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

基本信息

批准号：
10157455
负责人：
Emily Grace Peck
金额：
$ 4.6万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10157455
关键词：
Acute Affective American Animals Behavior Behavioral Chronic Clinical Co-Immunoprecipitations Cocaine Consumption Data Development Disease 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 Pharmaceutical Preparations Pharmacotherapy Price Procedures Proteins Proxy Psychological reinforcement Public Health Raja Rattus Reinforcement Schedule Reporting Research Role Running Scanning Self Administration Social Interaction Substance Use Disorder Synapses Synaptic Vesicles Techniques Testing Ventral Tegmental Area Viral Western Blotting Withdrawal 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

项目摘要

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 SYG3 在含有多巴胺的神经元中高度表达，并且直接表达。与多巴胺转运蛋白 (DAT) 相互作用，初步表明其在突触多巴胺动力学中发挥作用。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 水平呈负相关此外，我发现 VTA 多巴胺神经元中 SYG3 的过度表达减少。焦虑样行为并改变多巴胺系统功能因此，该提案的目标是检查 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我将通过回答以下 3 个具体问题来仔细研究这一假设：（1）什么？驱动可卡因断点和 SYG3 水平之间的反比关系？ (2) SYG3 会过度表达吗？ VTA 多巴胺神经元中的可卡因自我给药行为会减少吗？ (3) SYG3 的过度表达会减少吗？ VTA 多巴胺神经元可以预防可卡因引起的多巴胺功能障碍吗？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。这是很重要的，因为 FDA 还没有批准治疗可卡因使用障碍的药物疗法。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目标。