Analysis of modulation of the metabotropic glutamate receptor type 5 in a novel heritable model of drug abuse vulnerability

项目摘要 精神分裂症是一种使人衰弱的精神疾病，据估计，全球有1%的人口患有精神分裂症。 物质滥用共病在许多精神疾病中很常见，包括创伤后应激障碍 精神障碍、双相情感障碍和精神分裂症，尼古丁是最常被滥用的物质。这 共病有几个不利的影响，包括降低生活质量和治疗效果。 因此，我的实验室对开发药物干预措施感兴趣，以减少 尼古丁和缓解精神病内表型标记物的缺陷。之前在我们的网站上发表的作品 实验室已经证实，用多巴胺D2样受体(DAD2)激动剂治疗新生大鼠 在出生后的头21天，奎比罗对DAD2受体的敏感性终生增加，表现出许多 精神疾病中与物质滥用共病相关的行为表型，包括尼古丁增强 感觉运动门控的条件性位置偏爱和缺陷。我们的实验室最近开发出了一种 用奎比罗(NQ)饲养新生大鼠建立精神病药物滥用易感性的遗传模型 转移到另一只NQ或生理盐水(NS)处理的动物，以产生下一代。这一代F1 表现出与F0代NQ动物相当的增加的多巴胺信号。 DAD2受体与DAD2受体在功能上形成不同的异源受体复合体 代谢型谷氨酸5(MGlu5)受体，刺激mGlu5导致DAD2亲和力降低。 在具体目标1中，我将概述已经完成的博士前工作，这些工作已经显示出治疗 与mGlu5受体3-Cyano-N-(1，3-diphenyl-1H-pyrazol-5-yl)benzamide的正变构调节剂 (CDPPB)减少尼古丁的关联奖赏特性，并缓解感觉运动门控缺陷 在F1代动物身上，表明这种治疗剂可能是一种有前途的双重治疗的靶点 烟草使用障碍和精神病。在这项提案的F99阶段，我将确定治疗效果 CDPPB在预防多巴胺敏化系统中复发类行为中的作用 操纵大脑奖赏通路中的多巴胺能信号。多巴胺的亚细胞定位变化 给予CDPPB后的信号标志物将使用亚细胞分级进行分析，以确定 CDPPB的作用机制。此外，遗传力增强DAD2敏感性的机制在 F1代将使用下一代RNA测序技术进行评估。在具体目标2中，我将寻求 一个博士后职位，有一个强大的指导团队，这将使我能够扩大我的培训范围，包括 使用神经记录和成像技术来分析细胞水平上的变化如何转化为 可观察到的行为变化，可能有助于神经精神疾病的发展 该提案的K00阶段。

Project Summary Schizophrenia is a debilitating mental illness affecting an estimated 1% of the global population. Substance abuse comorbidity is common in a number of mental illnesses, including post-traumatic stress disorder, bipolar disorder, and schizophrenia, with nicotine being the most commonly abused substance. This comorbidity has several detrimental effects, including reduced quality of life and reduced efficacy of treatment. My lab is therefore interested in developing pharmacological interventions to reduce the rewarding effects of nicotine and alleviate deficits in endophenotypic markers of psychosis. Previously published work in our laboratory has established that rats neonatally treated with the dopamine D2-like receptor (DAD2) agonist quinpirole for the first 21 days of life show lifelong increases in DAD2 receptor sensitivity, displaying a number of behavioral phenotypes of relevance to substance abuse comorbidity in psychosis, including enhanced nicotine conditioned place preference and deficits in sensorimotor gating. Our lab has more recently developed a heritable model of drug abuse vulnerability in psychosis by breeding rats neonatally treated with quinpirole (NQ) to either another NQ or a saline (NS) treated animal to produce a subsequent F1 generation. This F1 generation displays increased dopamine signaling comparable to NQ animals in the F0 generation. DAD2 receptors have been found to form a functionally distinct heteroreceptor complex with the metabotropic glutamate type 5 (mGlu5) receptor, such that stimulation of mGlu5 results in reduced DAD2 affinity. In specific aim 1, I will outline predoctoral work that has been completed which has shown that treatment with the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) reduces the associative rewarding properties of nicotine and alleviates deficits in sensorimotor gating in F1 generation animals, suggesting this therapeutic agent may be a promising target for the dual treatment of tobacco use disorder and psychosis. In the F99-phase of this proposal, I will establish the therapeutic efficacy of CDPPB in preventing relapse-like behavior in a system sensitized to dopamine using optogenetic tools to manipulate dopaminergic signaling in the brain reward pathway. Changes in subcellular localization of dopamine signaling markers following administration of CDPPB will be analyzed using subcellular fractionation to determine mechanism of action of CDPPB. Further, mechanisms of heritability conferring enhanced DAD2 sensitivity in the F1 generation will be assessed using next generation RNA sequencing techniques. In specific aim 2, I will seek a postdoctoral position with a strong mentoring team that will allow me to expand my training to include use of neural recording and imaging techniques to analyze how changes on a cellular level translate to observable changes in behavior that may contribute to the development of neuropsychiatric conditions during the K00 phase of this proposal.