Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.
Neuropsychopharmacol. 2015-11-27; 41(9): 2192-2205
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1. Neuropsychopharmacology. 2016 Aug;41(9):2192-205. doi: 10.1038/npp.2015.351. Epub
2015 Nov 27.
Differential Control of Cocaine Self-Administration by GABAergic and
Glutamatergic CB1 Cannabinoid Receptors.
Martín-García E(1)(2)(3), Bourgoin L(1)(2), Cathala A(1)(2), Kasanetz F(1)(2),
Mondesir M(1)(2), Gutiérrez-Rodriguez A(4)(5), Reguero L(4)(5), Fiancette
JF(1)(2), Grandes P(4)(5), Spampinato U(1)(2), Maldonado R(3), Piazza PV(1)(2),
Marsicano G(2)(6), Deroche-Gamonet V(1)(2).
(1)INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux,
(2)University of Bordeaux, Bordeaux, France.
(3)Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra,
PRBB, Barcelona, Spain.
(4)Department of Neurosciences, Faculty of Medicine and Dentistry, University of
the Basque Country UPV/EHU, Leioa, Spain.
(5)Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park,
(6)INSERM U862, Endocannabinoids and Neuroadaptation, NeuroCentre Magendie,
Neuropsychopharmacology. 2016 Aug;41(9):2189-91.
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.
PMID: 26612422 [Indexed for MEDLINE]