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.

项目概要美国疾病控制与预防中心报告称，涉及可卡因的死亡率正在上升。对于可卡因使用障碍（CUD）仍然没有有效的药物治疗。可卡因与多巴胺转运蛋白（DAT），抑制多巴胺（DA）再摄取，从而提高细胞外 DA 水平纹状体。纹状体 DA 升高与人类欣快感的主观体验相关。最近的对 CUD 患者神经影像学的荟萃分析表明，急性可卡因诱导的 DA 升高是钝化了。这种失调可能会导致寻找可卡因和吸食可卡因的行为反复循环，意外服用过量。一个关键的知识差距是可卡因-DAT 相互作用如何被慢性疾病所破坏。可卡因暴露。 DAT 在富含胆固醇的膜中采用向外的构象适应高亲和力可卡因结合的环境。培养物中胆固醇稳态的扰动细胞和体外破坏可卡因-DAT 相互作用。我们的初步数据显示可卡因 SA 可以减少纹状体胆固醇含量，重要的是，纹状体突触体的离体胆固醇补充提高可卡因抑制 DA 再摄取的能力。根据这些观察，该提案将研究以前未知的可卡因调节脑胆固醇的分子机制代谢介导可卡因-DAT 相互作用。我们将探讨药理学和遗传是否调节胆固醇含量是减轻可卡因-DAT 相互作用破坏的新途径减弱可卡因的自我给药。