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. doi: 10.1111/acer.14456. Epub 2020 Oct 3.


Background: 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.

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.

Keywords: 2-Arachidonoyl Glycerol; Cyclooxygenase-2; Ethanol; Nucleus Accumbens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / drug therapy*
  • Animals
  • Arachidonic Acids / antagonists & inhibitors
  • Arachidonic Acids / pharmacology*
  • Biphenyl Compounds / pharmacology
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Endocannabinoids / antagonists & inhibitors
  • Endocannabinoids / pharmacology*
  • Glycerides / antagonists & inhibitors
  • Glycerides / pharmacology*
  • Male
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Polyunsaturated Alkamides / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / drug effects
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant / pharmacology
  • Self Administration
  • Sulfonamides / pharmacology


  • Arachidonic Acids
  • Biphenyl Compounds
  • Cyclooxygenase 2 Inhibitors
  • Endocannabinoids
  • Glycerides
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Sulfonamides
  • URB602
  • glyceryl 2-arachidonate
  • Rimonabant
  • anandamide
  • nimesulide