Cocaine self-administration and cholesterol metabolism

可卡因自我给药和胆固醇代谢

基本信息

批准号：
10509798
负责人：
Rong Chen
金额：
$ 23.25万
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：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509798
关键词：
Abstinence Acute Address Adopted Affinity Animals Attenuated Behavior Behavioral Binding Brain Centers for Disease Control and Prevention (U.S.)Cholesterol Cholesterol Homeostasis Chronic Cocaine Cocaine use disorder Corpus striatum structure Crystallization Cues Cultured Cells Data Death Rate Dopamine Dose Environment Enzymes Euphoria Excision Genes Genetic Human Infusion procedures Injections Intervention Knowledge Link Measures Mediating Membrane Meta-Analysis Microdialysis Microinjections Modeling Molecular Molecular Conformation Molecular Target Motivation Neurobiology Nucleus Accumbens Overdose Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Pharmacotherapy Rattus Recording of previous events Reporting Rodent Model Saline Schedule Signal Transduction Simvastatin Small Interfering RNA Structure Synaptosomes Testing Therapeutic Intervention Voriconazole analog base cocaine exposure cocaine relapse cocaine self-administration dopamine transporter drug development experience extracellular feasibility testing improved in vivo inhibitor innovation neurochemistry neuroimaging prevent response reuptake therapy development transmission process

项目摘要

Project Summary The Center for Disease Control and Prevention reports that death rates involving cocaine are on the rise. There is still no effective pharmacological treatment for cocaine use disorder (CUD). Cocaine binds to the dopamine transporter (DAT), inhibiting dopamine (DA) reuptake and thus elevating extracellular DA levels in the striatum. Striatal DA elevation is associated with subjective experience of euphoria in humans. Recent meta-analysis of neuroimaging in patients with CUD indicates that acute cocaine-induced elevation of DA is blunted. This dysregulation likely contributes to repeated cycles of cocaine-seeking and taking behavior and accidental overdoses. A critical knowledge gap is how cocaine-DAT interactions are disrupted by chronic cocaine exposure. DAT adopts an outward-facing conformation in a cholesterol-enriched membrane environment to accommodate high-affinity cocaine binding. Perturbation of cholesterol homeostasis in cultured cells and ex vivo disrupts cocaine-DAT interactions. Our preliminary data show that cocaine SA reduces striatal cholesterol content and importantly, ex vivo cholesterol replenishment to striatal synaptosomes improves the ability of cocaine to inhibit DA reuptake. Based on these observations, this proposal will investigate a previously unknown molecular mechanism whereby cocaine modulation of brain cholesterol metabolism mediates cocaine-DAT interactions. We will explore whether pharmacological and genetic modulation of cholesterol content is a new avenue to mitigate disrupted cocaine-DAT interactions and attenuate cocaine self-administration.

项目摘要疾病控制与预防中心报告说，涉及可卡因的死亡率正在上升。仍然没有可卡因使用障碍（CUD）的有效药理治疗。可卡因与多巴胺转运蛋白（DAT），抑制多巴胺（DA）再摄取，从而升高细胞外DA水平纹状体。纹状体DA升高与人类欣快感的主观经验有关。最近的 CUD患者的神经影像学的荟萃分析表明急性可卡因诱导的DA升高IS 钝了。这种失调可能有助于反复的可卡因寻求可卡因和采取行为和意外服药。关键的知识差距是可卡因-DAT相互作用如何被慢性破坏可卡因暴露。 DAT在富含胆固醇的膜上采用外向构象适应高亲和力可卡因结合的环境。培养的胆固醇稳态的扰动细胞和离体破坏可卡因-DAT的相互作用。我们的初步数据表明可卡因SA会减少纹状体胆固醇含量，重要的是，在体内胆固醇补充对纹状体突触体提高可卡因抑制DA再摄取的能力。基于这些观察，该提议将研究以前未知的分子机制，可卡因调节脑胆固醇代谢介导可卡因-DAT的相互作用。我们将探索药理学和遗传学调节胆固醇含量是减轻可卡因互动中断的新途径减轻可卡因自我管理。