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有帮助治疗成瘾的药物，但没有精神刺激剂，例如 安非他明及其同系物。它们也缺乏越来越多使用的用于模拟的合成药物 已知的精神刺激剂的作用。已知的和新的精神活性物质继续构成主要的 并不断增加对公共健康的威胁。为了开发有效的治疗方法，这些兴奋剂的机制 需要充分了解它们产生的与滥用有关的影响。许多兴奋剂与多巴胺(DA)相互作用 转运体(DAT)，这被认为是调解他们的滥用相关的影响。然而，针对DAT的策略有 在治疗精神刺激性药物成瘾方面收效甚微，这增加了这些兴奋剂 在其他地方对调节多巴胺能神经传递有重大作用。与此相一致的是，一个迅速 越来越多的文献支持有机阳离子转运蛋白3(Oct3)在调节多巴胺能系统中的重要作用 神经传递。我们的初步数据支持这一观点，表明Oct3抑制剂Decynium-22(D22)， 在体内抑制安非他明诱发的多动和DA释放，这些作用在组成性Oct3中消失 基因敲除(KO，-/-)小鼠。此外，D22还能抑制苯丙胺诱导的底物外流。 不依赖对可卡因敏感的转运体。这些数据增加了令人兴奋的可能性，即10月3日是一个关键 安非他明的作用，这可能有助于解释为什么基于DAT的疗法没有 在治疗苯丙胺滥用方面取得成功。我们打算提交一份R01，以建立在这些令人兴奋的发现的基础上， 但在这样做之前，还需要更多的初步数据。首先，我们需要确定潜在的补偿是否 在构成Oct3-/-小鼠中，解释了它们在运动和DA释放反应方面缺乏差异 苯丙胺与野生型(Oct3+/+)小鼠的比较。为了做到这一点，Oct3用牙线固定的小鼠最近被 由圣安东尼奥的德克萨斯大学健康科学中心(UTHSCSA)生成。我们要穿过这些老鼠 与商业上可获得的CRE线一起产生他莫昔芬可诱导的全球Oct3KO。通过这种方式，我们可以 暂时控制Oct3 KO，并在未来的研究中，使用不同的Cre系来创造大脑区域特异性诱导 科斯。我们将使用这些小鼠来测试安非他明诱导DA释放、运动和 与对照组相比，可诱导的Oct3KO小鼠的刻板印象将会减弱。此外，如果10月3日要成为 作为治疗苯丙胺滥用的有用靶点，我们需要证明Oct3在调节 苯丙胺的奖励和强化作用。为此，我们将使用条件位置偏好(CPP)， 在小鼠身上进行自我给药，以检验苯丙胺的奖励和增强作用的假设 在可诱导的Oct3KO小鼠中比对照组小鼠更少，D22将减弱CPP的发展到 苯丙胺和苯丙胺在对照组小鼠中自我给药，但在可诱导的Oct3KO中不存在。这些 拟议的研究将为R01提交提供必要的数据，并将开始填补关键的知识空白 关于Oct3在苯丙胺滥用相关影响中的作用。