Leigh C Walker1, Alice E Berizzi2, Nicola A Chen1, Patricia Rueda2, Victoria M Perreau1, Katherine Huckstep1, Jirawoot Srisontiyakul3, Piyarat Govitrapong3, Jia Xiaojian4, Craig W Lindsley5, Carrie K Jones5, Darren M Riddy2, Arthur Christopoulos2, Christopher J Langmead6, Andrew J Lawrence7. 1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. 2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. 3. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand. 4. Shenzhen Kangning Hospital, Shenzhen University Health Science Center, Shenzhen, China; Shenzhen Mental Health Center, Shenzhen University Health Science Center, Shenzhen, China. 5. Department of Pharmacology, Vanderbilt Center for Neuroscience and Drug Discovery, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt Center for Neuroscience and Drug Discovery, Vanderbilt University, Nashville, Tennessee. 6. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. Electronic address: chris.langmead@monash.edu. 7. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. Electronic address: andrew.lawrence@florey.edu.au.
Abstract
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.
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.
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