p r e - re s t r ic -t i o n v a l u e w i t h i n 5 - 6 d a y s f r o m t h e b e g i n n i n g o f t h er e s t ri c t io n p e r io d . A n i m a l s w e r e t h e n m a i n t a i n e d a t 9 0 % o ft h e i r w e i g h t f o r th e d u r a t i o n o f t h e e x p e r i m e n t b y d a i l ya d j u s t m e n t s o f th e i r ra t io n . A n i m a l s n o t u n d e r g o i n g t h ef o o d r e s t r i c t io n p r o c e d u r e w e r e w e i g h e d d a i l y , as w e r e t h er e s t r ic t e d a n i m a l s , b u t w e r e f e d a d l i b i t u m t h r o u g h o u t t h ee x p e r i m e n t .

F o r t h e a s s e s s m e n t o f t h e e f f e c ts o f f o o d r e s t ri c t io n a n dm e t y r a p o n e o n t h e l o c o m o t o r r e s p o n s e to c o c a i n e , a n i m a l sf e d a d l i b i t u m o r f o o d r e s t r i c t e d ( F R ) r e c e i v e d a n i n j e c t i o no f e i th e r v e h i cl e o r m e t y r a p o n e ( M E T Y ) . F o u r e x p e r i m e n -t a l g r o u p s w e r e t h e n co n s t i t u te d : V E H I C L E ( n = 1 5 ),V E H I C L E F R ( n = 1 6 ), M E T Y ( n = 1 5 ) a n d M E T Y F R( n = 1 6 ) . I n j e c t i o n s w e r e g i v e n a t 9 . 0 0 h . O n e h o u r l a t e rt h e a n i m a l s w e r e p l a c e d i n t h e c i r c u l ar c o r r i d o r a n d a l t e r 2h o f h a b i t u a t i o n , h a l f o f t h e a n i m a l s r e c e i v e d a n i . p .i n j e c ti o n o f s a l i n e a n d t h e o t h e r h a l f o f c o c a i n e . C o n s e -q u e n t l y t h e m e t y r a p o n e a n d c o c a i n e i n j e c t i o n s w e r e s p a c e db y a 3 - h p e r i o d . L o c o m o t o r r e s p o n s e s w e r e r e c o r d e d f o r 2h o v e r 1 0 - m i n i n t e r v a l s .

T o a s s e s s th e e f f e c ts o f f o o d r e s t ri c t io n a n d m e t y r a p o n eo n c o r t i c o s t e r o n e s e cr e t i o n , a d l i b i t u m - f e d a n d f o o d - r e -s t r i c t e d r a t s w e r e i n j e c t e d w i t h e i t h e r m e t y r a p o n e o r v e h i -c l e. F o u r e x p e r i m e n t a l g r o u p s ( n = 8 e a c h ) id e n t i c a l t o th eo n e s d e s c r i b e d a b o v e w e r e t h u s c o n s t it u t e d . T h i s t im e , 3 h

3 5 0

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7,L

LOCOMOTOR RESPONSESALINE COCAINE (10 mg/kg)

VE HIC LE FR ~ lo,: ,o n,oo !D M E T Y ~

: N1 E T } " FR [ ] 5 c J; , ~ T 5 o o\u T O T l h r ~ F o ,,

3 50

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_ 1 5 0ii 10 0

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1200 40 60 80 100 120 20 40 60 80 100TIME (min)

Fig. 1. Effect of metyrapone (100 m g/ kg , s.c.) and food restriction (90% of body weight) on locomotor response to saline (left panel) and cocaine 10mg / kg i.p. (right panel). Each poi nt represents the mean _+ S.E.M. of the locomotor acti vity over 10 min. Bars r epresent the mean _+ S.E.M. of the totallocomotor activity over the first hour of testing. Neither metyrapone nor food restriction had any effect on the locomotor response to a saline injection. Incontrast, food-restricted animals (VEHICLE FR) showed a higher locomotor response to cocaine than ad libitum-fed controls (VEHICLE) (P < 0.001). Anacute metyrapone injection (100 mg/kg) 3 h before cocaine totally abolished this effect. Thus food-restricted animals receiving metyrapone (METY FR)showed a lower response to cocaine than animals in the VEHICLE FR group (P < 0.01) and did not differ from ad libitum-fed controls (VEHICLE).Metyrapone treat ment also reduced the response to cocaine in control ad libitum- fed animals (METY vs. VEHICLE, P < 0.05).


