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

药物滥用易感性新型遗传模型中 5 型代谢型谷氨酸受体的调节分析

基本信息

批准号：
10754809
负责人：
Loren D Peeters
金额：
$ 4.13万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754809
关键词：
Acoustics Affect Affinity Agonist Animals Antipsychotic Agents Behavior Behavioral Benzamides Biological Assay Bipolar Disorder Blood Brain Brain region Breeding Cell Fractionation Complex Data Dependovirus Development Disease Dopamine Dopamine D2 Receptor Dose Drug Modelings Etiology Exhibits Extinction Fellowship Female GTP-Binding Proteins Generations Genetic Glutamates Goals Heritability Imaging Techniques Individual Intervention Laboratories Life Measures Mediating Mental disorders Mentors Metabotropic Glutamate Receptors Modeling Molecular Abnormality Neonatal Neurosciences Nicotine Nucleus Accumbens Outcome Parents Pathologic Pathway interactions Pharmaceutical Preparations Phase Phenotype Population Positioning Attribute Post-Traumatic Stress Disorders Postdoctoral Fellow Process Prognosis Property Protein Analysis Proteins Psychoses Psychotic Disorders Publishing Quality of life Quinpirole Rattus Receptor Signaling Relapse Research Research Personnel Research Project Grants Rewards Saline Schizophrenia Secure Signal Transduction Startle Reaction Stimulus Substance Use Disorder Substance abuse problem System Techniques Therapeutic Agents Tissue-Specific Gene Expression Tissues Tobacco Use Disorder Tobacco smoking behavior Tobacco use Training Translating Treatment Efficacy Treatment outcome Underrepresented Populations Ventral Tegmental Area Work behavioral phenotyping biological adaptation to stress career clinically relevant comorbidity conditioned place preference designer receptors exclusively activated by designer drugs diphenyl disability doctoral student drug abuse vulnerability drug development drug discovery drug of abuse drug reward effective therapy endophenotype experimental study genetic manipulation improved interest laterodorsal tegmentum male member molecular imaging nervous system disorder neural neural circuit neuromechanism neuropsychiatric disorder neuropsychiatry new therapeutic target next generation non-compliance novel offspring optogenetics pharmacologic phenotypic biomarker positive allosteric modulator postnatal pre-doctoral prepulse inhibition psychotic receptor receptor sensitivity relapse prevention response side effect small molecule substance use success tenure track tool transcriptome sequencing

项目摘要

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.

项目概要精神分裂症是一种使人衰弱的精神疾病，影响着全球约 1% 的人口。药物滥用合并症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，其中尼古丁是最常滥用的物质。这合并症具有多种有害影响，包括生活质量下降和治疗效果降低。因此，我的实验室有兴趣开发药物干预措施，以减少奖励效应尼古丁并减轻精神病内表型标志物的缺陷。我们之前发表的作品实验室已确定新生大鼠接受多巴胺 D2 样受体 (DAD2) 激动剂治疗生命前 21 天服用喹吡罗显示 DAD2 受体敏感性终生增加，显示出许多与精神病药物滥用合并症相关的行为表型，包括增强尼古丁条件性位置偏好和感觉运动门控缺陷。我们的实验室最近开发了一种通过饲养用喹吡罗 (NQ) 治疗的新生大鼠，建立精神病药物滥用易感性的遗传模型到另一只 NQ 或盐水 (NS) 处理的动物以产生后续的 F1 代。这一代F1 与 F0 代 NQ 动物相比，多巴胺信号增强。已发现 DAD2 受体与 DAD2 受体形成功能不同的异质受体复合物代谢型谷氨酸 5 型 (mGlu5) 受体，因此刺激 mGlu5 会导致 DAD2 亲和力降低。在具体目标 1 中，我将概述已完成的博士前工作，该工作表明治疗与 mGlu5 受体 3-氰基-N-(1,3-二苯基-1H-吡唑-5-基)苯甲酰胺的正变构调节剂 (CDPPB) 降低尼古丁的联想奖励特性并减轻感觉运动门控的缺陷在 F1 代动物中，表明该治疗剂可能是双重治疗的有希望的靶标烟草使用障碍和精神病。在这个提案的F99阶段，我将确定治疗效果 CDPPB 在预防多巴胺敏感系统中使用光遗传学工具预防复发样行为操纵大脑奖励通路中的多巴胺能信号。多巴胺亚细胞定位的变化 CDPPB 给药后的信号标记将使用亚细胞分级进行分析，以确定 CDPPB 的作用机制。此外，遗传机制赋予 DAD2 敏感性增强 F1代将使用下一代RNA测序技术进行评估。在具体目标2中，我将寻求拥有强大指导团队的博士后职位，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的变化如何转化为观察到的行为变化可能会导致神经精神疾病的发展该提案的 K00 阶段。