michela marinelli et al- corticosterone circadian secretion differentially facilitates...

8/3/2019 Michela Marinelli et al- Corticosterone Circadian Secretion Differentially Facilitates Dopamine-mediated Psychomotor

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The Journal of Neuroscience, May 1994, 1 4(5): 2724-2731

Corticosterone Circadian Secretion Differentially FacilitatesDopamine-mediated Psychomotor Effect of Cocaine and MorphineMichela Marine lli, Pier Vincenzo Piazza, Wronique Deroche, Stefania Maccari, Michel Le Meal, and Herv6SimonPsychobiologie des Comportements Adaptatifs, INSERM U259, Universitk de Bordeaux II, 33077 Bordeaux Cedex, France

Studies of intravenous self-administration and psychomotoreffect s of drugs have recently suggested that stress-in-duced corticosterone secretion may be an important facto rdetermining vulnerability to drugs of abuse. In this report,we studied if basal physiological corticosterone secretionmodulates sens itivi ty to cocaine and morphine, and ifchanges in the reac tivit y o f mesolimbic dopaminergic (DA)neurons, one of the principal substrates of drug-reinforcingeffects, are involved. For this purpose we determined thepsychomotor eff ects of these drugs in animals in which cor-ticosterone secretion was suppressed by adrenalectomy andin adrenalectomized animals submitted to different corti-costerone replacement therapies designed to mimic (1) onlythe diurnal levels of the hormone, obtained by the subcu-taneous implantation of 50 mg corticosterone pellets; (2) onlythe nocturnal levels, obtained by adding corticosterone (50pg/ml) to the drinking solution during the dark period; and(3) the entire circadian fluctuation, obtained by combiningthe two previous treatments. Locomotor response to cocaineand morphine was studied after both systemic and centralinjections, into the nucleus accumbens for cocaine and intothe ventral tegmental area for morphine. These sites werechosen because stimulant eff ects of cocaine and morphineinjected in these structures are dopamine dependent. Ourresults show that suppression of corticosterone by adre-nalectomy reduced the locomotor response to cocaine andmorphine, injected both systemically and centrally. The re-instatement of diurnal levels of corticosterone totally re-versed adrenalectomys eff ects on the behavioral responseto cocaine, whereas the reestablishment of the entire cor-ticosterone circadian fluctuation (diurnal plus nocturnal lev-els) was necessary to reverse the response to morphine. Inconclusion, our results indicate that physiological cortico-sterone secretion facilitates dopamine-mediated locomotoreffect s of cocaine and morphine. Since stimulant ef fec ts andactivation of DA mesencephalic neurons by these drugs arerelated to their reinforcing properties, an interaction betweencorticosterone and dopamine may be part of the patho-physiological mechanism underlying vulnerability to drugabuse.Received Aug. 3 1, 1993; accepted Oct. 19, 1993.

This work was supported by 1Institut National de la Sante et de la RechercheMedicale (INSERM) and IUnivers itt de Bordeaux II. M.M. w as supported by agrant of the Cons&ho Nazionale delle Ricerche (CNR).Correspondence should be addressed to Dr. Pier Vincenzo Piazza, INSERMU259, Rue Camille Saint-Saens, 33077 Bordeaux Cedex, France.Copyright 0 1994 Socie ty for Neuro scienc e 0270-6474/94/142724 -08$05.00/O

[Key words: cortkosterone, cocaine, morphine, dopamine,nucleus accumbens, ventral tegmental area, psychomotoreffects, drug abuse]Individual predisposition (De Wit et al., 1986; OBrien et al.,1986) and life experiences Piazza et al., 1991 ) are two im-portant factors influencing the development of drug addiction.Experimental studies have shown that although a higher vul-nerability to drug intake is spontaneouslyobserved in certainindividuals, it can also be induced by life events and, in partic-ular, by stress.For example, in the rat, only some subjectsspontaneouslydevelop amphetamine self-administration (Pi-azza et al., 1989, 1990b),whereas his behavior is enhancedbyconditions suchassocial solation (Alexander et al., 1978;Hada-way et al., 1979; Schenk et al., 1987; Bozarth et al., 1989),competition in the colony (Maccari et al., 199 ), immobilization(Derocheet al., 1992b; Shahamet al., 1992) repeated ail pinch(Piazza et al., 1990a), and prenatal stress Deminiere et al.,1992). Individual vulnerability and stress-induced redisposi-tion to drug intake are associatedwith an enhanced ocomotorresponse o psychostimulants, opioids, and novelty (Piazza etal., 1989, 1990a,b;Hooks et al., 1991; Deroche et al., 1992a),as shown also by the increase n addictive properties of drugsobserved when the locomotor effects of psychostimulantsandopioids are sensitized Lett, 1989; Piazza et al., 1990a;Gaiardiet al., 1991; Horger et al., 1991)by their repeated njections (forreview, seeRobinson and Becker, 1986; Kalivas and Stewart,1991).Several data have recently suggestedhat stress-induced or-ticosterone secretion may be an important factor determiningboth individual and stress-induced ulnerability to drug effects.First, predisposition to drug intake, spontaneouslypresent ncertain individuals or induced by stress n others, is associatedwith a longer-lasting orticosteronesecretion n responseo stress(Piazza et al., 199 a). Second, the administration of corticoste-rone, in the range of stress-induced evels, before self-admin-istration increases he reinforcing properties of amphetamine(Piazza et al., 199 a). Third, suppression f stress-induced or-ticosterone secretionabolishes he sensitization to the psycho-motor effectsof morphine and amphetamine nduced by stress(Deroche et al., 1992b, 1993) whereas epeatedcorticosteroneadministration, like repeated stress,sensitizes he locomotorresponse o amphetamine (Deroche et al., 1992a).In this report, two main questionswereaddressed. irst, maybasal physiological corticosterone secretion, similarly to whathas been observed for stress-induced ecretion Deroche et al.,1992a,b), modulate the behavioral sensitivity to the two main


