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

• 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
• 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

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.

项目摘要 精神分裂症是一种使人衰弱的精神疾病，估计影响全球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 精神分裂症、躁郁症和精神分裂症，尼古丁是最常滥用的物质。这 合并症具有几种不利影响，包括降低生活质量和降低治疗效果。 因此，我的实验室有兴趣开发药物干预，以减少奖励的影响， 尼古丁和减轻缺陷的内在表型标记的精神病。以前发表的工作在我们的 实验室已经确定，用多巴胺D2样受体（DAD 2）激动剂经腹腔治疗的大鼠 在出生后的前21天，喹吡罗显示出DAD 2受体敏感性的终身增加，显示出许多 与精神病中物质滥用共病相关的行为表型，包括增强的尼古丁 条件性位置偏爱和感觉运动门控缺陷。我们的实验室最近开发了一种 用喹吡罗（NQ）处理大鼠建立精神病药物滥用易感性遗传模型 另一只NQ或生理盐水（NS）处理的动物，以产生随后的F1代。F1代 显示出与F0代中的NQ动物相当的增加的多巴胺信号传导。 已经发现DAD 2受体与DAD 2受体形成功能上不同的异源受体复合物。 代谢型谷氨酸5型（mGlu 5）受体，使得mGlu 5的刺激导致DAD 2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，这些工作表明， 与mGlu 5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）降低尼古丁的关联奖励特性，并消除感觉运动门控缺陷 在F1代动物中，表明这种治疗剂可能是双重治疗的有希望的靶点， 烟草使用障碍和精神病。在本提案的F99阶段，我将确定治疗疗效 CDPPB在使用光遗传学工具对多巴胺致敏的系统中预防复发样行为， 操纵大脑奖赏通路中的多巴胺能信号。多巴胺亚细胞定位的变化 施用CDPPB后的信号传导标志物将使用亚细胞分级分离进行分析， CDPPB的作用机制。此外，遗传性机制赋予增强的DAD 2敏感性， 将使用下一代RNA测序技术评估F1代。在具体目标2中，我将寻求 一个博士后的位置，有一个强大的指导团队，这将使我能够扩大我的培训，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 行为的可观察变化，可能有助于神经精神疾病的发展， K 00阶段。