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Bimodal control of stimulated food intake by the endocannabinoid system


Activation of cannabinoid type-1 receptors (CB1) is universally recognized as a powerful endogenous orexigenic signal, but the detailed underlying neuronal mechanisms are not fully understood. Using combined genetic and pharmacological approaches in mice, we found that ventral striatal CB1 receptors exerted a hypophagic action through inhibition of GABAergic transmission. Conversely, brain CB1 receptors modulating excitatory transmission mediated the well-known orexigenic effects of cannabinoids.

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Figure 1: Deletion of CB1 from cortical glutamatergic or GABAergic neurons has opposing effects on fasting-induced food intake.
Figure 2: The hyperphagic and hypophagic effects of THC depend on CB1-mediated modulation of glutamatergic and ventrostriatal GABAergic transmission, respectively.


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We thank F. George, P. Ciofi, V. Deroche-Gamonet and O. Moustie for help, D. Gonzales and the Genotyping Platform of the NeuroCentre Magendie for mouse genotyping, S.K. Nave, J. Rubenstein, M. Ekker, G. Schütz, T. Lemberger for providing Cre-expressing mice, and C.T. Wotjak, U. Pagotto, K. Monory, J. Lourenço, M. Vallée, B. Lutz and all the members of the Marsicano laboratory for valuable suggestions. This work was supported by AVENIR/INSERM and Fondation Bettencourt-Schueller (G.M.), Agence National de la Recherche (ANR-06-NEURO-043-01 to G.M.), the European Foundation for the Study of Diabetes (G.M.), European Union Seventh Framework Program (REPROBESITY, HEALTH-F2-2008-223713 to G.M.), European Commission Network of European Neuroscience Institutes (ENINET) (LSHM-CT-2005-19063 to G.M.), the Basque Country Government (GIC07/70-IT-432-07 to P.G.), Red de Trastornos Adictivos, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Gobierno de España (RD07/0001/2001 to P.G.) and Basque Country University (N.P.).

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Authors and Affiliations



L.B. designed and performed experiments. P.L. carried out part of the food-intake experiments. A.C., N.P. and P.G. performed the anatomical experiments. D.C., F.C. and P.V.P. contributed to experimental design. P.V.P. and G.M. wrote the manuscript. All the authors edited the manuscript. G.M. conceived and supervised the project.

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Correspondence to Giovanni Marsicano.

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Competing interests

The authors have filed a patent application (European Patent Office, “Compositions targeting CB1 receptor for controlling food intake”, EP09306163.8) that is based, in part, on the results of this study.

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Supplementary Figures 1–14 and Supplementary Methods (PDF 2038 kb)

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Bellocchio, L., Lafenêtre, P., Cannich, A. et al. Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci 13, 281–283 (2010).

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