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M . M a r i n e l l i e t al . / B r a i n R e s e a r c h 7 2 4 ( 1 9 9 6 ) 2 5 1 - 2 5 5 25 3

a f t e r t h e v e h i c l e o r m e t y r a p o n e i n j e c t io n s , a n i m a l s w e r ep l a c e d i n a p la s t i c c y l i n d e r ( 7 c m d i a m e t e r , 2 5 c m l o n g )f o r 3 0 m i n , a n d t h r e e 3 0 0 / x l b l o o d s a m p l e s w e r e w i t h -d r a w n f r o m t h e t a i l v e i n . T h e f i r s t o n e w a s t a k e n w i t h i n 2r a i n f r o m t h e s t a r t o f t h e r e s t r a i n t s t r e ss p e r i o d , t h e s e c o n da n d t h e t h i r d o n e s 3 0 a n d 1 2 0 r ai n l a te r . B l o o d f o rc o r t i c o s t e r o n e a s s a y w a s c o l l e c t e d in h e p a r i n i z e d t u b e s a n dp l a s m a w a s o b t a i n e d a f t e r c e n t r i fu g a t i o n . P l a s m a c o r t i c o -s t er o n e w a s m e a s u r e d b y r a d i o i m m u n o - a s s a y ( R I A k i t,I C N B i o m e d i c a l s ) u s i n g a h i g h l y s p e c i f i c c o r t i c o s t e r o n ea n t i s e r u m w i t h a d e t e c t i o n th r e s h o l d o f 0 .1 / x g / 1 0 0 m l .

F o r t h e s t a t i s t ic a l a n a l y s i s o f t h e l o c o m o t o r r e s p o n s e t os a l i n e a n d c o c a i n e i n j e c t i o n s , l o c o m o t o r a c t i v i t y s c o r e sw e r e s u b m i t t e d to a n A N O V A c o n s i d e r in g t h e d i ff e re n te x p e r i m e n ta l g r o up s ( V E H I C L E , V E H I C L E F R , M E T Y ,M E T Y F R ) a s a b e t w e e n f a c t o r ( T r e a t m e n t , f o u r l e v e l s )a n d t h e d i f f e r e n t t i m e p o i n t s a f t e r t h e i n j e c t i o n a s a w i t h i nf a c t o r (T i m e , 1 2 l ev e l s ) . P l a s m a l e v e l s o f c o r t i c o s t e ro n ew e r e a n a l y z e d c o n s i d e r i n g t h e d i f f e r e n t t r e a t m e n t s a s b e -t w e e n f a c t o r ( T r e a tm e n t , 4 l e v e l s ) a n d t h e t i m e a t w h i c ht h e b l o o d s a m p l e s w e r e w i t h d r a w n a s w i t h i n f a c t o r ( T i m e ,t h r e e l e v e l s ) . N e w m a n - K e u l s t e s t w a s u s e d f o r p o s t - h o ca n a l y s i s .

Effects of foo d restriction and metyrapone on the loco-motor response to cocaine. F o o d r e s t ri c ti o n a n d m e t y r a p o n et r e a t m e n t s d i d n o t m o d i f y t h e l o c o m o t o r r e s p o n s e t o s a l in e[ T r e a t m e n t e f f e c t F 3 ,2 8 = 1 . 9 8 , P > 0 . 1 4 ] ( F i g . 1 l e f t p a n e l )b u t t h e y d i d a f f e c t t h e l o c o m o t o r r e s p o n s e t o c o c a i n e

PLASMA CORTICOSTERONE VEHICLET VEHICLEFR4 [] METY

16,-

141210 s t r e s s

O ' L - I I I0 30 120

TIME (min)Fig. 2. Effect of metyrapon e (100 m g/ kg , s.c.) and food restriction (90%of bo dy w eight) on corticosterone levels. Eac h value represents themean _+ S.E.M . of plasma corticosterone levels in b asal cond itions and 30and 120 rain after restraint stress. Food-restricted animals (VEHIC LE F R)showed a higher secretion of corticosterone than ad libitum-fed controls(VEH ICLE ) (P < 0.01). An acute metyrapone injection 3 h before stresstotally ab olished this e ffec t. Th us food-restricted animals receivingmetyrapone (METY FR) showed a lower corticosterone secretion thananimals in the VEHICLE FR group (P < 0.001) and did not dif fer f romad libitum-fed controls (VEHICLE). Metyrapone treatment also reducedcorticosterone secretion in control ad libitum-fed animals (METY vs.VEHICLE, P < 0.05) .