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The Journal of Neuroscience, May 1994, 14(5) 2725

classes of drugs of abuse, psychostimulants and opioids? Second,is the influence of corticosterone on drug effects exerted throughchanges in the react ivity of mesolimbic dopaminergic (DA) neu-rons, one of the principal substrates of drug-reinforcing effect s(for review, see Fibiger and Phillips, 1988; Koob and Bloom,

rodents, plasma concentrations of this hormone are low and

1988; Wise and Rompre, 1989; Le Moal and Simon, 1991)?In order to answer these questions, we studied the locomotor

response to the psychostimulant cocaine and to the opioid mor-phine. The two drugs were injected both system ically and cen-trally into the nucleus accumbens for cocaine and into the ven-tral tegmental area (VTA) for morphine. These sites were chosenbecause locomotor eff ect s of cocaine (Kelly and Iversen, 1976;Delfs et al., 1990) and morphine (Joyce and Iversen, 1979;Kalivas et al., 1983; Vezina and Stewart, 1984) injected intothesestructures are donamine denendent. Locomotor activitvwas nvestigated in animals completely lacking corticosteroneor submitted to specific treatments designed o mimic the dif-ferent phases f basalphysiological corticosterone secretion. n

costerone replacement therapy was intended to imitate the completecircadian rhythm of the hormone and thus combined the two above

Dkgs hnd dr& administration. Corticosterone 21-hemisuccinate

described treatments. Adrenalectomized animals in this group (circa-dian fluctuation group) were subcutaneously implanted with the corti-costerone pellet and received the corticosterone-enriched solution dur-ing the dark period. Adrenalectomized animals that did not receive anyreplacement therapy consti tuted the ADX group. Control animals (shamgroup) underwent the same surgical procedure as the ADX animalsexcept that the adrenals were not removed.Stereotaxic implantation. Rats were anesthetized with sodium pen-tobarbital (50 mg/kg, i.p.) and placed in a stereotaxic apparatus (KopfInstruments) with incisor bar 5.0 mm above the interaural line. Chronicbilateral guide cannulas (23 gauge stainless steel) positioned 2 mm abovethe final injection site were implanted according to the stereotaxic atlasof Pellegrino et al. (1979). The guide cannulas were secured in placewith the use of stainless steel screws and dental cement. Removable 30gauge stainless steel stylets were inserted in the guide cannulas to preventclogging between treatments. The stereotaxic coordinates relative tobregma were AP +3.7, L f 1.6, and V -5.8 from the skull fo r thenucleus accumbens and AP -3.2, L &OS, and V -5.7 for the VTA.At the end of the experiments, cannula placements were verified his-toloaicallv on 100 u thionin-stained coronal sections.relativelyconstant during the diurnal period, which correspondsto the inactive period of thesespecies, nd rise to reach a peakduring the first nocturnal hours (Akana et al., 1986). Threespecificcorticosterone substitutive therapieswereused n orderto reproduce (1) diurnal levels of the hormone, (2) nocturnallevels, or (3) the entire circadian fluctuation. The efficiency ofthese eplacement therapies n mimicking the different phasesof corticosterone physiological secretion was tested n the firstexperiment of this report.Materials and MethodsSubjects. Male Sprague-Dawley rats (Iffa-Credo, Lyon, France) weighing280-300 gm were used. Animals were individual ly housed with adlibitum access to food and water. A constant light/dark cycle (lights onfrom 6 A.M. to 8 P.M.) was maintained in the animal room, and tem-perature22C) and humidity (60%) were kept constant. Animals wereallowed at least 1 week of habituation to the animal room before startingexperiments.General methodsLocomotor act ivi ty and constitution of experimental groups. Locomotoract ivi ty was measured in a circular corridor (10 cm wide and 70 cm indiameter). Four photoelectric cells placed at the perpendicular axis ofthis apparatus automatically recorded locomotion. Since it has beenpreviously shown that locomotor response to nove lty is correlated tosens itiv ity to the psychomotor eff ect s of drugs (Piazza et al., 1989,199 1b; Hooks et al., 199 l), we ensured a homogeneous distribution ofthis factor throughout the different experimental groups. For this pur-pose, 1 d prior to being submitted to the surgery used for the differentcorticosterone replacement therapies, all animals were tested for theirlocomotor response to nove lty. Hence, rats were placed in the circularcorridor between 4 and 6 P.M. and evenly distributed among the dif-ferent experimental groups according to their activ ity score cumulatedover the 2 hr of testing.Adrenalectomy and corticosterone replacement therapies. Adrenalec-tom y was performed between 8 and 10 A.M. under ether anaesthesiavia the dorsal approach. Following surgery, NaCl (0.9%) was added tothe drinking water. Some of the adrenalectomized animals received oneof three different corticosterone replacement therapies. The firs t re-placement therapy was designed to mimic the basal diurnal levels ofcorticosterone. Thus, adrenalectomized animals in this group (diurnallevels group) were implanted with a subcutaneous solid pellet o f cor-ticosterone designed to provide a constant release of the hormone inthe range of the diurnal basal levels. Such pellets contained 50 mg ofcorticosterone, adjusted to 100 mg with cholesterol (Meyer et al., 1979).The second corticosterone replacement therapy was used to reproducethe nocturnal levels of the hormone (nocturnal levels group). This wasobtained by adding, from 7 P.M. to 8 A.M., corticosterone (50 rglml)to the drinking solution of adrenalectomized animals. The third corti-

