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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.

项目总结