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Title: Acetylcholine Muscarinic M<inf>4</inf> Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodents
Authors: Leigh C. Walker
Alice E. Berizzi
Nicola A. Chen
Patricia Rueda
Victoria M. Perreau
Katherine Huckstep
Jirawoot Srisontiyakul
Piyarat Govitrapong
Jia Xiaojian
Craig W. Lindsley
Carrie K. Jones
Darren M. Riddy
Arthur Christopoulos
Christopher J. Langmead
Andrew J. Lawrence
Monash Institute of Pharmaceutical Sciences
University of Melbourne
Mahidol University
Vanderbilt University
Shenzhen University
Keywords: Neuroscience
Issue Date: 1-Jan-2020
Citation: Biological Psychiatry. (2020)
Abstract: © 2020 Society of Biological Psychiatry 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.
ISSN: 18732402
Appears in Collections:Scopus 2020

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