Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission

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1 Proc. Ntl. Acd. Sci. USA Vol. 93, pp , August 1996 Neurobiology Glucocorticoids hve stte-dependent stimulnt effects on the mesencephlic dopminergic trnsmission (drug buse/corticosterone/nucleus ccumbens/individul differences/microdilysis) PIR VINCNZO PIAZZA*, FRAN(OIS ROUG'-PONT, VRONIQU DROCH, STFANIA MACCARI, HRVI SIMON, AND MICHL L MOAL Lbortoire de Psychobiologie des Comportements Adpttifs, Institut Ntionl de l Snte et de l Recherche Medicl Unite 259, Universite de Bordeux II, Domine de Crreire, Rue Cmille Sint-Sens, 3377 Bordeux Cedex, Frnce Communicted by Louis Sokoloff, Ntionl Institutes of Helth, Bethesd, MD, April 26, 1996 (received for review Jnury 12, 1996) ABSTRACT An increse in the ctivity of mesencephlic dopminergic neurons hs been implicted in the ppernce of pthologicl behviors such s psychosis nd drug buse. Severl observtions suggest tht glucocorticoids might contribute to such n increse in dopminergic ctivity. The present experiments therefore nlyzed the effects of corticosterone, the mjor glucocorticoid in the rt, both on dopmine relese in the nucleus ccumbens of freely moving nimls by mens of microdilysis, nd on locomotor ctivity, behvior dependent on ccumbens dopmine. Given tht glucocorticoids hve certin stte-dependent neuronl effects, their ction on dopmine ws studied in situtions differing in dopminergic tonus, including during the light nd drk phses of the circdin cycle, during eting, nd in groups of nimls differing in their locomotor rectivity to novelty. Dopminergic ctivity is incresed in the drk period, further incresed during food-intke, nd is higher in rts defined s high responders to novelty thn in low responders. Corticosterone, peripherlly dministered in dose tht pproximtes stress-induced plsm concentrtions, incresed extrcellulr concentrtions of dopmine, nd this increse ws ugmented in the drk phse, during eting, nd in high responder rts. Corticosterone hd little or no effects in the light phse nd in low responder rts. Corticosterone lso stimulted locomotor ctivity, n effect tht prlleled the relese of dopmine nd ws bolished by neurochemicl (6-hydroxydopmine) depletion of ccumbens dopmine. In conclusion, glucocorticoids hve stte-dependent stimulnt effects on mesencephlic dopminergic trnsmission, nd n interction between these two fctors might be involved in the ppernce of behviorl disturbnces. It is generlly dmitted tht n increse in the ctivity of the mesencephlic dopminergic (DA) neurons is relted to the ppernce of pthologicl behviors. The mjor ntipsychotic drugs re ntgonists of DA receptors (1) nd prolonged use of psychotropic compounds known to increse DA ctivity cn induce psychotic symptoms (2). Furthermore, n enhnced DA ctivity in the nucleus ccumbens is ssocited with n incresed vulnerbility to develop drug self-dministrtion in lbortory rts (3). Indirect observtions suggest tht glucocorticoids, the finl product of the ctivtion of the hypothlmus-pituitrydrenl xis by stress, might be one fctor cpble of incresing the ctivity of mesencephlic DA neurons. DA neurons express corticosteroid receptors (4) nd dopmine-medited behviors re profoundly fcilitted by glucocorticoids (5). Furthermore, incresed glucocorticoid levels cn induce behviorl chnges similr to those ttributed to enhnced DA ctivity. In humns, high levels of glucocorticoids cn induce The publiction costs of this rticle were defryed in prt by pge chrge pyment. This rticle must therefore be hereby mrked "dvertisement" in ccordnce with 18 U.S.C solely to indicte this fct. mood chnges rnging from euphori to psychosis (6, 7). In nimls, glucocorticoids, within the rnge of stressor-induced plsm concentrtions, increse the propensity to develop self-dministrtion of drugs of buse (8). The experiments reported here exmine the direct effect on dopmine of n increse in glucocorticoid levels mimicking tht induced by physiologicl stressor. Behviorl nd biochemicl indictors