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.