(Agrar, Italy ) was used for all experiments. Cocaine.HCl and morphinesulfate were used for both sys temic and intracerebral injections. Con-centrations ofcorticosterone and morphine are expressed as base. Drugsfor systemic administration were dissolved in sterile 0.9% NaCl solutionand injected subcutaneously in a 1 ml/kg volume at the doses of 15 mg/kg for cocaine and 2 mg/kg for morphine. Drugs for central adminis-tration were dissolved in a vehicle solution reproducing the electrolvticcontent o f cerebrospinal fluid and containing 125 rn; NaCl, 1.2 &IMCaCl,. 2.7 mM KCl. 1.0 mM MaCl,. and buffered with 0.2 mM ofNa,HPO,/NaH,PO, at pH 7.4. C&t& injections for both drugs wereperformed bilaterally in unrestrained rats over a period of 90 set in avolume of 1 &side. The injection cannulas (30 gauge stainless steel)descended 2 mm below the guide cannulas and were left in place for 60set both before and after the administration period. Cocaine was injectedin the nucleus accumbens at a dose of 50 &side. Its pH was adjustedto 7.2-7.4 with dilute NaOH before central administration. Morphinewas injected in the VTA at a dose of 1 &side.Corticosterone assay. Blood for corticosterone assay was collected inheparinized tubes. Plasma, obtained after centrifugation, was stored at-20C until assay. Plasma corticosterone was measured by radioim-munoassay (RIA kit, ICN Biomedicals, Inc.) using a highly spec ificcorticosterone antiserum with a detection threshold of 0.1 /~g/100 ml.ProceduresExperiment 1: eff ect of adrenalectomy and corticosterone substitutivetherapies on plasma corticosterone levels. Animals (n = 84) were sub-mitted to sham operation, adrenalectomy, or one of the three replace-ment therapies. The following five groups were thus constituted: sham(n = 15) ADX (n = 17), diurnal leve ls (n = 17), nocturnal leve ls (n =20), and circadian fluctuation (n = 15). Plasma corticosterone levelswere determined 1 week after the start of these treatments. In order todetermine both the diurnal and nocturnal corticosterone levels, half ofthe animals in each group were killed at 9 P.M., and the remaining halfat 9 A.M. the following morning.Experiment 2: ef fec t of adrenalectomy and corticosterone substitutivetherapies on locomotor response to systemic injection of cocaine or mor-phine. Animals (n = 101) were fir st submitted to sham operation, ad-renalectomy, or one of the three replacement therapies. Five groupswere thus consti tuted: sham (n = 24), ADX (n = 18), diurnal leve ls, (n= 19), nocturnal leve ls (n = 24), and circadian fluctuation (n = 16). Oneweek after the start o f these treatments, half of the animals in each groupwere tested for the locomotor response to cocaine, and the remaininghalf for the locomotor response to morphine. For this test, animals wereplaced in the circular corridor at 9 A.M. After a 2 hr period of habit-uation, all animals were injected subcutaneously with saline. Two hourslater, the animals were injected with either cocaine or morphine. Lo-comotor act ivi ty was recorded for 2 hr after saline and cocaine and for3 hr after morphine. Scores were recorded over 10 min intervals foranimals receiving cocaine and over 30 min in tervals for those receivingmorphine.Experiment 3: eff ec t of adrenalectomy and corticosterone substitu tivetherapies on locomotor response to intraaccumbens injection of cocaine,


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2726 Marinelli et al. * Corticosterone and Psycho motor Eff ect of Cocaine and Morphine

Figure 1. Effe ct of adrenalectomy andcorticosterone replacement therapies oncorticosterone plasma levels. In shamanimals, corticosterone levels werehigher in the dark period than in thelight period. Corticosterone levels of thesham group in the light period weresimilar to those observed in the diurnallevels and circadian fluctuation groupskilled at the same time. Corticosteronelevels o f the sham group in the darkperiod were similar to those of the cir-cadian fluctuation and nocturnal levelsgroups killed at the same time. Adre-nalectomized animals had lower cor-ticosterone levels than all groups.

PLASMA CORTICOSTERONE I

light dark

Animals (n = 28) -were fir st implanted with guide cannulas above thenucleus accumbens. Ten days later, they were submitted to either shamoperation, adrenalectomy, or a corticosterone replacement therapy. Threeexperimental groups were thus constituted: sham (n = lo), ADX (n =9) and diurnal levels (n = 9). This subst itutive therapy was chosenbecause the previous experiment revealed that corticosterone diurnallevels were suff icien t to abolish the effe ct of adrenalectomy on the lo-comotor response to cocaine. One week later, the animals were testedon 2 d for the locomotor response to centrally injected vehicle andcocaine. The firs t day the animals were placed in the circular corridorat 10 A.M.; after a 2 hr period of habituation, they were injected withthe vehicle solution and their locomotor response recorded for 2 hr over10 min intervals. The second day the same procedure was repeated, butinstead of receiving intraaccumbens vehicle, the animals were admin-istered cocaine.Experiment : effectof adrenalectomyndcorticosteroneubstitutivetherapies n locomotor esponseo intra-VTA injection f morphine.Animals (n = 20) were first implanted with guide cannulas aimed atthe VTA. Ten days later they were submitted to either sham operation,adrenalectomy, or a corticosterone replacement therapy. Three exper-imental groups were thus constituted: sham (n = 7), ADX (n= 6), andcircadian fluctuation (n= 7). This substitut ive therapy was chosen be-cause the experiment with systemic injection of morphine revealed thatthe complete circadian secretion was necessary to abolish the eff ects ofadrenalectomy. One week later, the locomotor response to vehicle andmorphine was determined by using the same procedure employed inthe intraaccumbens cocaine experiment. Locomotor response to bothsubstances was recorded for 3 hr over 30 min intervals.Statistical nalysis.nalysis of variance (ANOVA) was used to an-alyze plasma levels of corticosterone and activ ity scores. Newman-Keuls test was used for post hoc analysis.For experiment 1, the ANOVA was performed considering the dif-ferent hormonal manipulations as first between factor (treatment, fivelevels), and the time of the day at which the blood sample was withdrawnas second between factor (time of the day, two levels). Single pairwisecomparisons between treatments served to determine group differences.For experiment 2, data were initially submitted to an ANOVA, whichconsidered the different hormonal manipulations as between factor(treatment, fi ve levels) and the time after the injection of either salineor drugs as within factor (time, 12 levels for saline and cocaine whenconsidering the locomotor response to cocaine, and four levels for salineand six for morphine when considering the locomotor response to mor-phine). Subsequently, in order to better define the role of the differentcorticosterone replacement therapies on the response to each drug, abifactorial analysis was performed over the four groups that were ad-renalectomized (ADX, diurnal levels, nocturnal levels, and circadianfluctuation). The presence or the absence of subcutaneous corticosterone

light dark light dark light dark light dark

TIME OF DAYpellet was the first between factor. The presence or the absence of cor-ticosterone-enriched solution was the second between factor. Thus, thefirst factor (pellet) determined the influence ofthe diurnal corticosteronelevels while the second (corticosterone-enriched solution) ascertainedthe influence of the nocturnal corticosterone levels.For experiments 3 and 4, data were submitted to an ANOVA thatconsidered the hormonal manipulations of each experiment as betweenfactor (treatment, three levels), and the time after the injection of eitherthe vehicle or the drug as within factor (time, 12 levels for vehicle andcocaine in experiment 3, and six levels for vehicle and morphine inexperiment 4).