of the DA response to corticosterone were nlyzed in experimentl situtions known to differ with respect to the ctivity of the midbrin DA system. This experimentl setting ws chosen becuse glucocorticoids hve certin stte-dependent neuronl effects. In prticulr, electrophysiologicl dt suggest tht glucocorticoid effects depend on bckground neuronl ctivity (9). For exmple, glucocorticoids modify the membrne potentil of hippocmpl CAl cells in slice preprtion when these neurons re in depolrized stte, but hve no effect in resting conditions (9). In the first experiment, behviorl nd biochemicl DA effects of glucocorticoids were compred in the light nd drk phses of the circdin cycle, nd DA ctivity ws higher in the drk thn in the light phse (1). In the second experiment, the effects of glucocorticoids were studied during eting nd drinking, given tht DA ctivity further increses during these behviorl ctivities (11). In the third experiment, the behviorl nd biochemicl effects of glucocorticoids were studied in groups of nimls further differing in DA ctivity. For this purpose, rts seprted on the bsis of their behviorl rectivity to novelty were compred. As such, high responder rts (HRs) demonstrte higher behviorl response to stress nd psychostimulnt drugs (12) nd hve higher DA ctivity in comprison with low responder rts (LRs) (13, 14). In the experiments outlined bove, corticosterone-induced chnges in locomotion nd dopmine relese in the nucleus ccumbens hve been nlyzed. A behvior t lest prtilly dependent on nucleus ccumbens dopmine (15), locomotion ws studied in nimls either with n intct or with lesioned mesoccumbens DA projection. Dopmine relese ws estimted by mesuring chnges in extrcellulr concentrtions of dopmine in the nucleus ccumbens of freely moving rts using the microdilysis technique. Generl Methods MTHODS AND MATRIALS Animls nd Housing Conditions. Mle Sprgue-Dwely rts (Iff Credo) weighing 28-3 g were individully housed with d libitum ccess to food nd wter. The light/drk cycle (lights were on from 6.m. to 8 p.m.), temperture (22 C), nd humidity (6%) were kept constnt in the niml house. Abbrevitions: HR, high responder; LR, low responder; 6-OHDA, 6-hydroxy-dopmine; DA, dopminergic. *To whom reprint requests should be ddressed. 8716

2 Neurobiology: Pizz et L Proc. Ntl. Acd. Sci. USA 93 (1996) 8717 Animls were llowed to cclimte to the niml house for 1 week before experiments were strted. Drugs nd Drug Administrtion. For ll experiments, corticosterone-21-hemisuccinte (Agrr, Rome) ws used nd concentrtions were expressed s corticosterone bse. Corticosterone ws dministered either intrvenously (.75 mg/kg dissolved in.9% NCl sline solution) or orlly (1,tg/ml dissolved in tp wter). NCl (.9%) nd tp wter were lso used s vehicles for mtched controls. Locomotor Response to Corticosterone. Locomotor response to corticosterone ws evluted in ctivity boxes (35 x 37.5 cm bse, 5-cm high). A locomotor ctivity count ws recorded ech time rt crossed the full distnce (15 cm) between photocells locted on ech of the two long sides. Constitution of High nd Low Responder Groups. One dy t 4 p.m., before ny other experimentl mnipultion, nimls were plced in novel environment ( circulr corridor, 1 cm wide nd 7 cm in dimeter). Locomotor ctivity scores (expressed in photocell counts) ccumulted over 2 hr were used to divide rts into two-groups: (i) HR (rts with ctivity scores bove the medin of the whole group) nd (ii) LR (the reminder of the rts). This selection criteri is identicl to the one used to demonstrte differences between the HR nd LR groups in DA ctivity (13, 14), psychostimulnt-induced locomotion, nd self-dministrtion (12). Ctheter Implnttion. Animls were implnted with intrcrdic ctheters (Silstic, 8 ALI ded volume) under ether nesthesi nd llowed t lest 1 week of postopertory recovery. During this period, the ctheter ws filled with heprin solution (1 units/ml). Lesion of the Meso-DA Terminls. Under chlorl hydrte nesthesi (5 mg/kg, i.p.), rts were plced in stereotxic pprtus nd injected (over 