[ T r e a t m e n t e f f e c t , F 3 , 2 6 = 1 0 . 9 4 , P < 0 . 0 0 1 ] ( F i g . 1 r i g h tp a n e l ) i n a t im e - d e p e n d e n t m a n n e r [ T r e a t m e n t T i m e i n -t e r a c t i o n , F33 ,286 = 5 . 1 , P < 0 . 01 ] . A s F i g . 1 s ho w s , f oo dr e s t r ic t i o n i n c r e a s e d t h e l o c o m o t o r r e s p o n s e t o c o c a i n e( V E H I C L E F R v s . V E H I C L E , P < 0 . 0 0 1 ) a n d m e t y r a p o n et r e a t m e n t r e v e r s e d t h i s e f f e c t . T h u s a n i m a l s i n t h e M E T YF R g r o u p s h o w e d a l o w e r l o c o m o t o r r e sp o n s e t h a n a n i-m a l s i n th e V E H I C L E F R g r o u p ( P < 0. 0 1 ), b u t d i d n o td i f fe r f r o m a n i m a l s i n th e V E H I C L E g r o u p . M e t y r a p o n et r e a t m e n t a l s o r e d u c e d t h e r e s p o n s e t o t h e d r u g i n c o n t r o la n i m a l s ( M E T Y v s . V E H I C L E , P < 0 . 0 5) .

Effects of food restriction and metyrapone on cortico-sterone secretion. F o o d r e s t r i c ti o n a n d m e t y r a p o n e t r e a t -m e n t s i g n i f i c a n t l y m o d i f i e d p l a s m a c o r t i c o s t e r o n e le v e l s[ T r e a t m e n t e f f e c t , F 3 ,2 8 = 8 . 5 4 , P < 0 . 0 0 1 ] a n d t h i s e f f e c tw a s i n d e p e n d e n t f r o m t i m e f o l l o w i n g r e s t r a i n t s t re s s[ T r e a t m e n t X T i m e i n t e r a c t i o n , F 6 ,5 6 = 1 . 4 , P > 0 . 2 3 ] . T h ee f f e c ts o f t h e s e t r e a t m e n t s o n c o r t i c o s t e r o n e l e v e l s p a r al -l e l e d t h o s e o b s e r v e d o n t h e l o c o m o t o r r e s p o n s e t o c o c a i n e .O v e r a l l , a s F i g . 2 s h o w s , f o o d r e s t r i c t i o n s i g n i f i c a n t l yi n c r e a se d p l a s m a l e v e l s o f c o r t ic o s t e ro n e ( V E H I C L E F Rv s . V E H I C L E , P < 0 . 0 1 ) a n d m e t y r a p o n e t r e a tm e n t r e -v e r s e d t h is ef f e ct s . T h u s , t h e M E T Y F R g r o u p s h o w e dl o w e r l e v e l s o f c o r ti c o s te r o n e th a n V E H I C L E F R r at s( P < 0 .0 0 1 ) b u t d i d n o t d i ff e r f r o m t h e V E H I C L E g r o u p .F u r t h e r m o r e , m e t y r a p o n e a l s o d e c r e a s e d c o r t i c o s t e r o n e s e -c r e t i o n i n c o n t r o l r a t s . T h u s , a n i m a l s i n t h e M E T Y g r o u ps h o w e d l o w e r l e v e ls o f t h e h o r m o n e t h a n a n i m a l s i n th eV E H I C L E g r o u p ( P < 0 .0 5 ).

