Cocaine self-administration and cholesterol metabolism

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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.