MCH11, a new monoacylglycerol lipase inhibitor, reduces ethanol consumption and motivation to drink in mice, with sex-dependent differences

This study examined the effects of the new monoacylglycerol lipase (MAGL) inhibitor, MCH11, on ethanol consumption and motivation in male and female C57BL/6 J mice. First, we evaluated plasma concentrations of MCH11 at different doses (10, 20, 40 mg/kg; i.p.) and time points after its acute administration. Plasma endocannabinoid levels (eCBs) were also measured. Next, the acute dose-response (10, 20, 40 mg/kg; i.p.) effects on motor (open-field), emotional (elevated-plus maze, tail suspension), cognitive (step-down avoidance, object recognition), and impulsive (delayed reinforcement task) behaviors were evaluated. We then investigated MCH11's impact on voluntary ethanol consumption (VEC) and oral self-administration (OEA), along with its synergistic effects with topiramate (TOP) on OEA. Quantitative PCR (qPCR) was used to assess changes in tyrosine hydroxylase (Th), opioid receptor mu 1 (Oprm1), cannabinoid receptor 1 (Cnr1), and cannabinoid receptor 2 (Cnr2) expression in the ventral tegmental area (VTA) and nucleus accumbens (NAc). MCH11 reached its maximum plasma concentration one hour after administration and primarily modulates 2-AG and related eCBs. It produced anxiolytic and antidepressant-like effects without impairing locomotor or cognitive functions, and significantly reduced impulsivity. Ethanol consumption, preference, and drinking motivation decreased in both VEC and OEA. Notably, there were synergistic effects on OEA when combined with TOP. MCH11 significantly modulated the effects of ethanol exposure on Th and Oprm1, Cnr1 and Cnr2 in the VTA and NAc, respectively. The findings revealed remarkable gender-based differences in MCH11's pharmacological effects. These results suggest that MCH11 has potential for treating alcohol dependence but underline gender-related differences in treatment responses.