RT Journal Article
T1 COX-2 Inhibition Antagonizes Intra-Accumbens 2-Arachidonoylglycerol-Mediated Reduction in Ethanol Self-Administration in Rats.
A1 Pavon, Francisco J
A1 Polis, Ilham
A1 Stouffer, David G
A1 Roberto, Marisa
A1 Martin-Fardon, Remi
A1 RodrIguez de Fonseca, Fernando
A1 Parsons, Loren H
A1 Serrano, Antonia
K1 2-Arachidonoyl glycerol
K1 Cyclooxygenase-2
K1 Ethanol
K1 Nucleus accumbens
AB Ethanol (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.
PB Wiley
YR 2020
FD 2020-10-03
LK http://hdl.handle.net/10668/16274
UL http://hdl.handle.net/10668/16274
LA en
NO Pavon 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):2158-2165
NO This is manuscript number 29930 from The ScrippsResearch Institute. The present study has been supported bythe following grants: National Institute on Alcohol Abuseand Alcoholism (AA006420, AA017447, AA020404,AA022249, and AA026999), Instituto de Salud Carlos III(ISCIII) and European Regional Development Funds-Euro-pean Union (ERDF-EU; Subprograma RETICS Red deTrastornos Adictivos, RD16/0017/0001), Ministerio deEconom ıa y Competitividad and ISCIII (PI16/01953, PI16/01698, and PI17/02026), Ministerio de Sanidad, ServiciosSociales e Igualdad and Plan Nacional sobre Drogas(PND2017/043, PND2018/033, and PND2018/044), andConsejer ıa de Econom ıa, Innovaci on y Ciencia, Junta deAndaluc ıa and ERDF-EU (CTS-433). FJP and AS hold a“Miguel Servet II” research contract funded by ISCIII andERDF-EU (CPII19/00022 and CPII19/00031, respectively).
DS RISalud
RD Apr 18, 2025