Acetylcholine Muscarinic M₄ Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents

Background: Alcohol use disorder (AUD) is a major socioeconomic burden on society, and current pharmacotherapeutic treatment options are inadequate. Aberrant alcohol use and seeking alters frontostriatal function.

Methods: We performed genome-wide RNA sequencing and subsequent quantitative polymerase chain reaction and receptor binding validation in the caudate-putamen of human AUD samples to identify potential therapeutic targets. We then back-translated our top candidate targets into a rodent model of long-term alcohol consumption to assess concordance of molecular adaptations in the rat striatum. Finally, we adopted rat behavioral models of alcohol intake and seeking to validate a potential therapeutic target.

Results: We found that G protein-coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M₄ muscarinic acetylcholine receptor (mAChR) was downregulated at the gene and protein levels in the putamen, but not in the caudate, of AUD samples. We found concordant downregulation of the M₄ mAChR, specifically on dopamine D₁ receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M₄ mAChR positive allosteric modulator, VU0467154, reduced home cage and operant alcohol self-administration, motivation to obtain alcohol, and cue-induced reinstatement of alcohol seeking in rats. Local microinjections of VU0467154 in the rat dorsolateral striatum reduced alcohol self-administration and cue-induced reinstatement of alcohol seeking.

Conclusions: Collectively, these results identify the M₄ mAChR as a potential therapeutic target for the treatment of AUD and the D₁ receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M₄ mAChR in relation to alcohol consumption and seeking.