ResultsExperiment I: effect of adrenalectomy and corticosteronesubstitutive therapieson corticosteroneplasma levelsAdrenalectomy and the different corticosterone replacementtherapies significantly modified plasma corticosterone levels[treatment effect, F(4,74) = 7.5, p < 0.0011, and this effect wasdependent on the time of day [treatment x time interaction,F(4,74) = 6.7, p < O.OOl] (Fig. 1). In sham animals, cortico-sterone levels were higher during the dark period than the lightphase [F( 1,13) = 10.1, p < 0.011. Adrenalectomy was able toconstantly suppress ndogenouscorticosterone secretion.Cor-ticosterone levels in ADX rats were lower than the minimaldetection threshold of our assay 0.1 &I 00 ml of plasma)anddid not differ between the light and dark period [F( 1,15) = 0.1,p > 0.81. mplantation of corticosteronepelletsconstantly mim-icked diurnal levels of the hormone. Thus, in adrenalectomizedanimals submitted to this replacement therapy (diurnal levelsgroup), plasma corticosterone levels did not change over theday [F( 1,15) = 0.7, p > 0.41 and did not differ from levelsobserved in sham rats during the light cycle [F( 1,13) = 1.5, p> 0.31,but were ower than levels observed n sham ats duringthe dark period [F( 1,15) = 15.2, p < 0.011.Administration ofcorticosterone in the drinking solution specif ically reproducedthe nocturnal levels of the hormone. Thus, in the nocturnallevels group, the corticosterone evels during the dark phasedidnot differ from those observed in sham animals for the sameperiod of the day [F( 1,16) = 0.04, p > 0.81, whereas he levelsin the morning did not differ from those of ADX rats [F(1,17)


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LOCOMOTOR RESPONSE TO SUBCUTANEOUS INJECTIONSALINE COCAINE (15 mg/kg)

Circadian fluctuation

= 1.4, p > 0.31. The associationof the corticosterone pelletimplantation with the administration of corticosterone in thedrinking solution wasable o mimic the corticosteronecircadiansecretion. Consequently, adrenalectomizedanimals submittedto this replacement herapy (circadian fluctuation group) did notdiffer from sham ats during either the dark period [P(1,14) =0.001, p > 0.91or the light phase F(1,12) = 0.002, p > 0.91.Experiment 2: efect of adrenalectomyand corticosteronesubstitutive therapieson locomotor responseo systemicinjection of cocaine or morphineLocomotor responseo cocaine.Neither adrenalectomy nor thereplacement herapiesmodified the locomotor responseo saline[treatment effect, F(4,46) = 0.7, p > 0.61,although they affectedthe response o cocaine [treatment effect, F(4,46) = 3.2, p 0.31 Fig. 2). Suppressionof basalcorti-costerone evels reduced ocomotor response o cocaine. Thus,ADX rats exhibited lower activity scorescompared to thoseregistered n sham animals (p < 0.05). Reestablishmentof thecorticosteronediurnal levelssuppressedhe effectsof adrenalec-tomy. Animals in the diurnal levels group showed a highermotor response o cocaine han the one observed in ADX an-imals (p < 0.05), but not from the one of sham rats. The re-production of the nocturnal levels of corticosterone alone wasnot sufficient to restore the decreasen the response o cocaineinduced by adrenalectomy. In fact, there was no difference be-tween the locomotor response f animals n the nocturnal levelsgroup and that of ADX ones.Reestablishment f the completecircadian fluctuation did not improve the restoration of thelocomotor response o cocaine already obtained by providingthe animalswith the diurnal levels alone. Thus, animals of thecircadian fluctuation group showeda higher response han theone observed in ADX animals (p c 0.05) but did not differfrom either the sham or the diurnal levels groups. The depen-denceof the psychomotor effectsof cocaineon the diurnal levelsof corticosteronewas confirmed by the bifactorial analysis hatconsidered he effect of the different replacement therapies nthe four adrenalectomizedgroups.This analysis evealed a sig-nificant effect of corticosteronepellet implantation [pellet effect,

Figure2. Effectof adrenalectomyndcorticosteroneeplacementherapiesnthe ocomotor esponseo systemicn-jection of saline nd cocaine.No dif-ferencesbetween the experimentalgroupswereobserved n the responseto saline,whereas uppressionf cor-ticosterone ecretion y adrenalectomy(ADXgroup)decreasedhe esponseococaine.This effectwasabolished yreconstructingither he diurnalcorti-costeroneevels diurnal evels roup)or the entire corticosterone ircadiancycle circadianluctuationgroup),butnot by restoring he nocturnal evels(nocturnalevels roup).ADX animalsdid not differ from the nocturnalevelsgroup,but exhibited ower ocomotorscores omparedo thoseobservednsham, diurnal levels, and circadianfluctuationgroups *, p < 0.05). Fur-thermore, hese ast three groupsdidnot differ n activity scores.

