Abstract
The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.
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Acknowledgements
We thank Delphine Gonzales and the Genotyping Platform of the NeuroCentre Magendie for mouse genotyping. We thank Cédric Dupuy for providing excellent care to animals. We thank Dr R Rozeske and Vernon Garcia Rivas for precious help with editing. This work was supported by INSERM, the University of Bordeaux and the Aquitaine Region (to VDG, PVP, GM, UM), by the Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, and the Agence Nationale de la Recherche (ANR Blanc ANR-13-BSV4–0006-02) (to GM), the DG Research of the European Commission FP7 [#HEALTH-F2 2013–602891 (to RM), HEALTH-60319 and ERC–2010–StG–260515 (to GM)], the Spanish ‘RETICS-Instituto de Salud Carlos III’ (#RD12/0028/0023), the Spanish ‘Ministerio de Ciencia e Innovación’ (#SAF2011–29864, no. SAF2011–29864, #SAF2013-40592-R, no. SAF2013-40592-R) and the Catalan Government ‘AGAUR-Generalitat de Catalunya’ (#2009SGR00731 and #2014-SGR-1547) (to RM), The Basque Government grant BCG IT764-13, Ministerio de Economía y Competitividad (MINECO) grant BFU2012-33334, University of the Basque Country UPV/EHU UFI11/41 and Red de Trastornos Adictivos - Instituto de Salud Carlos III grant RD12/0028/0004 (to PG). The FEDER funds support is also acknowledged. EM-G was supported by a ‘Sara Borrell’ post-doctoral fellowship from the Spanish ‘Instituto de Salud Carlos III’. FK was supported by an Aquitaine Region post-doctoral grant.
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Martín-García, E., Bourgoin, L., Cathala, A. et al. Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors. Neuropsychopharmacol 41, 2192–2205 (2016). https://doi.org/10.1038/npp.2015.351
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DOI: https://doi.org/10.1038/npp.2015.351
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