Pavon, Francisco JPolis, IlhamStouffer, David GRoberto, MarisaMartin-Fardon, RemiRodrIguez de Fonseca, FernandoParsons, Loren HSerrano, Antonia2023-02-092023-02-092020-10-03Pavon FJ, Polis I, Stouffer DG, Roberto M, Martin-Fardon R, Rodriguez de Fonseca F, et al. COX-2 Inhibition Antagonizes Intra-Accumbens 2-Arachidonoylglycerol-Mediated Reduction in Ethanol Self-Administration in Rats. Alcohol Clin Exp Res. 2020 Nov;44(11):2158-2165http://hdl.handle.net/10668/16274Ethanol (EtOH) self-administration is particularly sensitive to the modulation of CB1 signaling in the nucleus accumbens (NAc) shell, and EtOH consumption increases extracellular levels of the endogenous cannabinoid CB1 receptor agonist 2-arachidonoyl glycerol (2-AG) in this brain region. Stimulation of CB1 receptor with agonists increases EtOH consumption, suggesting that EtOH-induced increases in 2-AG might sustain motivation for EtOH intake. In order to further explore this hypothesis, we analyzed the alterations in operant EtOH self-administration induced by intra-NAc shell infusions of 2-AG itself, the CB1 inverse agonist SR141716A, the 2-AG clearance inhibitor URB602, anandamide, and the cyclooxygenase-2 (COX-2) inhibitor nimesulide. Surprisingly, self-administration of 10% EtOH was dose-dependently reduced by either intra-NAc shell SR141716A or 2-AG infusions. Similar effects were found by intra-NAc shell infusions of URB602, suggesting again a role for accumbal 2-AG on the modulation of EtOH intake. Intra-NAc shell anandamide did not alter EtOH self-administration, pointing to a specific role for 2-AG in the modulation of EtOH self-administration. Finally, the inhibitory effect of intra-NAc shell 2-AG on EtOH intake was significantly reversed by pretreatment with nimesulide, suggesting that oxidative metabolites of 2-AG might mediate these inhibitory effects on operant self-administration. We propose that 2-AG signaling in the NAc exerts an inhibitory influence on EtOH consumption through a non-CB1 receptor mechanism involving the COX-2 pathway.en2-Arachidonoyl glycerolCyclooxygenase-2EthanolNucleus accumbensAlcohol drinkingAnimalsArachidonic acidsBiphenyl compoundsCyclooxygenase 2 inhibitorsDose-Response relationship, drugEndocannabinoidsGlyceridesMaleNucleus accumbensPolyunsaturated alkamidesRatsRats, WistarReceptor, cannabinoid, CB1RimonabantSelf administrationSulfonamidesresearch article32944989open accessAlcamidas poliinsaturadasAnimalesCompuestos de bifeniloConsumo de bebidas alcohólicasEndocannabinoidesGlicéridosInhibidores de la ciclooxigenasa 2Núcleo accumbensRatas wistarReceptor cannabinoide CB1RimonabantSulfonamidasÁcidos araquidónicos10.1111/acer.144561530-0277PMC7680444https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680444https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680444/pdf