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

总结 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、生产力下降和医疗支出。尽管几十年来进行了大量的研究工作， 只有几种FDA批准的治疗AUD的药物，每种药物的疗效都很有限。GET 73是 一种有前途的新药，在其最初的开发阶段显示出改善AUD的前景 症状，如临床前/动物研究中的抗饮酒和抗焦虑特性所证明的。 临床前研究还表明，GET 73的作用机制与其负变构调节有关 代谢型谷氨酸受体亚型5（mGluR 5），一种新的潜在的治疗靶点， 兴趣1期临床研究显示，GET 73在患有AUD和CHD的个体中均安全且耐受良好。 健康志愿者因此，相当多的初步证据支持GET 73作为一种新的，安全的，耐受性良好的， 可能治疗AUD。扩展这项临床前和临床研究，拟议的研究 该项目代表了GET 73对饮酒影响的首次调查，无论是在严格控制的 在实验室环境和自然环境中，对AUD患者进行研究。神经影像学指标 GET 73的作用机制，包括通过质子磁共振成像的额皮质谷氨酸和GABA水平 核磁共振波谱（1H-MRS）和通过功能磁共振对酒精线索的大脑反应性 成像（fMRI）将被研究为GET 73对饮酒的影响的潜在介质。不治疗- 寻求AUD受试者（N=90）将被随机分配至GET 73（300 mg，3x/天）或安慰剂组， 8-白天学习。在随机化前（第-1天），将完成治疗前MRI，在此期间， 将采集1H-MRS和酒精提示反应性fMRI扫描。在第7天，参与者在 将评估前五天的情况，并重复所有MRI程序。在第8天，参与者将消耗 一个标准的启动饮料，并进行有限的酒精自我管理（酒吧实验室）的范例，在类似的 与之前的查尔斯顿ARC临床研究一致。据推测，GET 73治疗的参与者，相对 对于安慰剂治疗的参与者，在5天的自由访问期间以及酒吧-实验室限制期间饮酒较少- 访问程序。GET 73治疗的参与者也被假设具有增加的额皮质水平。 谷氨酸和GABA，反映了正常化的病理性低谷氨酸和GABA水平，通常 在没有经历急性酒精戒断的AUD患者中发现， 在关键的认知控制和线索反应性相关的大脑区域中对酒精线索的反应性（例如，内侧前额叶 皮质和腹侧纹状体）。预计这些影响将介导 第73章喝酒总的来说，该项目有可能大大推动 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.