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、最危险的药物组合之一，证据如下： 它们的同时使用是紧急住院的主要原因，因此，这种药物组合不是。 仅对个人用户造成严重的健康威胁，但目前不存在重大的公共卫生负担。 针对可卡因和乙醇成瘾的有效治疗方法，强调了了解可卡因和乙醇成瘾的迫切需要 这种高度成瘾的药物配对的机制基础，以便发现新的治疗靶点 众所周知，可卡因和乙醇都会增加细胞外多巴胺（DA）的水平， 血清素 (5-HT) 和去甲肾上腺素 (NE) 是与神经递质密切相关的生物胺神经递质 可卡因通过抑制高亲和力、低容量的转运蛋白来实现这一点。 这些神经递质分别是 DAT、SERT 和 NET，但乙醇的作用机制却不同。 已知乙醇会抑制 DA、5-HT 和 NE 的摄取，但我们公布的数据， 结合文献证据，表明这种抑制与 DAT、SERT 和 NET 无关。 阳离子转运蛋白 3 (OCT3) 是一种低亲和力、高容量的 DA、5-HT 和 NE 转运蛋白，是一种新兴的转运蛋白 作为生物胺稳态调节的重要参与者。 皮质酮是 OCT3 的阻断剂，可增强可卡因诱导的 DA 信号传导并增强 此外，我们发现 OCT3 表达增加。 在缺乏 SERT (-/-) 的小鼠中，乙醇和皮质酮均抑制 SERT-/- 小鼠中的 5-HT 清除 总的来说，这些发现提出了这样的可能性： 乙醇可能与 OCT3 相互作用，抑制生物胺的摄取，从而增加成瘾性 可卡因的特性，并宣传这些药物的同时使用，为此，研究提出。 这个探索性的 R21 将测试总体假设，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，并且这种抑制增强了 可卡因产生的生物胺增加，从而阻止其通过 DAT、SERT 和 NET 的吸收。 重要的是，我们将确定乙醇增强奖励特性的能力的 OCT3 依赖性 我们将使用药理学和遗传学方法，结合体内神经化学，以及 无论这些探索性研究的结果如何，结果都会与奖励相关。 关于乙醇抑制生物源吸收的机制的基础知识差距 这些研究的结果将提高我们对可卡因的认识。 导致同时使用酒精和可卡因的滥用可能性如此之高的机制。 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，探索新的分子 目标（假定为 OCT3）用于治疗酒精和可卡因滥用的药物。