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The Journal of Neuroscience, June 27, 2007, 27(26):6937-6947; doi:10.1523/JNEUROSCI.3936-06.2007
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Behavioral/Systems/Cognitive
Role of Cannabinoid Type 1 Receptors in Locomotor Activity and Striatal Signaling in Response to Psychostimulants
Anne-Gaëlle Corbillé,1,2,3 * Emmanuel Valjent,1,2,3 * Giovanni Marsicano,4 Catherine Ledent,5 Beat Lutz,4 Denis Hervé,1,2,3 andJean-Antoine Girault1,2,3 1Inserm, U839, F-75005 Paris, France, 2Université Pierre et Marie Curie (UPMC-Paris 6), F-75005 Paris, France, 3Institut du Fer a Moulin, F-75005 Paris, France, 4Department of Physiological Chemistry, Johannes Gutenberg University, D-55099 Mainz, Germany, and 5Institut de Recherches en Biologie Humaine et Moléculaire, Université de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium
Correspondence should be addressed to Jean-Antoine Girault, Inserm U839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: jean-antoine.girault{at}fer-a-moulin.inserm.fr
A single administration of cocaine or D-amphetamine produces acute hyperlocomotion and long-lasting increased sensitivity to subsequent injections. This locomotor sensitization reveals the powerful ability of psychostimulants to induce brain plasticity and may participate in the alterations that underlie addiction. We investigated the role of cannabinoid receptor type 1 (CB1-R) in the effects of a single injection of psychostimulants. The acute locomotor response to cocaine was normal in mice pretreated with the CB1-R inverse agonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), whereas no sensitization was observed in response to a second administration a week later. Locomotor responses to cocaine and D-amphetamine were decreased in CB1-R-deficient mice, and sensitization was impaired. To determine how CB1-R controls long-lasting effects of psychostimulants, we studied cocaine-activated signaling pathways. Cocaine-induced cAMP-dependent phosphorylation of glutamate receptor 1 was altered in the striatum of CB1-R mutant mice but not of AM251-treated mice. In contrast, cocaine-induced phosphorylation of extracellular signal-regulated kinase (ERK) was blocked in both CB1-R mutant and antagonist-pretreated mice. Conditional deletion of CB1-R in forebrain principal neurons or GABAergic neurons prevented cocaine-induced ERK activation in dorsal striatum and nucleus accumbens. Our results provide strong evidence for the role of the endocannabinoid system in regulating neuronal circuits critical for long-lasting effects of cocaine, presumably by acting on CB1-R located on terminals of striatal medium spiny neurons.
Key words: cocaine; sensitization; extracellular signal-regulated kinase; endocannabinoids; striatum; GluR1; DARPP-32; AM251; rimonabant; conditional knock-out
Received Sept. 11, 2006; revised May 19, 2007; accepted May 19, 2007.
Correspondence should be addressed to Jean-Antoine Girault, Inserm U839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: jean-antoine.girault{at}fer-a-moulin.inserm.fr
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[Abstract] [Full Text] [PDF]
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