New molecule reduces ethanol intake and drinking motivation in mice, with sex-dependent differences

A new compound tested at the Miguel Hernández University of Elche (UMH) in Spain shows promising effects in reducing alcohol consumption and motivation to drink in mice, with marked sex-dependent differences in efficacy. Although MCH11 is not yet available for human use, it could pave the way for personalized treatments of alcohol use disorder.

The results, published in the journal Biomedicine & Pharmacotherapy, stem from four years of work by a team from the Institute of Neurosciences (a joint UMH–CSIC centre), the Institute for Health and Biomedical Research of Alicante (ISABIAL), and the Primary Care Addiction Research Network (RIAPAD).

Alcohol use disorder is one of the most prevalent addictions worldwide and causes approximately 2.6 million deaths annually. “However, current therapies show serious limitations,” says UMH researcher Abraham Torregrosa, first author of the study. He explains that up to 70% of patients relapse into alcohol use within the first year of treatment.

To seek a more effective pharmacotherapy, the investigators focused on the endocannabinoid system—a signalling network linking the nervous system to the rest of the organism, and involved in the regulation of pleasure, motivation, and stress—all key processes in alcohol addiction. In people with alcohol use disorder, the system becomes imbalanced, reducing levels of molecules such as 2-arachidonoylglycerol (2-AG), which is implicated in well-being and impulse control.

The molecule studied at UMH, MCH11, acts as an inhibitor of monoacylglycerol lipase, an enzyme that degrades 2-AG. By blocking this enzyme, the amount of 2-AG available in the brain increases, reducing both the need to drink and withdrawal symptoms. “Our results show that MCH11 acts on nervous-system mechanisms that help control the drinking impulse, but without undesirable side-effects,” at least in mice and at the doses tested, explains UMH Professor Jorge Manzanares, study leader. “This finding is particularly relevant because impulsive behaviours are closely linked with the development and maintenance of alcoholism,” he adds.

Treatment with MCH11 in mice was shown to be effective and selective, exhibiting anxiolytic and antidepressant properties without impairing motor or cognitive function. However, experiments revealed significant differences between sexes. “In males, the response to the treatment was effective at low and medium doses, while females required higher doses for similar effects,” says Manzanares.

The improvement is visible not only behaviourally, but also genetically. “We know that certain genes are altered in alcohol use disorder, and we found via PCR analysis that MCH11 corrects these alterations in mice of both sexes, although females require a higher dose,” adds Torregrosa.

The team also tested a combined treatment of MCH11 with topiramate, a medication already used clinically for alcohol addiction. “We found that the combination of both compounds is the most effective,” notes Manzanares, who highlights MCH11’s potential as part of a personalized, sex-adapted combined therapy. “The results are very promising, but still preliminary; there is a long road from demonstrating drug efficacy in animal models to applying it in patients,” the UMH Professor concludes.

The work was conducted by Abraham Torregrosa, María García Gutiérrez, Daniela Navarro, Francisco Navarrete, and Jorge Manzanares, members of the Translational Neuropsychopharmacology Group at UMH.

The research was funded by the Ministry of Science, Innovation and Universities; the State Research Agency; RIAPAD (Carlos III Health Institute), and ISABIAL.