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dc.contributor.authorLeigh C. Walkeren_US
dc.contributor.authorAlice E. Berizzien_US
dc.contributor.authorNicola A. Chenen_US
dc.contributor.authorPatricia Ruedaen_US
dc.contributor.authorVictoria M. Perreauen_US
dc.contributor.authorKatherine Huckstepen_US
dc.contributor.authorJirawoot Srisontiyakulen_US
dc.contributor.authorPiyarat Govitrapongen_US
dc.contributor.authorJia Xiaojianen_US
dc.contributor.authorCraig W. Lindsleyen_US
dc.contributor.authorCarrie K. Jonesen_US
dc.contributor.authorDarren M. Riddyen_US
dc.contributor.authorArthur Christopoulosen_US
dc.contributor.authorChristopher J. Langmeaden_US
dc.contributor.authorAndrew J. Lawrenceen_US
dc.contributor.otherMonash Institute of Pharmaceutical Sciencesen_US
dc.contributor.otherUniversity of Melbourneen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherVanderbilt Universityen_US
dc.contributor.otherShenzhen Universityen_US
dc.identifier.citationBiological Psychiatry. (2020)en_US
dc.description.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.en_US
dc.rightsMahidol Universityen_US
dc.titleAcetylcholine Muscarinic M<inf>4</inf> Receptors as a Therapeutic Target for Alcohol Use Disorder: Converging Evidence From Humans and Rodentsen_US
Appears in Collections:Scopus 2020

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