Suchergebnisse

Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches. The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction. Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction. The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction. However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped. Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors. Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches. ; We acknowledge the financial support of the Spanish MINECO (#SAF2017-84060-R-AEI/FEDER-UE), Instituto de Salud Carlos III-RETICS(##RD16/0017/0020), Ministerio de Sanidad, Servicios Sociales e Igualdad-Plan Nacional Sobre Drogas (#PNSD-2017I068), and the Generalitat de Catalunya-AGAUR ((#2017-SGR-669 and #ICREA Acadèmia2015) and the European Commission-DG RTD (#FP7-HEALTH-F2-2013-602891-NeuroPain) to RM. FEDER funding support is also acknowledged. This work was supported by Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU) (RD16/0017/0012), The Basque Government (BCG IT764-13) and MINECO/FEDER, UE(SAF2015-65034-R) to PG. This research was supported by Instituto de Salud Carlos III (RETICS, RD12/0028/0019, RD16/0017/0014 and RD06/0001/1004), Plan Nacional Sobre Drogas (PNSD 2016/016 and 2007/061), Ministerio de Economía y Competitividad (FIS, PI14/00438) and Ministerio de Ciencia e Innovación (SAF2008-01106) to JM

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. ; 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-13BSV4–0006-02) (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

Funding: This work was supported by CIBERobn (CB06/03/1008), Ministerio de Economía y Competitividad (MINECO) (PG: BFU2012-33334), Instituto de Salud Carlos III (ISCIII), MINECO, co-funded by UE-ERDF program (JS: CP12/03109), Red de Trastornos Adictivos (FRF: RD12/0028/0001, PG: RD12/0028/0004, JM: RD12/0028/0013), The Basque Country Government (PG: BCG IT764-13), Consejería de Economía, Innovación y Ciencia, Junta de Andalucía, UE-ERDF (FRF: CTS-8221, JM: CVI-6656), Consejería de Salud, Junta de Andalucía, UE-ERDF (FRF: SAS111224), and University of the Basque Country UPV/EHU (PG: UFI11/41). JS, FJP and AS hold "Miguel Servet" research contracts from the National System of Health, ISCIII, UE-ERDF (CP12/03109, CP14/00212, and CP14/00173 respectively) ; Peer reviewed ; Publisher PDF