COX-2 Inhibition Antagonizes Intra-Accumbens 2-Arachidonoylglycerol-Mediated Reduction in Ethanol Self-Administration in Rats.

Autor: Pavon FJ; From the, Department of Neuroscience, (FJP, IP, DGS, LHP, AS), The Scripps Research Institute, La Jolla, California, USA.; Instituto de Investigación Biomédica de Málaga, (IBIMA) (FJP, FRF, AS), Hospital Regional Universitario de Málaga, Unidad de Gestión Clínica de Salud Mental, Malaga, Spain., Polis I; From the, Department of Neuroscience, (FJP, IP, DGS, LHP, AS), The Scripps Research Institute, La Jolla, California, USA., Stouffer DG; From the, Department of Neuroscience, (FJP, IP, DGS, LHP, AS), The Scripps Research Institute, La Jolla, California, USA., Roberto M; Department of Molecular Medicine, (MR, RM-F), The Scripps Research Institute, La Jolla, California, USA., Martin-Fardon R; Department of Molecular Medicine, (MR, RM-F), The Scripps Research Institute, La Jolla, California, USA., Rodriguez de Fonseca F; Instituto de Investigación Biomédica de Málaga, (IBIMA) (FJP, FRF, AS), Hospital Regional Universitario de Málaga, Unidad de Gestión Clínica de Salud Mental, Malaga, Spain., Parsons LH; From the, Department of Neuroscience, (FJP, IP, DGS, LHP, AS), The Scripps Research Institute, La Jolla, California, USA., Serrano A; From the, Department of Neuroscience, (FJP, IP, DGS, LHP, AS), The Scripps Research Institute, La Jolla, California, USA.; Instituto de Investigación Biomédica de Málaga, (IBIMA) (FJP, FRF, AS), Hospital Regional Universitario de Málaga, Unidad de Gestión Clínica de Salud Mental, Malaga, Spain.
Jazyk: angličtina
Zdroj: Alcoholism, clinical and experimental research [Alcohol Clin Exp Res] 2020 Nov; Vol. 44 (11), pp. 2158-2165. Date of Electronic Publication: 2020 Oct 03.
DOI: 10.1111/acer.14456
Abstrakt: 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 CB 1 receptor agonist 2-arachidonoyl glycerol (2-AG) in this brain region. Stimulation of CB 1 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 CB 1 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.)
Databáze: MEDLINE
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