4 min) bilterlly with either 1,ul of 6-hydroxydopmine (6-OHDA) solution (4,tg/Iul) or 1,lI of vehicle (.9% NCl contining scorbic cid,.2 mg/ml). The coordintes of injection were A = 2.3 mm, L = 1.7 mm, V = 7.5 mm nd were mesured from bregm (16); the incisor br ws plced 5 mm bove the interurl line. One hour before the lesion, rts were injected with desiprmine (25 mg/kg, i.p.) to protect the nordrenergic system from the neurotoxin. Nucleus ccumbens concentrtions (nnogrms per milligrm of protein) of nordrenline, dopmine, nd serotonin were mesured in brin tissue by high-pressure liquid chromtogrphy (HPLC) with electrochemicl detection. Microdilysis. Under sodium pentobrbitl nesthesi (5 mg/kg, i.p.), rts were implnted with guide cnnul (CMA/ 11-Sweden) tht ws lowered to 2 mm bove the nucleus ccumbens. The coordintes reltive to bregm were A = 3.6 mm, L = 2. mm, V = 6.5 mm, t lterl ngle of 6 (16). After t lest 1 dys of recovery, the microdilysis probe (CMA/11, 2-mm membrne length) ws inserted through the guide cnnul. Two dys lter, the niml ws trnsferred to the dilysis cge (31 x 31 cm bse, 47 cm high), the probe ws connected to syringe pump (Hrvrd 22) vi two-chnnel swivel, nd the perfusion (2 Al per min) strted. Brin dilysis ws performed with fully utomtic on-line system (13). HPLC coupled to coulometric detector (Coulochem II, SA, Bedford, MA) ws used to detect dopmine (.5 pg detection limit). xperimentl mnipultions were begun fter three consecutive dilyste smples showed less thn 1% vrition in pek height. The verge dopmine bsl level of ll experimentl nimls ws.296 ±.15 pg/la (1.926 nm). Results were expressed s percentges of bseline (the verge of the lst three pretretment vlues). At the end of the experiments, cnnul plcements were verified histologiclly on 5,um thionin-stined coronl sections. Sttistics. Locomotor ctivity scores, chnges in extrcellulr dopmine concentrtions, nd corticosterone levels were compred by nlyses of vrince (ANOVA) for repeted mesures. For the studies of corticosterone-induced locomotion fter 6-OHDA lesion nd HRs/LRs, within-subject design ws used. For ll other nlyses, the tretment (two levels: vehicle nd corticosterone) ws used s between fctor. Procedures DA Responses to Corticosterone in the Light nd Drk Periods. Corticosterone-induced locomotion. Animls were plced in the ctivity cges for 2-hr hbitution period nd were infused fterwrd with either sline (n = 8) or corticosterone (.75 mg/kg; n = 8) two times: once in the drk period (9 p.m.) nd once in the light period (11.m.). 6-OHDA (n = 8) nd shm-lesioned rts (n = 8) received infusions in the drk period, over 2 dys, of either sline or corticosterone. For both experiments, ltin squre design ws used. Two dditionl groups of rts were infused in the light period with either 1.5 mg/kg corticosterone (n = 8) or sline (n = 8). Infusions were performed through the intrcrdic ctheter connected to polyethylene tube (4 cm long), which ws disconnected t the end of the infusion. Corticosterone-induced chnges in extrcellulr concentrtions ofdopmine. After 2 hr of hbitution to the dilysis cge, groups of rts were infused s described bove either in the light period (11.m.) [sline, n = 4; corticosterone (.75 mg/kg), n = 4] or in the drk period (9 p.m.) [sline, n = 4; corticosterone (.75 mg/kg), n = 5]. xtrcellulr concentrtions of dopmine were mesured for 2 hr over 2 min smples (4 pul). DA Response to Corticosterone During ting nd Drinking. Animls were brought to the dilysis room in their home cge 48 hr before the test nd connected to dummy perfusion pprtus to llow hbitution to the test condition. Two hours before the beginning of the drk period, the perfusion of the microdilysis probe strted nd drinking bottles were withdrwn. When three dopmine smples showed vrition of less thn 1%, hlf of the nimls (n = 8) received tp wter nd the other hlf (n = 1) received corticosterone solution (1,ug/ml). The three smples preceding the strt of drinking for ech niml were considered the bseline, nd vritions of extrcellulr dopmine