Exploring a role for organic transporter 3 in the mechanism of action of drugs of abuse

摘要 可卡因和酒精的共同滥用是最常见和最危险的药物配对之一， 它们的同时使用是急诊住院的主要原因。因此，该药物组合不是 这不仅对个人使用者构成严重的健康威胁，而且是一个重大的公共健康负担。目前没有 可卡因和乙醇成瘾的有效治疗，强调了了解 这种高度成瘾性药物配对的机制基础，以发现新的治疗靶点。 干预众所周知，可卡因和乙醇各自增加多巴胺（DA）的细胞外水平， 5-羟色胺（5-HT）和去甲肾上腺素（NE），生物胺神经递质，与 药物的奖励特性。皮质醇通过抑制高亲和力，低容量的转运蛋白来实现这一点。 这些神经递质，DAT，SERT和NET。然而，乙醇 这一点还不清楚。已知乙醇抑制DA、5-HT和NE的摄取，然而我们发表的数据， 与文献证据一起，表明这种抑制是DAT，SERT和NET独立的。有机 阳离子转运蛋白3（oct 3）是一种低亲和力、高容量的DA、5-HT和NE转运蛋白， 作为生物胺稳态调节的重要参与者。有趣的是，最近的报告显示， 皮质酮，一种OCT 3的阻断剂，增强可卡因诱导的DA信号传导， 可卡因寻求通过OCT 3依赖性机制。此外，我们发现OCT 3表达增加， 在缺乏SERT（-/-）小鼠中，乙醇和皮质酮均抑制SERT-/-小鼠中5-HT清除， 比它们的野生型对应物大得多。总之，这些发现提出了一种可能性， 乙醇可以与OCT 3相互作用以抑制生物胺的摄取，从而增加成瘾性。 可卡因的性质，并宣传这些药物的同时使用。为此目的， 这个探索性的R21将检验一个总体假设，即乙醇增加的一种机制 细胞外DA，5-HT和NE是通过抑制它们经由OCT 3的摄取，并且这种抑制增强了细胞外DA，5-HT和NE的表达。 可卡因产生的生物胺增加，通过DAT，SERT和NET阻止其吸收。 重要的是，我们将确定乙醇增强奖励特性的能力对OCT 3的依赖性 可卡因。我们将使用药理学和遗传学方法，结合体内神经化学， 与奖励相关的行为分析。无论这些探索性研究的结果如何， 关于乙醇抑制生物质吸收的机制的基本知识空白 胺和增强可卡因的奖励作用。这些研究的结果将增进我们对 同时使用酒精和可卡因的滥用潜力如此之高的机制。重要的是， 这些研究将形成一个重要的平台，在此基础上进行更大规模的研究， 目标，pupiloct 3，药物治疗滥用酒精和可卡因。

ABSTRACT Co-abuse of cocaine and alcohol is one of the most common, and dangerous drug pairings, as evidenced by their concurrent use being a major cause for emergency hospitalization. Thus, this drug combination is not only a serious health threat to the individual user, but a major public health burden. Currently, there are no effective treatments for addiction to cocaine and ethanol, underscoring the vital need to understand the mechanistic basis of this highly addictive drug pairing in order to discover new targets for therapeutic intervention. It is well-known that cocaine and ethanol each increase extracellular levels of dopamine (DA), serotonin (5-HT), and norepinephrine (NE), biogenic amine neurotransmitters that are strongly linked to the rewarding properties of drugs. Cocaine does this by inhibiting the high-affinity, low-capacity transporters for these neurotransmitters, DAT, SERT, and NET, respectively. However, the mechanisms by which ethanol does so are unclear. It is known that ethanol inhibits uptake of DA, 5-HT, and NE, however our published data, together with literature evidence, show this inhibition to be DAT-, SERT-, and NET-independent. Organic cation transporter 3 (OCT3) is a low-affinity, high-capacity transporter for DA, 5-HT, and NE, and is emerging as an important player in regulation of biogenic amine homeostasis. Interestingly, recent reports show that corticosterone, a blocker of OCT3, enhances cocaine-induced DA signaling and potentiates reinstatement of cocaine seeking via an OCT3-dependent mechanism. Moreover, we found that OCT3 expression is increased in mice lacking SERT (-/-), and that ethanol, and corticosterone, both inhibit 5-HT clearance in SERT-/- mice to a much greater extent than in their wild-type counterpart. Together, these findings raise the possibility that ethanol may interact with OCT3 to inhibit uptake of biogenic amines, thereby increasing the addictive properties of cocaine, and propagating the concurrent use of these drugs. To this end, the studies proposed in this exploratory R21 will test the overarching hypothesis that one mechanism by which ethanol increases extracellular DA, 5-HT and NE is by inhibition of their uptake via OCT3, and that this inhibition enhances the increase in biogenic amines produced by cocaine, which blocks their uptake via DAT, SERT and NET. Importantly, we will determine the OCT3-dependency of ethanol’s ability to enhance the rewarding properties of cocaine. We will use pharmacological and genetic approaches, combined with in vivo neurochemistry, and behavioral assays relevant for reward. Regardless of the outcome of these exploratory studies, results will fill fundamental knowledge gaps about the mechanism(s) through which ethanol inhibits uptake of biogenic amines and enhances rewarding effects of cocaine. Results from these studies will improve our understanding of mechanisms that make the abuse potential of concurrent alcohol and cocaine use so high. Importantly, these studies will form an essential platform on which to base larger scale studies probing novel molecular targets, putatively OCT3, for medications to treat abuse of alcohol and cocaine.