Cocaine self-administration and cholesterol metabolism

项目摘要 疾病控制和预防中心报告称，与可卡因有关的死亡率正在上升。 目前尚无有效的药物治疗可卡因使用障碍(CUD)。可卡因与可卡因 多巴胺转运体(DAT)，抑制多巴胺(DA)再摄取，从而提高细胞外DA水平 纹状体。在人类中，纹状体DA升高与欣快感的主观体验有关。近期 CUD患者神经影像的Meta分析表明，急性可卡因诱导的DA升高 迟钝的。这种失调很可能导致可卡因寻找和服用行为的反复循环 意外服药过量。一个关键的知识缺口是慢性疾病如何破坏可卡因-DAT相互作用 接触可卡因。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。培养细胞胆固醇稳态的扰动 细胞和体外破坏可卡因-DAT的相互作用。我们的初步数据显示可卡因SA减少了 纹状体胆固醇含量，更重要的是，纹状体突触体的体外胆固醇补充 提高可卡因抑制DA再摄取的能力。基于这些观察，这项提议将 研究以前未知的可卡因调节大脑胆固醇的分子机制 代谢调节可卡因-DAT的相互作用。我们将探索药理学和遗传性 调节胆固醇含量是缓解可卡因-DAT相互作用中断的新途径 减弱可卡因的自我给药。

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.