Dose- and sex-related effects of the MAGL inhibitor MCH11 on binge-like ethanol consumption in mice.

The effects of MCH11, a novel monoacylglycerol lipase inhibitor, were evaluated on binge-like ethanol consumption using the drinking-in-the-dark paradigm in male and female C57BL/6J mice. Rodents underwent 4 weeks of binge drinking, and MCH11 (20 and 40 mg kg-1, i.p.) was administered acutely (day 4, DID-3) or repeatedly (days 1-4, DID-4). Quantitative PCR assessed tyrosine hydroxylase (Th) in the ventral tegmental area (VTA); dopamine receptor 2 (Drd2) in the prefrontal cortex (PFC) and nucleus accumbens (NAc); and mu-opioid receptor (Oprm1), cannabinoid 1 (Cnr1), and cannabinoid 2 (Cnr2) receptors in the NAc. Across the DID paradigm, females consistently consumed more ethanol than males. Acute MCH11 (40 mg kg-1, i.p.) significantly reduced ethanol intake in both sexes. Following repeated administration, ethanol consumption decreased in females at both tested doses. In contrast, in males, this effect was observed only at the higher dose, indicating sex-related differences in dose sensitivity under chronic treatment conditions. Ethanol exposure induced sex-specific transcriptional adaptations, including male-predominant increases in Th in the VTA and Cnr1 in the NAc, and opposite regulation of Drd2 in the NAc between sexes. Oprm1 in NAc was upregulated in both, with a greater magnitude in males, whereas Cnr2 in NAc and Drd2 in PFC decreased equally. MCH11 modulated ethanol-associated transcriptional changes in males at 40 mg kg-1 and in females at 20 and 40 mg kg-1, in parallel with the observed behavioral effects. Together, these findings demonstrate that MCH11 attenuates binge-like ethanol consumption, with dose- and sex-related differences, and highlight its therapeutic potential to modulate binge drinking behavior.