F(l,35) = 9.3, p < 0.011, but not of the administration of cor-ticosterone in drinking solution [corticosterone-enrichedsolu-tion effect, F( 1,35) = 1.6, p > 0.21.Furthermore, no significantinteraction was found between the two factors.Locomotor response o morphine. Adrenalectomy and re-placement therapiesdid not affect the response o saline [treat-ment effect, F(4,45) = 0.90, p > 0.51, but significantly alteredthe locomotor response o morphine [treatment effect, F(4,45)= 6.6, p < O.OOl] in a time-dependent manner [treatment xtime interaction, F(20,225) = 2.0, p < 0.0 I] (Fig. 3). Suppressionof corticosteronesecretion educed he stimulant effectsof mor-phine. Thus, ADX animals showed ower activity scores hanthosedisplayed by sham ats (p < 0.0 1). Reproduction of eitherthe diurnal levels or the nocturnal levels only partially reversedthe effect of adrenalectomy. Thus, animals n both diurnal andnocturnal levels groupsdisplayed a higher activity compared othe one of ADX rats (p < 0.05 in both cases), ut still lowerthan the one observed n shamanimals p < 0.05 in both cases).Only the restoration of the entire corticosterone circadian se-cretion totally abolished he effects of adrenalectomy. Animalsin the circadian fluctuation group showeda higher locomotorresponseo morphine compared o that of ADX rats (p -C0.01)and did not differ from the one observed n shamanimals. Thebifactorial analysisconfirmed that both diurnal and nocturnallevels were necessary n order to abolish the effects of adre-nalectomy. A significant effect was detected for both factors[pellet effect, F( 1,34) = 10.8, p < 0.0 1; corticosterone-enrichedsolution effect, F( 1,34) = 9.8, p -C 0.011.Experiment 3: efect of adrenalectomy and corticosteronesubstitutive therapieson locomotor responseo intraaccumbensinjection of cocaineThe results obtained by intraaccumbenscocaine njections re-produced hoseobservedafter the systemic njection of the drug.Neither adrenalectomy nor the corticosterone eplacement her-apy used n this experiment significantly modified the locomotorresponse o intraaccumbensvehicle injection [treatment effect,F(2,25) = 2.0, p > 0.11. In contrast, a significant effect of thesetreatments was observed on the locomotor responseo cocaine[treatment effect, F(2,25) = 6.9, p < 0.011 Fig. 4). Suppression


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2728 Marinelli et al. l Corticosterone and Psychom otor Effect of Coca ine and Morphine

Figure 3. Effectof adrenalectomyndcorticosteroneeplacementherapiesnthe ocomotor esponseo systemicn-jectionof saline ndmorphine.The o-comotor responseo salinewas notmodifiedby the treatments; owever,suppressionf corticosteroneecretionby adrenalectomyADX group) de-creasedhe ocomotor esponseo mor-phine.Only the reconstruction f theentire corticosterone ycle (circadianfluctuationgroup)wasable o antago-nize thiseffectcompletely.According-ly, sham ndcircadian luctuationan-imalsexpressedquivalent ocomotorscores, nd both these roupsshoweda higher esponsehan ADX (p < 0.01in bothcases), iurnal evels p < 0.05in both cases),nd nocturnal evels@< 0.05 n both cases) nimals. n thediurnal levels and nocturnal levelsgroups nly a partial,but significantp< 0.05 n both cases),ecoveryof theeffects f adrenalectomy asobserved.

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LOCOMOTOR RESPONSE TO SUBCUTANEOUS INJECTIONSALINE MORPHINE (2 me/kg)

. 0 Sham0 ADX0 Diurnal levels

. n Nocturnal levels_ A Circadian fluctuation

30 60 90 120 30 60 90 120 150 150TIME (min) TIME (min)

of corticosterone diminished the locomotor response o in-traaccumbenscocaine. ADX animals showed activity scoreslower than those of sham rats (p < 0.01). Furthermore, therestoration of the diurnal levels suppressedhe effect of adre-nalectomy. Animals in the diurnal levels group showeda higherlocomotor response han that of ADX rats (p c 0.01) and didnot differ from shamanimals.Experiment 4: efect of adrenalectomy and corticosteronesubstitutive herapieson locomotor responseo intra- VTAinjection of morphine

effects on locomotor activity were, however, observed in re-sponseo intra-VTA morphine njection [treatment effect,F(2,17)= 14.2, p c O.OOl] (Fig. 5). Again, ADX animals showedalower locomotor responsecompared to the one observed insham ats (p c O.OOl), and the reinstatement of the entire cor-ticosterone circadian secretion eversed this effect. Thus, in an-imals of the circadian fluctuation group, the locomotor responseto morphine was higher than the one observed n ADX rats (p< O.OOl), but equivalent to the one of sham animals.Discussion

The results of this experiment reproduced the ones obtainedafter systemic administration of morphine. Neither adrenalec-tomy nor the replacement herapy used n this experiment sig-nificantly affected the locomotor responseo intra-VTA vehicleinjection [treatment effect, F(2,17) = 2.2, p > 0.11. Significant

Our results demonstrate that stimulant effects of cocaine andmorphine dependon physiologicalbasal evels of corticosteroneand that this hormone facilitates the psychomotor propertiesofboth drugs. Suppression f corticosteroneby adrenalectomy e-duced the locomotor response o the systemic or central injec-

Figure4. Effectof adrenalectomyndrestorationof diurnal corticosteronelevelson the ocomotor esponseo in-traaccumbens ehicle and cocaine.Groupsdid not differ n the ocomotorresponseo vehicle.Suppressionf cor-ticosterone evels by adrenalectomy(ADXgroup) educedhe ocomotor e-sponseo cocaine nd he einstatementof basal iurnal evels f corticosteronereversed his effect. Thus, ADX ani-mals xhibitedower ctivity scoreshanboth sham **, p < 0.01)and diurnallevels **, p < 0.01) groups,and thelatter two groups id not differ.

rLOCOYOTOR RESPONSE TO INTRA-ACCUMBENS INJECTION 1VEHICLE COCAINE (50 pg)

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I I t I I I I 1 I I30 60 90 120 150 180 30 60 90 120 150 180

