Effects of a Novel mGluR5 Negative Allosteric Modulator on Alcohol Drinking, Neurochemistry, and Brain Reactivity to Alcohol Cues in Alcohol Use Disorder

摘要 酒精使用障碍(AUD)是一个重大的公共卫生问题，给社会带来了巨大的成本 由于暴力、生产力下降和医疗保健支出。尽管进行了数十年的紧张研究， 只有几种FDA批准的治疗AUD的药物，每一种都只有一定的疗效。GET73是 一种有希望的新药，在最初的开发阶段显示出改善AUD的希望 症状，如临床前/动物研究中的戒酒和抗焦虑特性所证明的。 临床前研究也表明GET73的S作用机制与其负变构调节有关 代谢性谷氨酸亚型5受体(MGluR5)，一个新的潜在的治疗靶点 利息。1期临床研究显示，GET73对AUD和AUD患者都是安全和耐受性良好的 健康的志愿者。因此，相当多的初步证据支持GET73是一种新的、安全的、耐受性良好的 AUD的潜在治疗方法。扩展这项临床前和临床研究，拟议的研究 该项目是对GET73对饮酒影响的首次调查，两者都处于严格控制的状态 在实验室环境和自然环境中，在患有澳门氏症的个人中。据称的神经影像指标 GET73作用机制，包括通过质子磁作用的额叶皮质谷氨酸和GABA水平 磁共振波谱(1H-MRS)与脑功能磁共振对酒精刺激的反应 成像(FMRI)，将被作为GET73对饮酒影响的潜在中介进行研究。不接受治疗- 寻找患有AUD的参与者(N=90)将被随机分为GET73(300毫克，3次/天)或安慰剂，接受建议的 为期8天的学习。在随机化之前(第一天)，将完成治疗前的MRI，在此期间，解剖， 1H-MRS和酒精线索反应性fMRI扫描将获得。在第7天，参与者的饮酒超过 将对前五天进行评估，并重复所有MRI程序。在第8天，参与者将消费 一种标准的启动饮料，并接受有限进入酒精自我管理(酒吧-实验室)的范例，在类似的 与之前的查尔斯顿ARC临床研究相适应。假设GET73治疗的参与者，相对 对于接受安慰剂治疗的参与者，在5天的免费入场期和酒吧实验室限制期间将减少饮酒- 进入程序。GET73治疗的参与者也被假设增加了额叶皮质中的 谷氨酸和GABA，反映病理性低谷氨酸和GABA水平的正常化 在没有经历急性酒精戒断的AUD患者中发现，伴随着 认知控制和线索反应相关脑区(如前额内侧)对酒精线索的反应 皮质和腹侧纹状体)。这些影响预计将调停 GET73和饮酒。总体而言，该项目有可能显著推动 AUD的新药物治疗。

SUMMARY Alcohol use disorder (AUD) represents a significant public health concern and confers a large cost to society due to violence, lost productivity, and healthcare expenditures. Despite decades of intense research efforts, there are just a few FDA-approved medications for AUD, each of which are only modestly efficacious. GET73 is a promising new medication that has shown promise in its initial development phase for improving AUD symptoms, as evidenced by anti-alcohol-drinking and anxiolytic properties in preclinical/animal studies. Preclinical research also indicates that GET73’s mechanism of action relates to its negative allosteric modulation of the metabotropic glutamate subtype 5 receptor (mGluR5), a novel potential therapeutic target of growing interest. Phase 1 clinical studies show GET73 to be safe and well-tolerated in both individuals with AUD and healthy volunteers. Thus, considerable preliminary evidence supports GET73 as a new, safe, well-tolerated, and potentially therapeutic treatment for AUD. Extending this preclinical and clinical research, the proposed research project represents the first investigation of the effects of GET73 on alcohol drinking, both in a tightly controlled laboratory setting and in the natural environment, in individuals with AUD. Neuroimaging indicators of purported GET73 mechanisms of action, including fronto-cortical glutamate and GABA levels via proton magnetic resonance spectroscopy (1H-MRS) and brain reactivity to alcohol cues via functional magnetic resonance imaging (fMRI), will be investigated as potential mediators of the effect of GET73 on drinking. Non-treatment- seeking participants with AUD (N=90) will be randomized to GET73 (300 mg, 3x/day) or placebo for the proposed 8-day study. Prior to randomization (Day-1), a pre-treatment MRI will be completed, during which anatomical, 1H-MRS, and alcohol-cue reactivity fMRI scans will be acquired. On Day-7, participants’ drinking over the previous five days will be assessed, and all MRI procedures will be repeated. On Day-8, participants will consume a standard priming drink and undergo a limited-access alcohol self-administration (bar-lab) paradigm, in a similar fashion to previous Charleston ARC clinical studies. It is hypothesized that GET73-treated participants, relative to placebo-treated participants, will drink less in the 5-day free-access period as well as during bar-lab limited- access procedure. GET73-treated participants are also hypothesized to have increased fronto-cortical levels of glutamate and GABA, reflecting normalization of the pathologically low glutamate and GABA levels typically found in individuals with AUD who are not experiencing acute alcohol withdrawal, paired with decreased reactivity to alcohol cues in key cognitive-control and cue-reactivity-related brain regions (e.g., medial prefrontal cortex and ventral striatum, respectively). These effects are anticipated to mediate the relationship between GET73 and alcohol drinking. Overall, this project has the potential to significantly advance the development of a novel pharmacological treatment for AUD.