T h e r e s u l ts o f t h is s t u d y i n d i c a t e t h a t th e e n h a n c e m e n ti n th e p s y c h o m o t o r a c t i v a t i n g e f fe c t s o f c o c a i n e p r o d u c e db y a c h r o n i c s t r e s s c an b e r e v e r s e d b y a n a c u t e r e d u c t i o no f c o r t i c o s t e r o n e s e c r et i o n . A n i m a l s s u b j e c t e d t o f o o dr e s t r ic t i o n s h o w e d a n e n h a n c e d s e n s i t i v it y t o th e p s y -c h o m o t o r a c t i v a t i n g e f fe c t s o f c o c a i n e a n d a n e n h a n c e dc o r t i c o s t e r o n e s e c r e ti o n . T h e a c u t e a d m i n i s t r a ti o n o f t h ec o r t i c o s t e r o n e s y n t h e s i s i n h i b i t o r m e t y r a p o n e r e v e r s e dt h e s e e f f ec t s . T h u s f o o d - r e s t r i c t e d a n i m a l s t r e a t e d w i t hm e t y r a p o n e s h o w e d t h e s a m e a m o u n t o f c o c a i n e -i n d u c e dl o c o m o t o r a c t i v i t y a n d c o r t i c o s t e r o n e s e c r e t i o n a s a d l i b i -t u r n - f ed c o n t r o l r a t s. T h i s p a r a l l e l b e t w e e n c o r t i c o s t e r o n es e c r e t io n a n d l o c o m o t o r r e s p o n s e t o c o c a i n e i s a ls o s u p -p o r t e d b y t h e r e s u l t s o b t a i n e d i n c o n t r o l r a t s . A c u t e b l o c k -a d e o f c o r t i c o s t e r o n e s e c r e t i o n i n c o n t r o l , a d l i b i t u m - f e dr a ts , a l s o d e c r e a s e d t h e p s y c h o m o t o r e f f e c t o f co c a i n e , a n dt h i s e f f e c t w a s a c c o m p a n i e d b y a s i g n i f i c a n t r e d u c t i o n i np l a s m a c o r t i c o s t e r o n e l e v e l s . D e s p i t e t h e e f f e c t s o n c o -c a i n e - i n d u c e d l o c o m o t i o n a n d c o r t i c o s t e r o n e s e c r e t i o n ,n e i t h e r fo o d r e s t r i c t i o n n o r m e t y r a p o n e t r e a t m e n t s h a d a n ye f f e c t o n l o c o m o t o r a c t i v i ty p r o d u c e d b y a n i n j e c t i o n o fs a l i n e . T h i s s u g g e s t s t h a t th e e f f e c t s o f t h e s e t r e a t m e n t s o nc o c a i n e - i n d u c e d a c t i v a t i o n a r e n o t d u e t o a n o n - s p e c i f i ca c t i o n o n m o t o r a b i l i t ie s . T h e s e r e s u lt s c o n f i r m a n d e x t e n dp r e v i o u s f i n d i n g s i n d i c a t i n g t h a t t h e e n h a n c e m e n t i n d r u ge f f e c t s i n d u c e d b y s t r e s s d e p e n d s o n a n i n c r e a s e i n c i r c u -l a t in g l e v e l s o f c o r t i c o s te r o n e .


4/5

2 5 4 M. Marinelli e t al. / Brain Research 724 (1996) 251 255

Th e me c h a n is m b y wh ic h c o r t ic o s t e r o n e in c r e a s e s t h eresponse to cocaine is st ill not clear. In recent studies, wedetermined that the e f fect of cort icos terone is not due toc h a n g e s in c o c a in e p h a r ma c o k in e t ic s . Ne i t h e r me t y r a p o n etreatment , c ort icos terone adm inis trat ion, or adrenalectom yhad any e f fect on brain leve ls of cocaine [30 ,31] . Further-more , sens it iv ity to behavioral e f fect s of psychost imulantsi s e q u a l ly c o n t r o l l e d b y c o r t i c o s t e r o n e wh e n p s y c h o s t imu -lant drugs are e ither injected sys temical ly or direct ly inrelevant brain areas [12,29] .