concentrtions nd the mount of fluid consumed were mesured for 6 hr every 3 min. Corticosterone ws dissolved in the drinking wter to ensure tht its dministrtion ws contingent upon eting nd drinking, becuse they re strictly ssocited in the rodent (17). Furthermore, preliminry experiments hve shown tht spontneous eting is disrupted by the mnipultions necessry to perform prenterl injection. DA Response to Corticosterone in HR nd LR Rts. Corticosterone-induced locomotion. Corticosterone-induced locomotion ws studied only in the drk period. With procedure identicl to those previously described nd fter ltin squre design, HR (n = 8) nd LR (n = 8) nimls were infused intrvenously over 2 dys with either sline or corticosterone (.75 mg/kg). Corticosterone-induced chnges in extrcellulr concentrtions of dopmine. Corticosterone ws dministered in the drinking wter (1 mg/ml; HRs, n = 5; LRs, n = 5) ccording to procedure identicl to tht previously described. ffects of Corticosterone Administrtion on the Plsmtic Levels of the Hormone. Intrvenous infusion. Animls were implnted with two intrcrdic ctheters, one in ech jugulr vein. One ctheter ws used to infuse either corticosterone (.75 mg/kg; n = 8) or sline (n = 8), the other ws used to withdrw two blood smples, the first immeditely before the infusion (9 p.m.) nd the second 2 min lter. Orl dministrtion. One hour before the strt of the drk period, nimls were given either solution of corticosterone (1,ug/ml; n = 6) or tp wter (n = 6) in the drinking bottle of their home cge. The mount of liquid consumed ws recorded every 3 min nd blood smple ws withdrwn from

3 8718 Neurobiology: Pizz et l. the til vein 4 hr fter the nimls strted drinking. The totl mount of food intke over this period ws lso recorded. The smpling schedules of the two experiments were chosen becuse they correspond to the pek of corticosterone's effects on dopmine. RSULTS DA Responses to Corticosterone in the Light nd Drk Periods. Corticosterone-induced locomotion. Infusion of corticosterone incresed locomotor ctivity nd this effect ws dependent on the time of the dy [dy period x tretment interction; F(1,14) = 6.21, P <.2] (Fig. 1). A significnt effect of corticosterone ws found only in the drk period [F(1,14) = 5.46, P <.5]. The bsence of effects in the light period cnnot be due to lower plsmtic levels of corticosterone t this time. Infusion of higher dose (corticosterone, 1.5 mg/kg) in the light period did not increse locomotion [corticosterone = , vehicle = photocell counts, F(1,14) =.2, P >.95]. 6-OHDA infusion in the nucleus ccumbens induced n 8% depletion of dopmine content in this structure [F(1,14) = 22.65, P <.1], but did not modify nordrenline nd serotonine contents. The lesion suppressed corticosterone-induced locomotion in the drk period [lesion x tretment interction, F(1,14) = 5.82, P <.5] (Fig. 1). Shm nimls showed higher locomotor response to corticosterone thn to vehicle [F(1,7) = 9.44, P <.1] (dt not shown). In 6-OHDA lesioned rts, corticosterone- nd vehicle-induced locomotion did not differ [F(1,7) = 1.35, P >.3]. Corticosterone-induced chnges in extrcellulr concentrtions ofdopmine. Chnges in the extrcellulr concentrtions of dopmine fter the infusion of vehicle did not differ between the drk nd the light periods [F(1,6) =.45, P >.7]. For this reson, dopmine responses to vehicle were cumulted in Fig. 2. The infusion of corticosterone incresed extrcellulr dopmine [F(1,13) = 7.3, P <.2], but this effect ws dependent on the time of the dy nd chnged over time [dy period x tretment X time interction F(5,65) = 3.32, P <.1] (Fig. 2). During the drk period, the increse in dopmine ws higher in corticosterone- thn in vehicle-infused rts [F(1,11) = 8.21, P <.2], but the two groups did not differ significntly when infused in the light period [F(1,1) = 1.8, P >.2]. DA Response to Corticosterone During ting nd Drinking. Animls drinking the corticosterone solution (1,ug/ml) contingent upon eting showed higher increse in ccumbens dopmine thn nimls drinking