title: Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.
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.
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.|Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Bourgoin
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Cathala
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Fernando
authors.identifier: 0000-0003-4585-2314
authors.initials: F
authors.lastname: Kasanetz
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mondesir
authors.affiliation: Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Rodriguez
authors.affiliation: Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Reguero
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fiancette
authors.affiliation: Department of Neurosciences, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU, Leioa, Spain.|Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Grandes
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Umberto
authors.initials: U
authors.lastname: Spampinato
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Piazza
authors.affiliation: University of Bordeaux, Bordeaux, France.|INSERM U862, Endocannabinoids and Neuroadaptation, NeuroCentre Magendie, Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.affiliation: INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux, France.|University of Bordeaux, Bordeaux, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Deroche-Gamonet
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage*; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D058999:Drug-Seeking Behavior; D059330:GABAergic Neurons / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D043884:Receptor, Cannabinoid, CB1; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D003042:Cocaine; D004298:Dopamine