TIME (min) TIME (min)tion of both cocaine and morphine. In contrast, corticosteronereplacement herapies, mimicking physiological corticosteronesecretion, totally reversed this effect.Psychomotor effects of morphine and cocaine were differen-tially influenced by the different phasesof corticosterone cir-cadian secretion. Cocaineeffectswere dependentonly on basaldiurnal levels. For this drug, the effect of adrenalectomy wasnot significantly affected by restoration of the nocturnal peak,but was totally reversedby the substitutive therapy mimickingthe diurnal levels. In contrast, the stimulant effect of morphinedependedon the entire circadian corticosterone secretion,sincethe effect of adrenalectomy was only partially reversed by thereinstatementof diurnal or nocturnal levels but totally reversedby the substitutive therapy restoringboth diurnal and nocturnallevels of the hormone. This finding may explain the circadianvariation in the intensity of certain behavioral effectsof opioids.Higher effects in the dark than in the light period have beendemonstrated or morphine-induced feeding (Bhakthavatsalamand Leibowitz, 1986) lethal effectsof morphine (Camposet al.,1983),and naloxone reversible pain sensitivity (MC Givem andBemston, 1980). These esultshighlight the important and dif-ferent physiological roles of the phasesof corticosterone circa-dian fluctuation. This aspect,often neglected,of glucocorticoidphysiology may be crucial for the understandingof the func-tional effectsof glucocorticoids on the CNS.The effects of corticosterone on the locomotor response ococaineand morphine appear o be mediated by changesn thereactivity of DA mesencephalic eurons to these drugs. Thus,the influence of adrenalectomy and corticosterone replacementtherapieson the stimulant effects of cocaine and morphine wascomparablewhen the drugs were injected systemically or cen-trally, in the nucleusaccumbens or cocaineand in the VTA formorphine. Several studies have shown that motor activationinduced by administration of cocaine in the accumbens Delfset al., 1990) or of morphine in the VTA (Joyce and Iversen,1979;Vezina and Stewart, 1984) dependson the activation ofDA A10 neuronsprojecting to the nucleusaccumbens.The dependency on corticosterone of dopamine-mediatedpsychomotoreffectsof cocaineand morphine supportsprevious

Figure 5. Effectof adrenalectomyndreconstructionf the entire corticoste-rone fluctuation on the locomotor re-sponse to intra-VTA vehic le and mor-phine. Groups did not differ in thelocomotor response to vehicle. Sup-pression of corticosterone levels by ad-renalectomy (ADX group) reduced thelocomotor response to morphine andthe reinstatement of the entire circa-dian secretion of corticosterone re-versed this effect. Thus, ADX animalsexhibited lower act ivi ty scores than bothsham (p < 0.001) and circadian fluc-tuation groups (p < 0.00 l), whereas thelatter two groups did not differ.works suggestinghat endogenous orticosterone secretionmaybe involved in the predisposition to drug abuse.MesencephalicDA neurons are considered an important substrate of drug-reinforcing effects Fibiger and Phillips, 1988;Koob and Bloom,1988;Wise and Rompre, 1989; Le Moal and Simon, 1991) anda higher sensitivity to the stimulant effects of drugs has beenassociatedwith an increasedvulnerability to their reinforcingproperties (Piazza et al., 1989; Wise and Bozarth, 1989). Fur-thermore, the higher sensitivity to the reinforcing and stimulanteffects of psychostimulants, spontaneously present in certainindividuals or inducedby stressn others, spositively correlatedwith a long-lastingcorticosterone secretion n responseo stress(Piazza et al., 1991a,b). Finally, corticosterone njection to sub-jects spontaneously esistant to develop amphetamine self-ad-ministration increasesheir propensity to acquire this behavior(Piazza et al., 1991a).Although the effects of corticosterone on cocaine and mor-phine involve dopamine, the different sensitivity of the twodrugs to the circadian variation of the hormone indicates theexistenceof different primary mechanisms f action. Two prin-cipal hypothesesmay be drawn. First, different types of centralcorticosteroid receptorsmay be nvolved: type I receptors,whichare almost totally saturated by diurnal levels of corticosterone(Reul and De Kloet, 1985; Reul et al., 1987) may mediate theeffects of the hormone on cocaine; type II receptors,which arefully occupied only during the nocturnal peak (Reul and DeKloet, 1985; Reul et al., 1987) may be the substrate of theeffects of corticosterone on morphine. Second, different neuralsubstratesmay be involved. The primary site of action of co-caine and morphine is, in fact, different. Cocaine s an indirectdopamine agonist that principally blocks dopamine reuptake(Reith et al., 1980; Ritz et al., 1987)and exercises ts stimulanteffect by acting on DA terminals, but not cell bodies.Conversely,morphine activation of DA neurons occurs in the VTA andresults from the releaseof DA cells from an inhibitory GABAinput (for review, seeKalivas and Stewart, 1991). This hypoth-esis s supportedby the fact that corticosterone can act on bothDA and opioid transmission.DA neurons have corticosteroidreceptors HPrfstrand et al., 1986)and DA activity seemso be


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2730 Marinelli et al. - Corticosterone and Psycho motor Effe ct of Cocaine and Morphine

increased by glucocorticoid hormones (Rothschild et al., 1985;Mittleman et al., 1992). Proenkephalin mRNA in the striatumis decreased by adrenalectomy (Chao and McEwen, 1990), andthe eff ect s of enkephalin on hippocampal slices are potentiatedby corticosterone (Vidal et al., 1986).

The action of corticosterone on the psychomotor eff ect s ofdrugs may also involve other neurotransmitters, such as GABA,5-HT, and excitatory amino acids. All these neurotransmitterscan modulate dopamine-mediated responses to opioids and psy -chostimulants (Scheel-Kriiger et al., 1981; Kalivas et al., 1989;Kelland et al., 1990; Pulvirenti et al., 199 l), and are influencedby corticosterone. Glucocorticoids have been reported to mod-if y the binding capacity of 5-HT receptors (Biegon et al., 1985;De Kloet et al., 1986; Martire et al., 1989) and GABA receptors(Majewska et al., 1986; Majewska, 1987, Sutanto et al., 1989)and to potentiate glutamatergic transmission (Tischler et al.,1988; Sapolsky, 1990).

