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.

项目概要 Synatptogyrin-3 (SYG3) 是一种可卡因敏感的突触小泡蛋白，尚未在 可卡因使用障碍的背景。 SYG3 在含多巴胺的神经元中高表达，并直接 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发挥作用。初步的 我们实验室的研究表明，可卡因断点在渐进比例强化计划中， “动机”的行为代理，与可卡因自我中的中脑边缘 SYG 和 DAT 水平呈负相关 管理大鼠。此外，我发现 VTA 多巴胺神经元中 SYG3 的过度表达会降低 焦虑样行为并改变多巴胺系统功能。因此，本提案的目标是 检查 SYG3、DAT 和可卡因自我给药之间的关系。我的总体假设 SYG3 的高先天水平会诱导弹性行为表型并防止可卡因诱导的行为表型 多巴胺功能障碍。我将通过回答以下 3 个具体问题来仔细研究这个假设：(1) 什么 驱动可卡因断点和 SYG3 水平之间的反比关系？ (2) SYG3会过度表达 VTA 多巴胺神经元减少可卡因自我给药行为？ (3) SYG3是否会过度表达 VTA 多巴胺神经元可预防可卡因引起的多巴胺功能障碍？我们将追求这些目标 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是否 SYG3 影响可卡因服用行为和可卡因诱导的多巴胺功能障碍。拟议的研究 意义重大，因为 FDA 还没有批准治疗可卡因使用障碍的药物疗法。由此得出的结果 该提案将进一步表征相对未知的突触小泡蛋白 SYG3，作为一种富有成效的细胞 治疗可卡因使用障碍的药物治疗的目标。