Cort icos terone could modify s tress - induced sens it iza-t ion to psychost imulants by act ing direct ly on the neuralsubstrates that mediate sens it izat ion o f the psyc hom otorand re inforc ing e f fect s of cocaine . In this respect theme s e n c e p h a l ic d o p a min e r g ic n e u r o n s a r e g o o d c a n d id a t e s .An e n h a n c e me n t o f t h e r e s p o n s e o f t h e s e n e u r o n s t opsychost imulants is cons idered the main neural substrateof sens it izat ion ( for review see [24 ,45 ,46] ) . Several datasupport an interact ion between g lucocort ico ids andd o p a min e in b e h a v io r a l s e n s i t i z a t io n . Do p a min e r g ic n e u -rons express g lucocort ico id receptors [19] and an increasein g lu c o c o r t ic o id l e v e l s s e e ms a b le t o in c r e a s e d o p a min e r -g ic act iv ity . These hormones inhibit DA reuptake [17] ,reduce dopamine catabolism [47 ,54] and increase extrace l-lu lar concentrat ions of d opam ine [22 ,41] . In paral le l , ar e d u c t io n o f g lu c o c o r t ic o id s in c r e a s e s DA c a t a b o l i s m [ 5 ]and blocks the sens it izat ion- induced increase in thedopaminergic response to cocaine [48] . Of course ,dopaminergic sys tems do not operate in iso lat ion andcort icos terone could act through many other neuronal sub-s trates such as GABA, 5-HT, exc itatory amino ac ids ando p io id s . Glu c o c o r t ic o id s h a v e b e e n s h o wn t o mo d i f y t h eact iv ity of these neurotransmit ters [2 ,9 ,2 7 ,28 ,3 2 ,49 ,52 ,53 ]wh ic h , in t u r n , c a n mo d u la t e d o p a min e - d e p e n d e n t b e -haviours [23 ,25 ,42 ,50] .

In conclus ion, the increase in the e f fect s o f c o c a i n ep r o d u c e d b y a chronic s t r e s s c a n b e r e v e r s e d b y a n acutep h a r m a c o l o g i c a l i n h i b i t io n o f c o r t i c o s t e r o n e s e c r e ti o n . Th iss tudy provides further ev idence that the enhancement indrug ef fect s produced by s tress depends on an increase incort icos terone leve ls . S ince s tress - induced sens it izat ion isc o n s id e r e d o n e o f t h e c o n d i t io n s p r e d i s p o s in g t o d r u gabuse , the present result s might have implicat ions for thetreatment of addiction.

A c k n o w l e d g e m e n t s

This work was supported by Ins t itut Nat ional de laS a n t 6 e t d e la Re c h e r c h e M 6 d ic a le ( I NS ERM ) , Un iv e r s i t 6d e Bo r d e a u x I I, Co n s e i l Rd g io n a l d 'Aq u i t a in e , P6 1 e M ~ d i -cament d'Aquita ine , Minis t~re de la Recherche e t de FEn-s e ig n e me n t S u p &ie u r . W e t h a n k Dr . T . E . Ro b in s o n f o rhelpful comments on an ear l ier vers ion of th is manuscr ipt .

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5/5

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[2 6] M a c c a r i , S . , P i a z z a , P .V . , De m i n i ~ re , J . M . , L e m a i r e , V . , M o rm ~ d e ,P . , S i m o n , H . , An g e l u c c i , L . a n d L e M o a l , M . , L i f e e v e n t s - i n d u c e dd e c re a s e o f t y p e I c o r t i c o s t e ro d r e c e p t o r s i s a s s o c i a t e d w i t h r e d u c e dc o r t i c o s t e ro n e f e e d b a c k a n d e n h a n c e d v u l n e ra b i l i t y t o a m p h e t a m i n es e l f - a d m i n i s t r a t i o n , B ra i n R e s . , 5 4 7 ( 1 9 9 1 ) 7 - 1 2 .

[2 7] M a j e w s k a , M . D. , A n t a g o n i s t - t y p e i n t e r a c ti o n o f g l u c o c o r t i c o i d s w i t ht h e G A B A r e c e p t o r -c o u p l e d c h l o ri d e c h a n n e l , B ra i n R e s . , 4 1 8 (1 9 8 7 )3 7 7 - 3 8 2 .

[2 8 ] M a j e ws k a , M . D. , Ha r r i s o n , N . L . , S c h wa r t z , R . D . , B a rk e r , J . L . a n dP a u l , S . M . , S t e ro i d h o rm o n e m e t a b o l i t e s ar e b a rb i t u r a t e- l i k e m o d u l a -t o r s o f t h e G A B A r e c e p to r s , S c i e n c e , 2 3 2 (1 9 8 6 ) 1 0 0 4 -1 0 0 7 .