vehicle (tp wter) [F(1,16) o 5 _ 3 Vehicle * Corticosterone 84 3 Z2 1 j Intct Intct 6-OHDA Lesion Light Period Drk Period FIG. 1. Corticosterone-induced locomotion during the drk nd light periods. Animls with n intct DA system (Intct) showed higher locomotor response to corticosterone (.75 mg/kg, i.v.) thn to vehicle (.9% NCl) when infused in the drk (9 p.m.) but not in the light (11.m.) period. Corticosterone-induced locomotion ws suppressed in nimls in which the DA terminls in the nucleus ccumbens hd been lesioned (6-OHDA Lesion). *, P <.5, ANOVA with respect to the mtched vehicle group. Proc. Ntl. Acd. Sci. USA 93 (1996) Xj Vehicle T Corticosterone (light) 12 Corticosterone (drk) _ ~~~~~Infusion Time, min FIG. 2. Corticosterone-induced chnges in extrcellulr concentrtions of dopmine in the nucleus ccumbens during the drk nd light periods. Animls infused with.9% NCl in the drk (9 p.m.) nd in the light (11.m.) periods did not differ nd were cumulted in the vehicle group (Vehicle). Animls infused with corticosterone in the drk period (.75 mg/kg, i.v.) [Corticosterone (drk)] showed significnt increse in dopmine. Infusion of corticosterone during the light period [Corticosterone (light)] hd no significnt effects. = 7.86, P <.1] (Fig. 3). However, these nimls did not differ for the totl mount of fluid consumed [corticosterone = ml; tp wter = ± 1.3 ml; F(1,16) = 1.23, P >.25] or for its consumption over time [F(11,176) =.47, P >.7]. Drinking ws eqully distributed over the 6 hr of testing [men intke per hr: corticosterone, ml; tp wter, ml]. DA Response to Corticosterone in HR nd LR Rts. Corticosterone-induced locomotion. HRs nd LRs showed different sensitivity to corticosterone [group x tretment interction, F(1,14) = 7.65, P <.1] (Fig. 4). HRs hd higher corticosterone-induced locomotion thn LRs [F(1,7) = 1.48, P <.1]. Furthermore, in the LR group, corticosterone- nd vehicle-induced locomotion did not differ [F(1,7) =.58, P >.8]. Corticosterone-induced chnges in extrcellulr concentrtions of dopmine. HRs drinking the corticosterone solution (1,tg/ml) showed fster [group x time interction F(11,88) = 2.93, P <.2] nd higher [F(1,8) = 4.65, P <.5] increse in dopmine thn LRs (Fig. 5). The two groups, over the 6 hr of testing, did not differ in their totl intke of the corticosterone solution [HRs = ml, LRs = 14.6 ± 2.8 ml, F(1,8) =.15, P >.7] or in its intke over time [F(11,88) =.88, P >.5]. ffects of Corticosterone Administrtion on the Plsmtic Levels of the Hormone. Intrvenous infusion of corticosterone (.75 mg/kg) significntly rised plsmtic levels of this hormone to within the rnge induced by mild stressors (8) [before ) 'p._ CL Vehicle * Corticosterone 1Strtdrinking Time, hr FIG. 3. Corticosterone-induced chnges in extrcellulr concentrtions of dopmine in the nucleus ccumbens during eting. Animls drinking the corticosterone solution (1,ug/ml) in the drk period during eting (Corticosterone) showed higher increse in dopmine thn nimls drinking tp wter (Vehicle)

4 - 7.' o _ \ Vehicle Corticosterone * * 5i LR Group HR Group FIG. 4. Corticosterone-induced locomotion in HR nd LR nimls. In the drk period (9 p.m.), the HR nd LR groups did not differ in response to the infusion of vehicle (.9% NCl); in contrst, HRs showed higher locomotor response to corticosterone (.75 mg/kg, i.v.) thn LRs. **, P <.1, ANOVA with respect to the mtched vehicle group. infusion = , fter infusion = 19.2 ± 2.12,ug per 1 ml, F(1,7) = 9.52, P <.1], wheres the infusion of vehicle did not [before infusion = , fter infusion = 12.2 ± 1.41,tg per 1 ml, F(1,7) = 1.4, P >.2]. Administrtion of corticosterone in the drinking wter significntly incresed plsm corticosterone [tp wter = 8 + 2, corticosterone = 23.8 ± 6.4 jig per 1 ml, F(1,1) = 5.4, P <.5] to levels tht were similr to those observed fter the intrvenous infusion. Fluid intke over 4 hr in this experiment nd in those studying dopmine did not differ (tp wter = 6.9 ± 1.3 ml nd 8.2 ± 1.2 ml, respectively; corticosterone = 9.8 ± 2. ml nd 1.4 ± 1.3 ml). Food