The relative paucity of data implicating 2-AG in mediating the reinforcing effects of ethanol is due to the lack of selective pharmacological and genetic tools available when the previous studies were conducted. However, some of the data presently available do implicate this EC transmitter in mediating the reinforcing properties of ethanol. Notably, self-administration of ethanol increases interstitial levels of 2-AG in the NAc that are correlated with the amount of ethanol consumed, but does not alter levels of AEA in this brain region (Caillé et al., 2007). Additionally, a methamphetamine-induced neurotoxic lesion of nigrostriatal dopaminergic projections (Granado et al., 2010; Sanchez et al., 2003) is associated with increased levels of ethanol consumption and preference, and this mouse model of enhanced ethanol intake displays increased tissue concentrations of 2-AG in limbic forebrain sections containing anterior cingulate and NAc (Gutierrez-Lopez et al., 2010). Furthermore, these investigators found that enhanced ethanol consumption and preference were also observed in intact mice treated with the MAGL inhibitor N-arachidonyl maleimide. However, future studies using more specific MAGL inhibitors and MAGL KO mice should be employed to discriminate the roles of AEA and 2-AG in mediating the effects of ethanol.
