Organic cation transporter 3: a novel molecular target to treat amphetamine abuse

有机阳离子转运蛋白 3：治疗苯丙胺滥用的新型分子靶点

• 批准号: 9808668
• 负责人: LYNETTE C DAWS
• 金额: $ 23.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808668
• 关键词: 1-Methyl-4-phenylpyridinium; Address; Age; Amphetamine Abuse; Amphetamine Addiction; Amphetamines; Attenuated; Bathing; Behavioral; Brain region; Cocaine; Data; Development; Dopamine; Drug Combinations; Drug Design; Drug abuse; Drug usage; Extracellular Space; Financial compensation; Future; Genetic; Genome engineering; Goals; Health Sciences; Intention; Knock-out; Knockout Mice; Knowledge; Legal; Literature; Locomotion; LoxP-flanked allele; Mediating; Methamphetamine; Molecular; Molecular Target; Mus; Neurotransmitters; Organic Cation Transporter; Pharmaceutical Preparations; Pharmacology; Play; Property; Psychostimulant dependence; Public Health; Rewards; Role; Salts; Self Administration; Speed; System; Tamoxifen; Testing; Texas; Therapeutic; Universities; addiction; base; cathinone; cell type; dopamine transporter; drug of abuse; effective therapy; in vivo; inhibitor/antagonist; monoamine; mouse genome; neurotransmission; noradrenaline transporter; novel; preference; psychostimulant; response; serotonin transporter; stereotypy; stimulant abuse; synthetic drug; therapeutic target

Medications to help treat addiction exist for many major drugs of abuse, but not for psychostimulants, such as amphetamine, and its congeners. They are also lacking for increasingly used synthetic drugs designed to mimic the actions of known psychostimulants. Both known and new psychoactive substances continue to pose a major and increasing public health threat. To develop effective treatments, the mechanisms by which these stimulants produce their abuse-related effects need to be fully understood. Many stimulants interact with the dopamine (DA) transporter (DAT), which is thought to mediate their abuse-related effects. However, strategies targeting DAT have yielded little to no benefit in the treatment of psychostimulant addiction, raising the possibility that these stimulants have significant actions elsewhere to modulate dopaminergic neurotransmission. Consistent with this, a rapidly growing literature supports a prominent role for organic cation transporter 3 (OCT3) in regulating dopaminergic neurotransmission. Our preliminary data support this idea, showing that an OCT3 inhibitor, decynium-22 (D22), inhibits amphetamine-evoked hyperlocomotion and DA release in vivo, effects that were lost in constitutive OCT3 knockout (KO, -/-) mice. Furthermore, amphetamine-induced substrate efflux could be inhibited by D22 in a manner independent of cocaine-sensitive transporters. These data raise the exciting possibility that OCT3 is a critical player in the actions of amphetamine, which may help to explain why DAT-based therapeutics have not been successful in treating amphetamine abuse. Our intention is to submit an R01 to build on these exciting findings, but before doing so, additional preliminary data are needed. First, we need to determine if potential compensation in constitutive OCT3-/- mice accounts for the lack of difference in their locomotor and DA releasing responses to amphetamine compared with wild-type (OCT3+/+) mice. To do this, OCT3 floxed mice have recently been generated at the University of Texas Health Science Center at San Antonio (UTHSCSA). We will cross these mice with a commercially available Cre line to generate a tamoxifen inducible global OCT3 KO. In this way, we can temporally control OCT3 KO, and in future studies, use different Cre lines to create brain region specific inducible KOs. We will use these mice to test the hypothesis that amphetamine-induced DA release, locomotion, and stereotypy will be attenuated in inducible OCT3 KO mice compared with control mice. Moreover, if OCT3 is to be a useful target in the treatment of amphetamine abuse, we need to demonstrate that OCT3 is important in mediating the rewarding and reinforcing effects of amphetamine. To this end, we will use conditioned place preference (CPP), and self-administration in mice to test the hypotheses that the rewarding and reinforcing effects of amphetamine are less in inducible OCT3 KO mice than control mice, and that D22 will attenuate development of CPP to amphetamine and amphetamine self-administration in control mice, but not in the inducible OCT3 KO. These proposed studies will provide data essential for an R01 submission, and will begin to fill crucial knowledge gaps about the role of OCT3 in abuse-related effects of amphetamine.

许多主要的滥用药物都存在帮助治疗成瘾的药物，但对于精神刺激剂，例如 苯丙胺及其同类物。他们还缺少越来越使用的合成药物来模仿 已知的心理刺激物的作用。已知和新的精神活性物质都继续构成专业 并增加公共卫生威胁。为了开发有效的治疗，这些兴奋剂的机制 产生与滥用相关的效果需要充分理解。许多兴奋剂与多巴胺相互作用（DA） 转运蛋白（DAT），被认为可以调解其与滥用相关的效果。但是，针对DAT的策略具有 在治疗心理刺激成瘾方面几乎没有任何好处，这增加了这些兴奋剂的可能性 在其他地方采取重大行动来调节多巴胺能神经传递。与此一致，迅速 不断增长的文献支持有机阳离子转运蛋白3（OCT3）在调节多巴胺能的重要作用 神经传递。我们的初步数据支持这一想法，表明OCT3抑制剂Decynium-22（D22）， 抑制苯丙胺诱发的超氯局局部和DA释放，在本构中损失了oct3 敲除（KO， - / - ）小鼠。此外，苯丙胺诱导的底物外排被D22以某种方式抑制 独立于可卡因敏感转运蛋白。这些数据增加了Oct3是关键的令人兴奋的可能性 苯丙胺行动中的玩家，这可能有助于解释为什么基于DAT的治疗剂没有 成功治疗苯丙胺滥用。我们的目的是提交R01以基于这些令人兴奋的发现， 但是在此之前，需要其他初步数据。首先，我们需要确定潜在的补偿 在本构中，OCT3 - / - 小鼠的运动和DA释放的反应缺乏差异 与野生型（OCT3+/+）小鼠相比，苯丙胺。为此，Oct3 Floxed小鼠最近是 在得克萨斯大学圣安东尼奥分校（UTHSCSA）上产生。我们将越过这些老鼠 具有市售的CRE系列，以产生他莫昔芬诱导的全球Oct3 KO。这样，我们可以 在时间上控制OCT3 KO，在未来的研究中，使用不同的CRE线来创建大脑区域特异性诱导 科斯。我们将使用这些小鼠来检验苯丙胺诱导的DA释放，运动和 与对照小鼠相比，在可诱导的OCT3 KO小鼠中，刻板印象会减弱。而且，如果要oct3是 在治疗苯丙胺滥用方面的一个有用的目标，我们需要证明OCT3在调解中很重要 苯丙胺的奖励和增强作用。为此，我们将使用条件位置偏好（CPP）， 和在小鼠中的自我管理，以测试苯丙胺的奖励和增强作用的假设 与对照小鼠相比，在诱导的OCT3 KO小鼠中，D22的诱导型小鼠少，并且会使CPP的发展降低到 在对照小鼠中的苯丙胺和苯丙胺自我给药，但在诱导的OCT3 KO中不进行。这些 拟议的研究将为R01提交提供必不可少的数据，并开始填补关键的知识差距 关于OCT3在苯丙胺与滥用相关作用中的作用。