[2 9] M a r i n e l l i , M . , P i a z z a , P .V . , De ro c h e , V . , M a c c a r i , S . , L e M o a l , M .a n d S i m o n , H . , C o r t i c o s t e ro n e c i r c a d ia n s e c re t i o n d i f f e r e n t ia l l y f a ci l -i t at e s d o p a m i n e - m e d i a t e d p s y c h o m o t o r e f f e c t o f c o c a i n e a n d m o r -p h i n e , J . N e u ro sc i . , 1 4 (1 9 9 4 ) 2 7 2 4 -2 7 3 1 .

[3 0 ] M a r i n e l l i , M . , R o u g 6 -P o n t , F . , De J e s u s -Ol i v e i r a , L e M o a l , M . a n dP i a z z a , P . V . , Ac u t e b m o c k a d e o f c o r t i c o s t e ro n e s e c re t i o n d e c re a s e st h e p s y c h o m o t o r a c t i v a t i n g e f f e c t s o f c o c a i n e , S u b m i t t e d .

[3 1] M a r i n e l li , M . , R o u g 6 -P o n t , F . , L e M o a l , M . a n d P i a z z a , P . V . ,In f l u e n c e o f c o r t i c o s t e ro n e o n t h e p s y c h o m o t o r e f f e c t s o f c o c a i n e : ad o s e - r e s p o n s e s t u d y . A n n u a l M e e t i n g o f t h e S o c i e ty f o r N e u r o -sc i e n c e , Ab s t r . 7 6 6 . 6 (1 9 9 5 ) .

[32] Mart i re , M. , P i s t r i t to , G. and Prez ios i , P . , Di ff e ren t regula t ion ofs e ro t o n i n r e c e p t o r s fo l l o wi n g a d re n a l h o rm o n e i m b a l a n c e i n r a th i p p o c a m p u s , J . N e u ra l T ra n sm . , 7 8 ( 1 98 9 ) 1 0 9 - 1 2 0 .

[3 3 ] M i c z e k , K . A . , V i v i a n , J . A . a n d Va l e n t i n e , J . O . , S o c i a l s t r e s s : c o -c a i n e r e i n fo rc i n g a n d s t i m u l u s e f f e c t s . A n n u a l M e e t i n g o f t h e S o c i-e t y f o r N e u r o s c i e n c e , Ab s t r . 2 4 8 . 9 (1 9 9 4 ) .

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[3 5 ] P i a z z a , P . V . , De m i n i ~ re , J . M . , L e M o a l , M . a n d S i m o n , H . , F a c t o r st h a t p r e d i c t i n d i v i d u a l v u l n e ra b i l i t y t o a c q u i s i t i o n o f a m p h e t a m i n es e l f - a d m i n i s t r a t i o n , S c i e n c e , 2 4 5 (1 9 8 9 ) 1 5 1 1 -1 5 1 3 .

[3 6 ] P i a z z a , P . V . , De m i n i ~ re , J . M . , L e M o a l , M . a n d S i m o n , H . , S t r e s s -a n d p h a rm a c o l o g i c a l l y - i n d u c e d b e h a v i o ra l s e n s i t i z a t i o n i n c re a s e sv u l n e ra b i l i t y t o a c q u i s i t i o n o f a m p h e t a m i n e s e l f - a d m i n i s t r a t i o n ,B ra i n R e s . , 5 1 4 ( 1 9 9 0 ) 2 2 - 2 6 .

[3 7] P i a z z a , P .V . , De m i n i ~ re , J .M . , M a c c a r i , S ., L e M o a l , M . , M o rm ~ d e ,P . a n d S i m o n , H . , I n d i v i d u a l v u l n e ra b i l i t y t o d ru g s e l f - a d m i n i s t r a -t i o n : a c t i o n o f c o r t i c o s t e ro n e o n d o p a m i n e rg i c s y s t e m s a s a p o s s i b l ep a t h o p h y s i o l o g i c a l m e c h a n i s m . In P . W i l l n e r a n d J . S c h e e l -Kr t i g e r(E d s . ) T h e M e s o l i m b i c D o p a m i n e S y s t em : F r o m M o t i v at i o n t o A c -t ion, W i l e y , C h i c h e s t e r , 1 9 9 1 , p p . 4 7 3 -4 9 5 .

[3 8] P i a z z a , P . V . a n d L e M o a l , M . , P a t h o p h y s i o l o g i c a l b a s is o f v u l n e ra -b i l i ty t o d ru g a b u s e : r o l e o f a n i n t e r a c t io n b e t w e e n s t r e s s , g l u c o c o r t i -c o i d s , a n d d o p a m i n e rg i c n e u ro n s , A n n . R e v . P h a rm a c o l . T o x i c o l . ,3 6 ( 1 9 9 6) 3 5 9 - 3 7 8 .

