Involvement of 2-arachidonoyl glycerol in the increased consumption of and preference for ethanol of mice treated with neurotoxic doses of methamphetamine

Background and purpose: Methamphetamine (METH) is a psychostimulant amphetamine that causes long-term dopaminergic neurotoxicity in mice. Hypodopaminergic states have been demonstrated to increase voluntary ethanol (EtOH) consumption and preference. In addition, the endocannabinoid system has been demonstrated to modulate EtOH drinking behaviour. Thus, we investigated EtOH consumption in METH-lesioned animals and the role of cannabinoid (CB) signalling in this EtOH drinking. Experimental approach: Mice were treated with a neurotoxic regimen of METH, and 7 days later exposed to increasing concentrations of drinking solutions of EtOH (3, 6, 10 and 20%). Seven days after neurotoxic METH, the following biochemical determinations were carried out in limbic forebrain: CB(1) receptor density and stimulated activity, 2-arachidonoyl glycerol (2-AG) and monoacylglycerol lipase (MAGL) activity, dopamine levels and dopamine transporter density. Key results: EtOH consumption and preference were increased in METH-treated mice. Seven days after METH, a time at which both dopamine levels and density of dopamine transporters in limbic forebrain were decreased, CB(1) receptor density and activity were unaltered, but 2-AG levels were increased. At this same time-point, MAGL activity was reduced. The CB(1) receptor antagonist AM251 prevented the METH-induced increase in EtOH consumption and preference, while N-arachidonoyl maleimide, an inhibitor of MAGL, increased EtOH consumption and preference in both saline- and METH-treated mice. Conclusions and implications: An increase in endocannabinoid tone may be involved in the increased consumption of and preference for EtOH displayed by METH-lesioned mice as blockade of the CB(1) receptor decreased EtOH-seeking behaviours, whereas the MAGL inhibitor increased EtOH consumption. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x.