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The Journal of Neuroscience, June 1, 2003, 23(11):4785-4790

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The Glucocorticoid Receptor as a Potential Target to Reduce Cocaine Abuse

Véronique Deroche-Gamonet,^1 * Inge Sillaber,^2 * Bruno Aouizerate,¹ Ryozuke Izawa,¹ Mohamed Jaber,¹ Sandy Ghozland,¹ Christoph Kellendonk,³ Michel Le Moal,¹ Rainer Spanagel,⁴ Günther Schütz,³ François Tronche,^3,5 and Pier Vincenzo Piazza¹

¹ Institut National de la Santé et de la Recherche Médicale, Unité 588, Bordeaux 33077, France, ² Max Planck Institute of Psychiatry, D-80804 Munich, Germany, ³ Molecular Biology of the Cell I, Deutsches Krebsforschungzentrum, 69120 Heidelberg, Germany, ⁴ Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, 68159 Mannheim, Germany, and ⁵ Centre National de la Recherche Scientifique, FRE2401, Institut de Biologie, Collège de France, Paris 75231 Cedex 5, France

Several findings suggest that glucocorticoid hormones are involved in determining the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor. In this study, we show that the selective inactivation of the GR gene in the brains of mice profoundly flattened the dose–response function for cocaine intravenous self-administration and suppressed sensitization, two experimental procedures considered relevant models of addiction. Furthermore, administration of a GR antagonist dose-dependently reduced the motivation to self-administer cocaine. Importantly, the absence of GR did not modify the basal behavioral and molecular effects of cocaine but selectively modified the excessive response to the drug spontaneously present in certain vulnerable individuals or induced by repeated drug exposure in others. In conclusion, we provide the first genetic evidence that the GR gene can modulate cocaine abuse. This suggests that targeting GR function in the brain could provide new therapeutic strategies to treat cocaine addiction for which there is no available treatment.

Key words: cocaine; self-administration; intravenous; sensitization; glucocorticoid receptor; mifepristone; transgenic; c-Fos

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Received Dec. 9, 2002; revised Mar. 21, 2003; accepted Mar. 21, 2003.

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