In conclusion, our results indicate that physiological cor-ti-costerone secretion facilita tes dopamine-mediated stimulant ef-fec ts of both cocaine and morphine. Since, fo r these drugs, thestimulant eff ect s and the activation of DA mesencephalic neu-rons are closely related to their reinforcing properties (Wise andBozarth, 1989; Pulvirenti et al., 1991), our data support thehypothesis that an interaction between corticosterone and do-pamine may b: a pathophysiological mechanism underlyingvulnerability to drug intake. Consequently, the understandingof the mechanisms by which these two biological systems in-teract may open new insights for the development of futuretherapeutic strategies o f addiction.ReferencesAkana SF, Cascio CS, Du J-Z, Levin N, Dallman MF (1986) Resetof feedback in the adrenocortical sys tem: an apparent shi ft in sensi-tiv ity of adrenocorticotropin to inhibition of corticosterone in themorning and evening. Endocrinology 119:2325-2332.Alexander BK, Coambs RB, Hadaway PF (1978) The effect of housingand gender on morphine self-administration in rats. Psycho-pharmachology (Berlin) 58: 175-l 79.Bhakthavatsalam P, Leibowitz SF (1986) Morphine-elicited feeding:diurnal rhythm, circulating corticosterone and macronutrient selec-tion. Pharmacol Biochem Behav 24:9 1 -9 17.Biegon A, Rainbow TC, McEwen BS (1985) Corticosterone modu-lation of neurotransmitter receptors in rat hippocampus: a quanti-tative autoradiographic study. Brain Res 332:309-314.Bozarth MA, Murray A, Wise RA (1989) Influence of housing con-ditions on intravenous heroin and cocaine self-administration in rats.Pharmacol Biochem Behav 33:903-907.Campos AE, Luijan M, Lopez E, Figueroa-Hemandez JL, Rodriguez R(1983) Circadian variation in the lethal effects of morphine in themouse. Proc West Pharmacol Sot 26: 10 l-l 03.Chao HM, McEwen BS (1990) Glucocorticoid regulation of proen-kephalin messenger ribonucleic acid in the rat striatum. Endocrinol-ogy 126:3124-3130.De Kloet ER, Sybesma H, Reul JMHM (1986) Selective control bycorticosterone of serotonin 1 receptor capacity in raphe-hippocampalsystem. Neuroendocrinology 425 13-52 1.De Wit H. Uhlenhuth EH. Johanson CE (1986) Individual differences~ Iin the reinforcing and subiective eff ect s of amphetamine and diaze-pam. Drug Alcohol Depend 16:341-360. -Delfs JM, Schreiber L, Kelley AE (1990) Microinjection of cocaineinto the nucleus accumbens el icits locomotor activation in the rat. JNeurosci 10:303-310.Deminiere JM. Piazza PV. Gueean G. Abrous N. Maccari S. Le MoalM, Simon H (1992) Increased locomotor response to nove lty andpropensity to intravenous self-administration in adult offspring ofstressed mothers. Brain Res 586: 135-l 39.Deroche V, Piazza PV, Maccari S, Le Moal M, Simon H (1992a)Repeated corticosterone administration sensitizes the locomotor re-

sponse to amphetamine. Brain Res 584:309-3 13.

Deroche V, Piazza PV, Casolini P, Maccari S, Le Moal M, Simon H(1992b) Stress-induced sensitization to amphetamine and morphinepsychomotor eff ect s depend on stress-induced corticosterone secre-tion. Brain Res 598:343-348.Deroche V, Piazza PV, Casolini P, Le Moal M, Simon H (1993) Sen-sitization to the psychomotor eff ect s of amphetamine and morphineinduced by food restriction depend on corticosterone secretion. BrainRes 611:352-356.Fibiger HC, Phillips AG (1988) Mesocorticolimbic dopamine sys temsand reward. Ann NY Acad Sci 537:206-215.Gaiardi M, Bartoletti M, Bacchi A, Gubellini C, Costa M, Babbini M(199 1) Role of repeated exposure to morphine in determining itsaffect ive properties: place and taste conditioning studies in rats. Psy-chopharmacology (Berlin) 103: 183-186.Hadaway PF, Alexander BK, Coambs RB, Beyerstein B (1979) Theeff ect of housing and gender on preference for morphine-sucrose so-lutions in rats. Psychopharmacology (Berlin) 66:87-9 1.Hlrfstrand A. Fuxe K. Cintra A. Annati LF. Zini I . Wilkstrom AC.Okret S, YuZY, Goldstein M, Steinbuch H, Verhofstad A, GustafssonJA (1986) Glucocorticoid receptor immunoreactivity in monoam-inergic neurons of rat brain. Proc Nat1 Acad Sci USA 238:302-322.Hooks MS, Jones GH, Smith AD, Neil1 DB, Justice JB (1991) Re-sponse to nove lty predicts the locomotor and nucleus accumbensdopamine response to cocaine. Synapse 9:121-128.Horger BA, Shelton K, Schenk S (1991) Preexposure sensitizes ratsto the rewarding effect s of cocaine. Pharmacol Biochem Behav 37:707-711.Joyce EM, Iversen SD (1979) The effect of morphine applied locallyto mesencephalic dopamine cell bodies on spontaneous motor act ivi tyin the rat. Neurosci L&t 14:207-212.Kalivas PW, Stewart J (199 1) Dopamine transmission in the initiationand expression of drug- and stress-induced sensitization of motoract ivi ty. Brain Res Rev 161223-244.Kalivas PW, Widerlov E, Stanley D, Breese G, Prange AJ Jr (1983)Enkephalin action on the mesolimbic system: a dopamine-dependentand dopamine-independent increase in locomotor act ivi ty. J PharmacolExv Ther 2271229-237.Kalivas PW, Dufi P, Barrow J (1989) Regulation of the mesocorti-colimbic dopamine system by glutamic acid receptor subtypes. JPharmacol Exp Ther 251:378-387.Kelland MD, Freeman AS, Chiodo LA (1990) Serotoninergic afferentregulation of the basic physiology and pharmacological responsive-ness of nigrostriatal dopamine neurons. J Pharmacol Exp Ther 253:803-811.Kelly PH, Iversen SD (1976) Selective 6-OHDA-induced destructionof mesolimbic dopamine neurons: abolition of psychostimulant-in-duced locomotor act ivi ty in rats. Eur J Pharmacol40:45-56.Koob GF, Bloom FE (1988) Cellular and molecular mechanisms ofdrug dependence. Science 242~7 15-723.Le Moal M, Simon H (199 1) Mesocorticolimbic dopamine network:functional and regulatory roles. Physiol Rev 7 1: 155-234.Lett BT (1989) Repeated exposures intensify rather than diminish therewarding effect s of amphetamine, morphine, and cocaine. Psycho-uharmacoloav (Berlin) 98:357-362._. ,Maccari S, Piazza PV, Deminitre JM, Lemaire V, Mormtde P, SimonH, Angelucci L, Le Moal M (199 1) Life events-induced decrease ofcorticosteroid type I receptors is associated with reduced corticoste-rone feedback and enhanced vulnerability to amphetamine self-ad-ministration. Brain Res 547:7-12.Majewska MD (1987) Antagonist-type interaction of glucocorticoidswith the GABA receptor-couuled chloride channel. Brain Res 418:377-382.Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986)Steroid hormone metabolites are barbiturate-like modulators of theGABA receptors. Science 232: 1004-1007.Martire M, Pistritto G, Preziosi P (1989) Diffe rent regulation of se-rotonin receptors fol lowing adrenal hormone imbalance in the rathippocampus. J Neural Transm 78: 109-120.MC Givem RF, Bemston GG (1980) Mediation ofdiumal fluctuationsin pain sensit ivity in the rat by food intake patterns: reversal b ynaloxone. Science 2 10:2 1O-2 12.Meyer JS, Micco DJ, Stephenson BS, Krey LC, McEwen BS (1979)Subcutaneous implantation method for chronic glucocorticoid re-placement therapy. Physiol Behav 22:867-870.

