期刊
BIOLOGICAL PSYCHIATRY
卷 88, 期 12, 页码 898-909出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2020.02.019
关键词
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资金
- University of Sydney
- National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health [R28AA012725]
- National Health and Medical Research Council [1120576, 1116930]
- Thai Royal Golden Jubilee PhD Program [PHD/0253/2552]
- Mahidol University
- National Health and Medical Research Council of Australia [1120576] Funding Source: NHMRC
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 M-4 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 M-4 mAChR, specifically on dopamine D-1 receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M-4 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 M-4 mAChR as a potential therapeutic target for the treatment of AUD and the D-1 receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M-4 mAChR in relation to alcohol consumption and seeking.
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