Neurobiology and Treatment Development for Alcohol Use Disorder in Schizophrenia: A Pre-clinical Multi-modal Neuroimaging Study

虽然酒精使用障碍(AUD)在精神分裂症(SCZ)患者中普遍存在，但 大多数用于治疗SCZ的药物并不能减少他们的酒精使用量。 一种似乎可以减少这些患者酒精使用量的抗精神病药物氯氮平是 因其毒性而不常使用。格林(我的导师)和他的同事们提出，一个不受监管的 大脑奖赏回路是SCZ患者饮酒的基础。然而，确切的神经机制 在SCZ中对澳元的作用以及氯氮平的作用基础尚不清楚。我一直在找 建立一种新颖的、具有机制相关性、可用于实验的AUD动物模型 在这一难以治疗的人群中，减少饮酒的潜在治疗剂。为此，我 最近开始了对NVHL(新生腹侧海马区病变)大鼠的研究，NVHL是一种神经发育 SCZ的动物模型。我们(和其他人)已经证明，如果在青少年时期接触酒精， 成年NVHL大鼠表现为饮酒增加。此外，我们的初步药理学研究表明， 与SCZ患者一样，氯氮平减少了这种动物的饮酒量。因此，青少年-酒精- 成年NVHL大鼠可作为SCZ的AUD模型。在我的K99-R00项目中，我将研究这种动物以 阐明SCZ中AUD的神经机制，这些机制可以为 在SCZ开发AUD的新治疗方法。在K99阶段，我将使用多模式 磁共振成像技术研究(A)通过磁共振检测谷氨酸、谷氨酰胺和GABA的水平 波谱，以及(B)通过静息状态功能连接的大脑奖励电路连接，在 青春期酒精刺激的成年NVHL大鼠在饮酒过程中。我的初步研究表明 这些技术可以检测大脑奖赏回路中谷氨酰胺和GABA水平的异常，以及 在这样的成年NVHL大鼠中，功能连接。在R00阶段，我将评估氯氮平对 这些措施为其减少饮酒的能力建立了一个机械蓝图。然后，我将使用 一种针对已发现的谷氨酰胺功能障碍的谷氨酰胺合成酶抑制剂，以评估它是否也可以 逆转神经代谢和连接功能障碍，以及是否还能减少饮酒。 从这些研究中获得的数据将是有影响的，因为它们提供了关于机制的重要线索 在这个模型中潜在的饮酒，作为新治疗药物的潜在靶点。在K99期间 阶段，在格林博士的持续指导下，由Elliot Stein博士、韩冰博士和 Hermes Yeh，我将接受关于啮齿动物磁共振波谱和休息状态的教学和实践培训 在酒精暴露对神经发育的影响以及在翻译研究中的功能连通性， 撰写和研究计划的制定。这种指导，与高级课程相结合，将 为我的职业生涯做好准备，成为一名翻译科学家，研究同时发生的精神和酒精使用障碍。

Although alcohol use disorder (AUD) occurs commonly in patients with schizophrenia (SCZ) and dramatically worsens their overall clinical course, most medications used to treat SCZ do not decrease their alcohol use. The one antipsychotic medication that appears to decrease alcohol use in these patients, clozapine, is infrequently used because of its toxicity. Green (my mentor) and colleagues have proposed that a dysregulated brain reward circuit underlies alcohol use in patients with SCZ. However, the exact neural mechanisms contributing to AUD in SCZ, as well as the basis of clozapine’s actions, remain unknown. I have been looking to establish a novel animal model of AUD in SCZ that has mechanistic relevance and can be used to test potential therapeutic agents to reduce alcohol drinking in this difficult-to-treat population. Toward this end, I have recently begun studies with the NVHL (neonatal ventral hippocampal lesion) rat, a neurodevelopmental animal model of SCZ. We (and others) have demonstrated that if exposed to alcohol as an adolescent, the adult NVHL rat displays increased alcohol drinking. Moreover, our initial pharmacologic studies suggest that, like in patients with SCZ, clozapine decreases alcohol drinking in this animal. Thus, the adolescent-alcohol- primed adult NVHL rat can serve as a model of AUD in SCZ. In my K99-R00 program, I will study this animal to elucidate the neural mechanisms underlying AUD in SCZ, mechanisms that could provide targets for development of new treatment approaches for AUD in SCZ. During the K99 phase, I will use multi-modal magnetic resonance (MR) imaging techniques to study (a) levels of glutamate, glutamine and GABA via MR spectroscopy, and (b) brain reward circuit connectivity via resting state functional connectivity, before and during alcohol drinking in adolescent-alcohol-primed adult NVHL rats. My preliminary studies have suggested that these techniques can detect brain reward circuit abnormalities in glutamine and GABA levels, and in functional connectivity, in such adult NVHL rats. During the R00 phase, I will assess the effects of clozapine on these measures to establish a mechanistic blueprint for its ability to decrease alcohol drinking. Then, I will use a glutamine synthetase inhibitor targeting the identified glutamine dysfunction to assess whether it can also reverse the neurometabolic and connectivity dysfunctions, and whether it also decreases alcohol drinking. Data gained from these studies will be impactful, since they provide important clues about the mechanisms underlying alcohol drinking in this model, as potential targets for new therapeutic agents. During the K99 phase, under continued mentorship by Dr. Green, and co-mentorship by Drs. Elliot Stein, Hanbing Lu and Hermes Yeh, I will receive didactic and hands-on training in rodent MR spectroscopy and resting state functional connectivity, in neurodevelopmental effects of alcohol exposure, and in translational research, grant writing and research program development. This mentorship, combined with advanced coursework, will prepare me for a career as a translational scientist studying co-occurring psychiatric and alcohol use disorders.