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：
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
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/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

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.

项目摘要 Synatpogyrin-3（SYG3）是一种对可卡因敏感的合成囊泡蛋白，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度表达，直接表达与多巴胺转运蛋白（DAT）相互作用，表明在突触多巴胺动力学中起作用。初步的我们实验室的研究表明，可卡因断点是根据加强的渐进比例时间表 “动机”的行为代理，与可卡因自我的中唇级SYG和DAT级别负相关管理大鼠。此外，我发现VTA多巴胺神经元中SYG3的过表达逐渐下降焦虑般的行为和改变多巴胺系统功能。因此，该提议的目的是检查SYG3，DAT和可卡因自我管理之间的关系。我的总体假设是天生的SYG3含量很高会引起弹性的行为表型并防止可卡因诱导多巴胺功能障碍。我将通过回答以下三个特定问题来仔细研究这一假设：（1）什么驱动可卡因断点与SYG3水平之间的反比关系？（2）SYG3的过表达在VTA多巴胺神经元中，可卡因自我管理行为减少了？（3）SYG3在 VTA多巴胺神经元可以预防可卡因诱导的多巴胺功能障碍？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，可卡因自我给药，病毒操作以及分子和神经化学分析，都可以确定 SYG3影响可卡因的发生行为和可卡因诱导的多巴胺功能障碍。拟议的研究很重要，因为没有FDA批准的可卡因使用障碍药物疗法。从中的结果提案将进一步将相对未知的突触囊泡蛋白SYG3表征为一种富有富有成果的细胞药物治疗可卡因使用障碍的靶标。