intke in nimls drinking either tp wter or corticosterone lso did not differ. DISCUSSION The results of these experiments indicte tht glucocorticoids stimulte mesoccumbens DA trnsmission nd tht these effects re stte dependent. Corticosterone-induced increses in extrcellulr concentrtions of dopmine were higher in the drk thn in the light period nd higher in HR thn in LR rts. In ddition, in the drk period, dopmine further incresed when the hormone ws dministered contingent upon eting nd drinking. Corticosterone-induced increses in ccumbens dopmine lso hd stimulting behviorl effects, given tht corticosterone incresed locomotion with n intensity tht prlleled its DA effects nd ws without effects in nimls with lesioned DA fferents to the ccumbens. These neurochemicl nd behviorl effects were cused by plsmtic concentrtions of corticosterone within the physiologicl stress rnge. e c. 22 O 2 18 Cc s 4 Neurobiology: Pizz et L ' X J Strt drinking (corticosterone 1 giml) Time, hr I 8 FIG. 5. Corticosterone-induced chnges in extrcellulr concentrtions of dopmine in HR nd LR nimls. HRs drinking the corticosterone solution (1 Zg/ml) in the drk period (HR Group) showed fster nd higher increse in ccumbens dopmine thn LRs (LR Group). Proc. Ntl. Acd. Sci. USA 93 (1996) 8719 These findings confirm nd extend previous dt from the literture indicting tht physiologicl effects of corticosterone my depend on the contingent ctivtion of the centrl nervous system (9, 18, 19). This lrgely neglected feture of corticosterone physiology might in fct be generl principle governing the ction of these hormones on behvior. Indeed, other behviorl effects of corticosterone, such s stimultion of eting behvior, seem to follow similr principle (18). The ctivity level of DA neurons t the time of the increse in plsmtic concentrtions of corticosterone my be the fctor determining the stte-dependent effects of this hormone. It is known tht DA ctivity is higher in the drk thn in the light period (1), increses further during eting (11), nd is higher in HR nimls thn in LRs (13, 14).t This interction between glucocorticoids nd DA ctivity my explin previously reported contrdictory results. Imperto et l. (2) performed their experiments during the light cycle, when DA ctivity is low, nd found no effect of corticosterone on ccumbens extrcellulr dopmine. In contrst, Mittlemn et l. (21) performed their experiment under nesthesi, condition tht increses DA ctivity (22), nd demonstrted cler corticosterone-induced increse in ccumbens extrcellulr dopmine. Three principl mechnisms my medite the elevtion of extrcellulr concentrtions of dopmine induced by corticosterone. First, glucocorticoids my modify the firing of DA neurons. Although there is no direct evidence for such n effect, modultion of membrne potentil in other neuronl popultions by glucocoticoids hs been reported nd these effects, consistently with our findings, depend on bckground electricl ctivity (9). Second, glucocorticoids my decrese dopmine ctbolism by cting s reversible monomino oxidse inhibitor (23-25). This effect is consistent with the fct tht dministrtion of synthetic glucocorticoids decreses deminted products of dopmine, such s HVA nd DOPAC (25, 26), tht depend on monomino oxidse ctivity, while incresing 3MT levels (25). Third, glucocorticoids my decrese ctecholmine reuptke (27, 28). This ction of glucocorticoids seems consistent with the stte dependency reported here, given the evidence tht dopmine reuptke by stritl synptosomes is decresed by glucocorticoids only if the synptosoml preprtion is K+ stimulted, but not in resting conditions (28). On the bsis of the results reported here, it is resonble to suggest tht glucocorticoids might ct s endogenous psychostimulnts. Glucocorticoids shre the neurochemicl ctions of psychostimulnts in tht they both increse extrcellulr concentrtions of dopmine (this pper) nd both seem to exert this effect through inhibition of dopmine reuptke nd inhibition of monomino oxidse ctivity (23-29). At the behviorl