Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Biol Psychiatry. 2020 Dec 15;88(12):898-909. doi: 10.1016/j.biopsych.2020.02.019. Epub 2020 Feb 29.
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.
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.
We found that G protein-coupled receptors were the top canonical pathway differentially regulated in individuals with AUD. The M 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 mAChR, specifically on dopamine D receptor-expressing medium spiny neurons in the rat dorsolateral striatum. Systemic administration of the selective M 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.
Collectively, these results identify the M mAChR as a potential therapeutic target for the treatment of AUD and the D receptor-positive medium spiny neurons in the dorsolateral striatum as a key site mediating the actions of M mAChR in relation to alcohol consumption and seeking.
酒精使用障碍（AUD）是社会面临的重大社会经济负担，而目前的药物治疗选择并不充分。异常的饮酒行为和觅酒行为改变了额眶皮质-纹状体功能。
我们对人类 AUD 样本的尾状核-壳核进行了全基因组 RNA 测序，并随后进行了定量聚合酶链反应和受体结合验证，以确定潜在的治疗靶点。然后，我们将我们的顶级候选靶点反向翻译成长期饮酒的啮齿动物模型，以评估大鼠纹状体中分子适应的一致性。最后，我们采用了大鼠酒精摄入和觅酒行为模型来验证潜在的治疗靶点。
我们发现，G 蛋白偶联受体是 AUD 患者中差异调节的顶级经典途径。纹状体中的 M 毒蕈碱乙酰胆碱受体（mAChR）在基因和蛋白水平上均下调，但尾状核中没有下调。我们发现，大鼠背外侧纹状体多巴胺 D 受体表达的中型棘神经元上的 M mAChR 表达也存在一致的下调。系统给予选择性 M mAChR 正变构调节剂 VU0467154 可减少大鼠的自发饮酒、操作式酒精自我给药、获取酒精的动机以及线索诱导的觅酒复燃。在大鼠背外侧纹状体局部微注射 VU0467154 可减少酒精自我给药和线索诱导的觅酒复燃。
总的来说，这些结果表明 M mAChR 可作为治疗 AUD 的潜在治疗靶点，而背外侧纹状体中的 D 受体阳性中型棘神经元作为介导 M mAChR 与酒精消耗和觅酒相关作用的关键部位。
