Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants.

A.-G. Corbille, E. Valjent, G. Marsicano, C. Ledent, B. Lutz, D. Herve, J.-A. Girault
Journal of Neuroscience. 2007-06-27; 27(26): 6937-6947
DOI: 10.1523/jneurosci.3936-06.2007

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1. J Neurosci. 2007 Jun 27;27(26):6937-47.

Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling
in response to psychostimulants.

Corbillé AG(1), Valjent E, Marsicano G, Ledent C, Lutz B, Hervé D, Girault JA.

Author information:
(1)Inserm, U839, F-75005 Paris, France.

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
-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.

DOI: 10.1523/JNEUROSCI.3936-06.2007
PMID: 17596442 [Indexed for MEDLINE]

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