[3 9] P i a z z a , P .V . , M a c c a r i , S . , De m i n i ~ re , J . M . , L e M o a l , M . , M o rm ~ d e ,P . a n d S i m o n , H . , C o r t i c o s t e ro n e l e v e ls d e t e rm i n e i n d i v i d u a l v u l n e r -a b i l i t y t o a m p h e t a m i n e s e l f - a d m i n i s t r a t i o n , Proc . Na t l . Acad . Sc i .USA , 8 8 ( 1 9 9 1 ) 2 0 8 8 - 2 0 9 2 .

[4 0 ] P i a z z a , P . V . , M a r i n e l l i , M . , J o d o g n e , C . , De ro c h e , V . , R o u g E -P o n t ,F . , M a c c a r i , S . , L e M o a l , M . a n d S i m o n , H . , I n h i b i t i o n o f c o r t i c o -s t e ro n e s y n t h e s i s b y m e t y ra p o n e d e c re a s e s c o c a i n e - i n d u c e d l o c o m o -t i o n a n d r e l a p s 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 , B ra i n R e s . , 6 5 8( 1 9 9 4 ) 2 5 9 - 2 6 4 .

[4 1] P i a z z a , P .V . , R o u g 6 -P o n t , F . , De ro c h e , V . , Kh a ro u b y , M . , L e M o a l ,M . a n d S i m o n , H . , C o r t i c o s t e ro n e s e n s i t i v it y to d r a g s o f a b u s e : r o l eo f d o p a m i n e r e l e a s e . A n n u a l M e e t i n g o f t h e S o c i e ~ ' f o r N e u r o -sc i e n c e , Abst r . 760.14 (1993) .

[4 2] P u l v i r e n t i, L . , S we rd l o w , N . R . , Hu b n e r , C . B . a n d K o o b , G . F . , T h ero l e o f l i m b i c -a c c u m b e n s -p a l l i d a l c i r c u i try i n t h e a c t i v a t in g a n dre i n fo rc i n g p ro p e r t i e s o f p s y c h o s t i m u l a n t d ru g s . I n P . W i l l n e r a n d J .S c h e e l -Kr i J g e r (E d s . ) , T h e M e s o l i m b i c D o p a m i n e S y s t e m : F r o mM o t i v a t i o n t o A c t i o n , W i l e y , C h i c e s t e r , 1 9 9 1 , p p . 1 3 1 -1 3 9 .

[4 3 ] R o b i n s o n , T . E . , S t i m u l a n t d ru g s a n d s t r e s s : fa c t o r s i n f l u e n c i n gi n d i v i d u a l s u s c e p t i b i l i t y t o s e n s i t i z a t i o n . I n P . W . Ka l i v a s a n d C .B a rn e s (E d s . ) , S e n s i t i za t i o n o f t h e N e rv o u s S y s t e m , T e l fo rd P re s s ,C a l d we l l , NJ , 1 9 8 8 , p p . 1 4 5 -1 7 3 .

[4 4 ] R o b i n s o n , T . E . , An g u s , A . L . a n d B e c k e r , J . B . , S e n s i t i z a t i o n t os t r e s s : t h e e n d u r i n g e f f e c t s o f p r i o r s t r e s s o n a m p h e t a m i n e - i n d u c e dro t a t io n a l b e h a v i o r , Li f e Sc i . , 3 7 (1 9 8 5 ) 1 0 3 9 -1 0 4 2 .

[4 5 ] R o b i n s o n , T . E . a n d B e c k e r , J . B . , E n d u r i n g c h a n g e s i n b r a i n a n db e h a v i o r p ro d u c e d b y c h ro n i c a m p h e t a m i n e a d m i n i s t r a t i o n : a r e v i wa n d e v a l u a ti o n o f a n i m a l m o d e l s o f a m p h e t a m i n e p s y c h o s i s , B ra i n .R e s . R e v . , 1 1 (1 9 8 6 ) 1 5 7 -1 9 8 .