Mittleman G, Blaha CD, Phillips AG (1992) Pituitary-adrenal and


8/8


dopaminergic modulation ofschedule-induced polydipsia: behavioral Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptorsand neurochemical evidence. Behav Neurosci 106:402-408. on dopamine transporters are related to self-administration of co-Caine. Science 237: 1219-1223.Brien CP, Ehrman RN, Terns JN (1986) Classical conditioning inhuman. In: Behavioral analysis of drug dependence (Goldberg SR,Stolerman IP, eds), pp 329-338. London: Academic.Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlasof the rat brain. New York: Plenum.Piazza PV, Deminitre JM, Le Moal M, Simon H (1989) Factors thatpredict individual vulnerability to amphetamine self-administration.Science 245:1511-1513.Piazza PV, Deminitre JM, Le Moal M, Simon H (1990a) Stress- andpharmacologically-induced behavioral sensitization increases vul-nerability to acquisition of amphetamine self-administration. BrainRes 5 14:22-26.Piazza PV, Deminitre JM, Maccari S, Mormede P, Le Moal M, SimonH (1990b) Individual reactivi ty to nove lty predicts probability ofamphetamine self-administration. Behav Pharmacol 1:339-345.Piazza PV, Maccari S, Deminitre JM, Le Moal M, Mormtde P, SimonH (199 1a) Corticosterone levels determine individual vulnerabilityto amphetamine self-administration. Proc Nat1 Acad Sci USA 88:2088-2092.Piazza PV, Deminiere JM, Maccari S, Le Moal M, Mormede P, SimonH (199 1b) Individual vulnerability to drug self-administration: ac-tion of corticosterone on dopaminergic systems as a possible patho-physiological mechanism. In: The mesolimbic dopamine system: frommotivation to action (Willner P, Scheel-Kruger J, eds), pp 473-495.Chichester: Wiley.Pulvirenti L, Swerdlow NR, Hubner CB, Koob GF (1991) The roleof limbic-accumbens-pallidal circuitry in the activating and reinforc-ing propertieS o f psychostimulant drugs. In: The mesolimbic dopa-mine system: from motivation to action (Willner P, Scheel-Kruger J,eds), pp 13 l-l 39. Chichester: Wiley.Reith MEA, Shersen H, Laitha A (1980) Saturable [)H]-cocaine bind-

Robinson TE, Becker JB (1986) Enduring changes in brain and be-havior produced by chronic amphetamine administration: a reviewand evaluation of animal models of amphetamine psychosis. BrainRes Rev 11:157-198.Rothschild AJ, Langlais PJ, Schatzberg AF, Miller MM, Saloman MS,Lerbinger JE, Cole JO, Bird ED (1985) The ef fec t of single acutedose of dexamethasone on monoamine and metabolites levels in therat brain. Life Sci 36:2491-2505.Sapolsky RM (1990) Glucocorticoids, hippocampal damage and theglutamatergic synapse. Prog Brain Res 86: 12-23.Scheel-Krtiger J, Magelund G, Olianas MC (1981) Role of GABA inthe striatal output system: globus pallidus, nucleus entopeduncolaris,substantia nigra and nucleus subthalamicus. In: GABA and the basalganglia (Di Chiara G, Gessa GL, eds), pp 165-l 86. New York: Raven.Schenk S, Lacelle G, Gorman K, Amit Z (1987) Cocaine self-admin-istration in rats influenced by environmental conditions: implicationsfor the etiology of drug abuse. Neurosci Lett 8 1:227-23 1.Shaham Y, Alvares K, Nespor SM, Grundberg NE (1992) Eff ect ofstress on oral morphine and fentanyl self-administration in rats.Pharmacol Biochem Behav 4 1:6 15-6 19.Sutanto W, Handelmann G, De Bree F, de Kloet ER (1989) Multi-faceted interaction of corticosteroids with the intracellular receptorsand with membrane GABA-A receptor complex in the rat brain. JNeuroendocrinol 1:243-247.Tischler ME, Hemiksen EJ, Cook PH (1988) Role of glucocorticoidsin increased muscle glutamine production in starvation. Muscle Nerve11:752-756.Vezina P, Stewart J (1984) Conditioning and place-specific sensiti-zation of increases in act ivi ty induced by morphine in the VTA.Pharmacol Biochem Behav 20:925-934.ing in central nervous system of.mouse. Life Sci 27:lCl55-1062.Reul JMHM, De Kloet ER (1985) Two receptor systems for corti-costerone in rat brain: microdistribution and different ial occupation.Endocrinology 117:2505-25 11.Reul JMHM, Van den Bosch FR, De Kloet ER (1987) Differentialresponse of type I and type II corticosteroid receptors to changes inplasma steroid level and circadian rhythmici ty. Neuroendocrinology45:407-412.

Vidal C, Jordan W, Ziegelgansberger W (1986) Corticosterone reducesthe excitability of hippocampal pyramidal cells in vitro. Brain Res383:54-59.Wise RA, Bozarth MA (1989) A psychomotor stimulant theory ofaddiction. Psycho1 Rev 94:469492.Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu RevPsycho1 40: 191-225.

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