Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants.
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.
Corbillé
Anne-Gaëlle
AG
Inserm, U839, F-75005 Paris, France.
Valjent
Emmanuel
E
Marsicano
Giovanni
G
Ledent
Catherine
C
Lutz
Beat
B
Hervé
Denis
D
Girault
Jean-Antoine
JA
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000697:Central Nervous System Stimulants; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine