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The Journal of Neuroscience, May 1, 2003, 23(9):3572

BRIEF COMMUNICATION
₁ Receptor-Related Neuroactive Steroids Modulate Cocaine-Induced Reward

Pascal Romieu¹, Rémi Martin-Fardon², Wayne D. Bowen³, and Tangui Maurice¹

¹ Centre National de la Recherche Scientifique Unité Mixte de Recherche 5102, University of Montpellier II, 34095 Montpellier cedex 5, France, ² Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92307, and ³ Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

The ₁ receptor is critically involved in the rewarding effect of cocaine, as measured using the conditioned place preference (CPP) procedure in mice. Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA_A, NMDA, and ₁ receptors. At the ₁ receptor level, 3-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and 3-hydroxy-5-pregnen-20-one (pregnenolone) act as agonists, whereas 4-pregnene-3,20-dione (progesterone) is an efficient antagonist. The present study sought to investigate the action of neuroactive steroids in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these steroids induced CPP alone. However, pretreatment with DHEA or pregnenolone (5-20 mg/kg, s.c.) during conditioning with cocaine (10 mg/kg, i.p.) increased the conditioned score. On the contrary, pretreatment with either progesterone (10 or 20 mg/kg, s.c.) or finasteride (25 mg/kg, twice a day), a 5-reductase inhibitor, blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed pharmacology was observed between steroids and ₁ ligands. The ₁ antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine blocked cocaine-induced CPP and its potentiation by DHEA or pregnenolone. Progesterone blocked cocaine-induced CPP and its potentiation by the ₁ agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the ₁ receptor. Therefore, neuroendocrine control of cocaine addiction may not involve solely glucocorticoids. The importance of neuroactive steroids as factors of individual vulnerability to drug addiction should, thus, be considered.

Key words: cocaine; neuroactive steroids; locomotor activity; reward; convulsions; ₁ receptor

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2393572-05$05.00/0

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