Synaptogyrin-3 promotes behavioral resilience and protects against cocaine-induced dopaminergic adaptations

Synaptogyrin-3 促进行为弹性并防止可卡因诱导的多巴胺能适应

• 批准号: 10440248
• 负责人: Emily Grace Peck
• 金额: $ 4.68万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2024-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440248
• 关键词: Acute; Affective; American; Animals; Behavior; Behavioral; Chronic; Clinical; Co-Immunoprecipitations; Cocaine; Cocaine use disorder; Consumption; Data; Development; Dopamine; Down-Regulation; Drug usage; Exocytosis; FDA approved; Functional disorder; Future; Goals; Individual; Individual Differences; Laboratories; Literature; Measures; Mediating; Microdialysis; Molecular; Motivation; Neurons; Nucleus Accumbens; Output; Periodicity; Persons; Pharmaceutical Preparations; Pharmacotherapy; Price; Procedures; Proteins; Proxy; Psychological reinforcement; Public Health; Raja; Rattus; Reinforcement Schedule; Reporting; Research; Role; Running; Scanning; Social Interaction; Substance Use Disorder; Synapses; Synaptic Vesicles; Techniques; Testing; Ventral Tegmental Area; Viral; Western Blotting; Withdrawal; abuse liability; addiction; anxiety-like behavior; base; behavior test; behavioral economics; behavioral phenotyping; cellular targeting; cocaine exposure; cocaine self-administration; cocaine use; cohort; dopamine system; dopamine transporter; dopaminergic neuron; extracellular; in vivo; mesolimbic system; motivated behavior; neurochemistry; new therapeutic target; novel; osmotic minipump; overexpression; prevent; resilience; synaptogyrin; uptake

PROJECT SUMMARY Synatptogyrin-3 (SYG3) is a cocaine-sensitive synaptic vesicle protein that is yet to be fully characterized in the context of cocaine use disorder. SYG3 is highly expressed in dopamine-containing neurons and directly interacts with the dopamine transporter (DAT), suggesting a role in synaptic dopamine dynamics. Preliminary studies from our laboratory suggest that cocaine breakpoint on a progressive ratio schedule of reinforcement, a behavioral proxy for “motivation”, negatively correlates with mesolimbic SYG and DAT levels in cocaine self- administering rats. Moreover, I found that overexpression of SYG3 in VTA dopamine neurons decreases anxiety-like behavior and alters dopamine system function. Therefore, the objective of this proposal is to examine the relationship between SYG3, the DAT, and cocaine self-administration. My overarching hypothesis is that high innate levels of SYG3 induce a resilient behavioral phenotype and prevent cocaine-induced dopamine dysfunction. I will peruse this hypothesis by answering the following 3 specific questions: (1) What drives the inverse relationship between cocaine breakpoint and SYG3 levels? (2) Will overexpression of SYG3 in VTA dopamine neurons reduce cocaine self-administration behaviors? (3) Will overexpression of SYG3 in VTA dopamine neurons protect against cocaine-induced dopamine dysfunction? We will pursue these aims using both behavioral and neurochemical techniques, including affective behavioral tests, cocaine self- administration, viral manipulations, as well as molecular and neurochemical analyses—all to determine if SYG3 influences cocaine-taking behavior and cocaine-induced dopamine dysfunction. The proposed research is significant, since there is no FDA approved pharmacotherapy for cocaine use disorder. The results from this proposal will further characterize the relatively unknown synaptic vesicle protein, SYG3, as a fruitful cellular target for pharmacotherapeutics to treat cocaine use disorder.

项目摘要 突触回蛋白-3（SYG 3）是一种可卡因敏感的突触囊泡蛋白，其在可卡因代谢中的作用尚未完全确定。 可卡因使用障碍的背景。SYG 3在含多巴胺的神经元中高度表达，并直接与多巴胺受体结合。 与多巴胺转运蛋白（DAT）相互作用，表明在突触多巴胺动力学中的作用。初步 我们实验室的研究表明，可卡因断点上的渐进比例强化计划， “动机”的行为代表，与可卡因自我中的中边缘SYG和DAT水平呈负相关 给大鼠注射。此外，我发现SYG 3在腹侧被盖区多巴胺神经元中的过表达减少了 焦虑样行为和改变多巴胺系统功能。因此，本建议的目的是 检查SYG 3，DAT和可卡因自我管理之间的关系。我的首要假设是 高先天水平SYG 3诱导弹性行为表型并防止可卡因诱导的 多巴胺功能障碍我将通过回答以下3个具体问题来细读这个假设：（1）什么 可卡因断点和SYG 3水平之间的反向关系？(2)SYG 3的过度表达 腹侧被盖区多巴胺神经元减少可卡因自我给药行为？(3)SYG 3的过表达是否会在 腹侧被盖区多巴胺神经元对可卡因诱导的多巴胺功能障碍有保护作用？我们将努力实现这些目标 使用行为和神经化学技术，包括情感行为测试，可卡因自我， 管理，病毒操作，以及分子和神经化学分析-所有这些都是为了确定 SYG 3影响可卡因服用行为和可卡因诱导的多巴胺功能障碍。拟议研究 这是重要的，因为没有FDA批准的可卡因使用障碍的药物疗法。结果是 该提案将进一步描述相对未知的突触囊泡蛋白SYG 3作为一种富有成效的细胞 用于治疗可卡因使用障碍药物治疗的靶点。