1. COX-2 Inhibition Antagonizes Intra-Accumbens 2-Arachidonoylglycerol-Mediated Reduction in Ethanol Self-Administration in Rats.
- Author
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Pavon FJ, Polis I, Stouffer DG, Roberto M, Martin-Fardon R, Rodriguez de Fonseca F, Parsons LH, and Serrano A
- Subjects
- Animals, Arachidonic Acids antagonists & inhibitors, Biphenyl Compounds pharmacology, Dose-Response Relationship, Drug, Endocannabinoids antagonists & inhibitors, Glycerides antagonists & inhibitors, Male, Nucleus Accumbens physiology, Polyunsaturated Alkamides pharmacology, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1 drug effects, Receptor, Cannabinoid, CB1 metabolism, Rimonabant pharmacology, Self Administration, Sulfonamides pharmacology, Alcohol Drinking drug therapy, Arachidonic Acids pharmacology, Cyclooxygenase 2 Inhibitors pharmacology, Endocannabinoids pharmacology, Glycerides pharmacology, Nucleus Accumbens drug effects
- Abstract
Background: Ethanol (EtOH) self-administration is particularly sensitive to the modulation of CB
1 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., Methods: 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., Results: 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., Conclusions: 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., (© 2020 by the Research Society on Alcoholism.)- Published
- 2020
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