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

探索有机转运蛋白 3 在滥用药物作用机制中的作用

• 批准号: 9788402
• 负责人: LYNETTE C DAWS
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788402
• 关键词: 1-Methyl-4-phenylpyridinium; Adrenergic alpha-Antagonists; Adult; Affinity; Alcohol abuse; Alcohol consumption; Alcohols; Anesthesia procedures; Behavior; Behavioral; Behavioral Assay; Biogenic Amine Neurotransmitters; Biogenic Amines; Brain; Brain region; Cations; Cells; Chemosensitization; Cocaine; Cocaine Abuse; Corpus striatum structure; Corticosterone; Dangerousness; Data; Dependence; Dopamine; Dorsal; Dose; Drug Combinations; Drug effect disorder; Drug usage; Emergency Situation; Ethanol; Ethanol dependence; Female; Genotype; Health; Homeostasis; Hospitalization; Human; Individual; Knock-out; Knowledge; Link; Literature; Mediator of activation protein; Molecular Target; Mus; National Institute of Drug Abuse; Neurotransmitters; Norepinephrine; Nucleus Accumbens; Organic Cation Transporter; Outcome; Overdose; POU2F1 gene; POU2F2 gene; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Property; Protein Isoforms; Public Health; Publishing; Regulation; Reporting; Rewards; Rodent; Role; Sedation procedure; Serotonin; Signal Transduction; Testing; Therapeutic Intervention; addiction; alcohol effect; base; cocaine use; dopamine transporter; drug of abuse; effective therapy; extracellular; genetic approach; improved; in vivo; male; neurochemistry; new therapeutic target; novel; overexpression; preference; targeted treatment; uptake

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.

抽象的 可卡因和酒精的共同滥用是最常见，最危险的药物配对之一，这证明了 他们的同时使用是紧急住院的主要原因。那不是这种药物的组合 对个人用户只有严重的健康威胁，但伯恩伯恩（Burnen）是一个主要的公共卫生。目前，没有 对可卡因和乙醇成瘾的有效治疗方法，了解了解理解的至关重要的需求 这种高度添加药物配对的机械基础，以发现新的治疗目标 干涉。众所周知，可卡因和乙醇各自增加了细胞外多巴胺（DA）， 5-羟色胺（5-HT）和去甲肾上腺素（NE），生物胺神经递质，它们与 奖励药物的特性。可卡因通过抑制高亲和力的低容量转运蛋白来做到这一点 这些神经递质，DAT，SERT和NET分别。但是，乙醇的机制 这样做不清楚。众所周知，乙醇抑制了DA，5-HT和NE的吸收，但是我们已发布的数据， 与文献证据一起，表明这种抑制作用是dat，sert-和网络无关的。有机的 阳离子转运蛋白3（OCT3）是DA，5-HT和NE的低亲和力，高容量转运蛋白，并且正在出现 作为调节生物胺稳态的重要参与者。有趣的是，最近的报告表明 皮质酮是OCT3的阻滞剂，增强了可卡因诱导的DA信号传导，并恢复了势 通过OCT3依赖机制寻求可卡因。此外，我们发现Oct3表达增加了 在缺乏SERT（ - / - ）的小鼠中，乙醇和皮质酮都抑制了Sert - / - 小鼠中的5-HT间隙 比野生型的程度要大得多。这些发现一起增加了 乙醇可能与Oct3相互作用以抑制生物胺的摄取，从而增加添加剂 可卡因的特性，并同时使用这些药物。为此，提出的研究 该探索性R21将检验总体假设，即乙醇增加的一种机制 细胞外DA，5-HT和NE是通过OCT3抑制其摄取的，并且这种抑制可以增强 可卡因产生的生物胺增加，可卡因通过DAT，SERT和NET阻止其吸收。 重要的是，我们将确定乙醇增强奖励性能的能力的OCT3依赖性 可卡因。我们将使用药物和遗传方法，结合体内神经化学，以及 行为分析与奖励相关。无论这些探索性研究的结果如何 基本知识差距有关乙醇抑制摄取生物源的机制的差距 胺并增强可卡因的奖励作用。这些研究的结果将改善我们的理解 使同时酒精和可卡因使用的机制如此之高。重要的是， 这些研究将形成一个必不可少的平台，以探测新分子的大规模研究基础。 靶标的定为OCT3，用于治疗滥用酒精和可卡因的药物。