level, corticosterone induces self-dministrtion (19) nd dopmine-dependent locomotor ctivity s do psychostimulnts (3). Furthermore, repeted dministrtion of glucocorticoids, like psychostimulnts (3), cn induce psychotic symptomtology in humns (6, 7) nd behviorl sensitiztion in nimls (31). However, glucocorticoids nd psytthe stte-dependent effects of glucocorticoids on dopmine reported here do not pper to be explined by differences in the plsm levels of corticosterone occurring during these different sttes. First, infusion during the light period of doses of corticosterone twice s high s the dose effective in the drk period ws without significnt effects. Second, orl nd intrvenous dministrtions of corticosterone, t the moment of their highest effects on dopmine, induced similr increses in the plsmtic levels of corticosterone. Third, HRs nd LRs do not differ either with respect to their bsl corticosterone levels or their levels fter exogenous corticosterone dministrtion in this nd other experimentl conditions (8, 19). In ddition, dministrtion of corticosterone in the drinking wter does not seem to induce behviorl chnges, s for exmple chnges in drinking nd eting, tht my indirectly ccount for the higher increse in dopmine observed in this condition.

5 872 Neurobiology: Pizz et l. chostimulnts differ in the degree to which their effects re stte dependent. As demonstrted here, stimulnt effects of glucocorticoids re evident only in situtions ssocited with existing behviorl ctivtion, which this hormone mplifies. In contrst, psychostimulnts cn trigger psychomotor ctivtion in situtions in which glucocorticoids cnnot, for exmple, in the light period. A higher sensitivity to the DA effects of glucocorticoids might be relevnt mechnism in the ppernce of pthologicl behviors. Indeed, HR nimls, which hve been demonstrted by these experiments to be more sensitive thn LR rts to the DA effect of corticosterone, re lso known to hve higher behviorl rectivity to stress nd propensity to develop psychostimulnt self dministrtion (3, 8, 12). An interction between glucocorticoids nd dopmine might be prticulrly relevnt for psychostimulnt buse given tht the rewrding effects of these drugs hve been ttributed to their bility to increse nucleus ccumbens dopmine (3). Clinicl observtions lso support the theory tht individul differences in the sensitivity- to glucocorticoids my be involved in behviorl pthology. For exmple, dministrtion of synthetic glucocorticoids induces behviorl disturbnces, such s psychotic symptoms, in only some subjects (6, 7). In ddition, higher sensitivity to certin DA effects of these hormones hs been found ssocited with schizophreni (32); physiologicl concentrtions of glucocorticoids increse DA receptors in the lymphocytes of schizophrenic ptients but not in helthy controls (32). In conclusion, the results of the experiments presented here demonstrte tht glucocorticoids hve stte-dependent stimulnt effects on the ctivity of mesencephlic DA neurons. In physiologicl conditions, through their ction on DA trnsmission, these hormones might ct s endogenous stimulnts nd enhnce behviorl dpttion. In ddition to this dptive physiologicl role, however, n bnorml sensitivity to the DA effects of glucocorticoids in certin individuls might render this dopmine-hormone interction possible cuse of behviorl disturbnces. We thnk Prof. Jne Stewrt for very helpful comments on this mnuscript nd Mrtine Khrouby for precious technicl help. This work ws supported by the Institut Ntionl de l Snte et de l Recherche Medicle, the Universitd de Bordeux II, the Conseil Rdgionl d'aquitine, the P6le Mddicment d'aquitine, nd the Ministere de l Recherche et de l'nseignement Supdrieur. 1. Seemn, P. (1995) in Psychophrmcology: The Fourth Genertion ofprogress, eds Bloom, F.. & Kupfer, D. J. (Rven, New York), pp Robinson, T.. & Becker, J. B.(1986) Brin Res. Rev. 11, Pizz, P. V. & Le Mol, M. (1996) Annu. Rev. Phrmcol. Toxicol. 36, Proc. Ntl. Acd. Sci. USA 93 (1996) 4. 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