Inactivation of the cholinergic M4 receptor results in a disinhibited endophenotype predicting alcohol use

The muscarinic cholinergic M4 receptor subtype (M4 mAChR) is densely expressed in brain areas known to be involved in the reinforcing effects of drugs of abuse and we were the first to show that mice lacking M4 mAChRs exhibit elevated operant responding for alcohol and reduced capacity to extinguish this alcohol-seeking behaviour. Here we explore possible underlying determinants of this phenotype. We subjected M4 mAChR knockout mice and their littermate wildtype controls to tests of spontaneous activity, learning and memory, novelty seeking, as well as anxiety and examined the relationship of a newly discovered “disinhibited” endophenotype of these mice with voluntary alcohol consumption and relapse. We found a positive correlation between “disinhibited” behaviour on the plus maze and alcohol preference as well as relapse to alcohol drinking after a period of abstinence. Taken together, these data point to M4 mAChRs as a potential target for improved treatment strategies for alcohol use disorder. This receptor should be further investigated for its involvement in modulating behavioural inhibition in relation to loss of control over consumption of alcohol. •Deletion of the cholinergic M4 receptor leads to a disinhibited endophenotype in mice.•M4 deficient mice drink more alcohol and show a greater preference for alcohol.•M4 deficient mice show more relapse-like drinking after a period of abstinence.•Disinhibited behavior correlates with alcohol consumption and relapse-like drinking.