[4 6 ] R o b i n s o n , T . E . a n d B e r r i d g e , K . C . , T h e n e u ra l b a s i s o f d ru g c r a v -i n g : a n i n c e n t i v e s e n s i t i z a ti o n t h e o ry o f a d d i c t i o n , B ra i n R e s . R e v . ,1 8 (1 9 9 3 ) 2 4 7 -2 9 1 .

[4 7 ] R o t h s c h i l d , A . J . , L a n g l a i s , P . J . , S c h a t z b e rg , A . F . , M i l l e r , M . M . ,S a l o m a n , M . S . , L e rb i n g e r , J . E . , C o l e , J . O . a n d B i rd , E . , T h e e f f e c to f a s i n g le a c u te d o s e o f d e x a m e t h a s o n e o n m o n o a m i n e a n d m e t a b o -l i t e l eve ls in the ra t bra in , Li f e Sc i . , 3 6 ( 1 9 85 ) 2 4 9 1 - 2 5 0 5 .[4 8 ] R o u g 6 -P o n t , F . , M a r i n e l l i , M . , L e M o a l , M . , S i m o n , H . a n d P i a z z a ,P . V . , S t r e s s - i n d u c e d s e n s i t i z a ti o n a n d g l u c o c o r t i c o i d s . I I . S e n s i t i z a-t i o n o f t h e i n c re a s e i n e x t r a c e l l u l a r d o p a m i n e i n d u c e d b y c o c a i n ed e p e n d s o n s t r e s s - i n d u c e d c o r t i c o s t e ro n e s e c ret i o n , J . N e u ro sc i . , 15( 1 9 9 5 ) 7 1 8 9 - 7 1 9 5 .

[4 9 ] S a p o l s k y , R . M . , G l u c o c o r t i c o i d s , h i p p o c a m p a l d a m a g e a n d t h e g l u -t a m a t e rg i c s y n a p s e , P ro g . B ra i n R e s . , 8 6 (1 9 9 0 ) 1 2 -2 3 .

[5 0] S c h e e l -Kr i i g e r , J . , M a g e l u n d , G . a n d O l i a n a s , M . C . , R o l e o f GAB Ai n t h e s t r i a t a l o u t p u t s y s t e m : g l o b u s p a l l i d u s , n u c l e u s e n t o p e d u n c o -l a r i s s u b s t a n t i a n i g ra a n d n u c l e u s s u b t h a l a m i c u s . I n G . D i C h i a raa n d G . L . Ge s s a (E d s . ) , G A B A a n d t h e B a sa l G a n g l i a , R a v e n P re s s ,Ne w Yo rk , 1 9 8 1 , p p . 1 6 5 -1 8 6 .

[5 1] S c h e n k , S . , L a c e l le , G . , Go rm a n , K . a n d Am i t , Z . , 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 n r a t s i n f l u e n c e d b y e n v i ro n m e n t a l c o n d i t i o n s : im p l i c a -t i o n s fo r t h e e t i o l o g y o f d ru g a b u s e , N e u ro sc i . L e t t . , 81 (1987)2 2 7 - 2 3 1 .

[5 2 ] S u t a n t o , W . , Ha n d e l m a n , G . , De B re e , F . a n d De Kl o e t , E . R . ,M u l t i f a c e t e d i n t e r a c t i o n o f c o r t i c o s t e ro i d s w i t h t h e i n t r a c e ll u l a r r e -c e p t o r s a n d w i t h m e m b r a n e G A B A - A r e c e p t o r c o m p l e x i n t h e r a tbra in . , J . N e u ro e n d o c r i n o l . , 1 ( 1 9 8 9 ) 2 4 3 - 2 4 7 .

[5 3] T i s c h l e r , M . E . , He n r i k s e n , E . J . a n d C o o k , P . H . , R o l e o f g l u c o c o r t i -c o l d s i n i n c re a s e d m u s c l e g l u t a m i n e p ro d u c t i o n i n s t a rv a t i o n , M u s -c l e N e rv e , 1 1 (1 9 8 8 ) 7 5 2 -7 5 6 .

[5 4 ] Ve a l s , J . W . , Ko rd u b a , C . A . a n d S y m c h wi c z , S . , E f f e c t o f d e x a -m e t h a s o n e o n m o n o a m i n e o x i d a s e i n h i b i t i o n b y i p ro n i a z i d i n r a tbra in , E u r . J . P h a rm a c o l . , 4 1 ( 1 9 7 7 ) 2 9 1 - 2 9 9 .

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