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The Journal of Neuroscience, February 1, 2002, 22(3):1146-1154

Motivational Effects of Cannabinoids Are Mediated by µ-Opioid and -Opioid Receptors

Sandy Ghozland¹, Hans W. D. Matthes², Frederic Simonin², Dominique Filliol², Brigitte L. Kieffer², and Rafael Maldonado¹

¹ Laboratori de Neurofarmacologia, Facultat de Ciéncies de la Salut i de la Vida, Universitat Pompeu Fabra, 08003 Barcelona, Spain, and ² Centre National de la Recherche Scientifique Unité Propre de Recherche 9050, Ecole Superieure de Biotechnologie de Strasbourg, 67400 Illkirch, France

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored 9-tetrahydrocannabinol (THC) activity in mice lacking µ-, - or -opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of µ receptors abolishes THC place preference. Deletion of  receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of µ- and -opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

Key words: 9-tetrahydrocannabinol; place preference; place aversion; knock-out; tolerance; dependence; reward

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2231146-09$05.00/0

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