Glucocorticoids and Behavioral Effects of Psychostimulants. II: Cocaine Intravenous Self-administration and Reinstatement Depend on Glucocorticoid Levels VÉRONIQUE DEROCHE, MICHELA MARINELLI, Michel LE MOAL and PIER

Observations suggest that corticosterone, the principal glucocorticoid hormone in the rat, can modulate the behavioral effects of drugs of abuse. In this report, the influence of corticosterone on intravenous self-administration of cocaine was studied. In the first experiment, cocaine intravenous self-administration in adrenalectomized rats and in adrenalectomized rats receiving corticosterone replacement treatments was studied as a function of corticosterone concentrations and as a function of cocaine doses (0.025, 0.05, 0.1, 0.2, 0.4, 0.8 mg/ kg/infusion). In a second experiment, we tested, in intact rats, the effect of different doses of corticosterone (0.09, 0.18, 0.37, 0.58, 0.75 mg/kg) on the reinstatement of an extinguished cocaine self-administration behavior. It is reported that adrenalectomy markedly shifts the cocaine self-administration dose-effect curve downward. This effect was dose-dependently reversed by corticosterone; a complete restoration being obtained for corticosterone levels in the range of those induced by stress. Corticosterone administration also precipitated dose-dependently the reinstatement of cocaine self-administration. The maximal effect was obtained for a dose of corticosterone producing an increase in plasma levels similar to the increase produced by an intense stress. In conclusion, our results show that glucocorticoids facilitate the reinforcing effects of cocaine and support the hypothesis that glucocorticoids are one of the biological factors determining vulnerability to substance abuse. Several observations suggest that corticosterone, the principal glucocorticoid hormone in the rat, facilitates the locomotor response to psychostimulant drugs. In intact rats, the amplitude of amphetamine-induced locomotion is positively related to the plasma levels of corticosterone at the time of the drug injection (Piazza et al., 1991). Suppression of corticosterone secretion by ADX (Marinelli et al., 1994) or pretreatment with the corticosterone synthesis inhibitor metyrapone (Piazza et al., 1994) reduces the locomotor response to an injection of cocaine. In particular, suppression of corticosterone secretion reduces the locomotor response to medium and high doses of cocaine (between 15 and 30 mg/kg) without modifying the response to lower doses (between 0 and 7.5 mg/kg) (Marinelli et al., 1997, companion paper). Finally, administration of corticosterone to adrenalectomized animals dose-dependently increases the locomotor response to cocaine (Marinelli et al., 1997, companion paper): a complete restoration of cocaine-induced locomotion is obtained with substitutive treatments reproducing basal diurnal levels of the hormone (Marinelli et al., 1994 and 1997, companion paper). Plasma levels of corticosterone are also positively correlated with the susceptibility to acquire psychomotor stimulant SA when corticosterone is measured after stress (Piazza et al., 1991) or immediately before a SA session (Goeders and Guerin, 1994). The administration of corticosterone concomitantly with amphetamine induces the acquisition of SA in animals which do not acquire this behavior spontaneously (Piazza et al., 1991). Finally, a chronic pharmacological blockade of corticosterone secretion with metyrapone decreases the intake of cocaine during a test for relapse (Piazza et al., 1994). In this report, we extended the pharmacological study of the influence of glucocorticoids on the reinforcing effects of psychostimulants. In particular, we investigated the effects of corticosterone on cocaine SA as a function of cocaine doses and corticosterone concentrations. These experiments were undertaken because only single-dose investigations have as yet been reported. Indeed, without complete dose-response information, the relationship between corticosterone and the reinforcing effects of psychostimulants can not be clearly understood. To better characterize the interaction between Received for publication August 5, 1996. 1 This work was supported by INSERM, Université de Bordeaux II, IFRno8 Conseil Régional d’Aquitaine, Pôle Médicament Aquitaine. ABBREVIATIONS: SA, intravenous self-administration; ADX, adrenalectomy. 0022-3565/97/2813-1401$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 281, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 281:1401–1407, 1997 1401 at A PE T Jornals on M ay 9, 2017 jpet.asjournals.org D ow nladed from corticosterone and the reinforcing effects of the drug, the influence of corticosterone on the reinstatement of cocaine SA was also investigated. Reinstatement of drug SA is believed to reflect craving for the drug (de Wit and Stewart, 1981, 1983). In the first experiment, we studied intravenous SA of cocaine (0.8 mg/kg/infusion) in rats in which endogenous corticosterone had been removed by ADX and in adrenalectomized rats receiving substitutive treatments reproducing different plasma corticosterone levels. Once the corticosterone-substitutive treatment reversing the effects of ADX was identified, a full dose-response curve for cocaine SA was performed. In the second experiment, we tested the effects of the administration of different doses of corticosterone (0.09, 0.18, 0.37, 0.58, 075 mg/kg i.v.) on the reinstatement of cocaine SA in intact rats which were submitted to extinction after the stabilization of cocaine SA (0.25 mg/kg/infusion). Finally, in the third experiment, we measured the effect, on plasma corticosterone levels, of the two doses of corticosterone (0.37 and 0.58 mg/kg i.v.) which had a significant effect on reinstatement of cocaine SA.