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.

许多主要滥用药物都有帮助治疗成瘾的药物，但精神兴奋剂却没有，例如 安非他明及其同系物。他们还缺乏越来越多地使用的旨在模仿的合成药物 已知精神兴奋剂的作用。已知的和新的精神活性物质仍然是主要的 和日益严重的公共卫生威胁。为了开发有效的治疗方法，这些兴奋剂的作用机制 需要充分了解其产生与滥用相关的影响。许多兴奋剂与多巴胺 (DA) 相互作用 转运蛋白（DAT），被认为可以调节其滥用相关的影响。然而，针对 DAT 的策略 在治疗精神兴奋剂成瘾方面几乎没有效果，这增加了这些兴奋剂的可能性 在其他地方具有调节多巴胺能神经传递的重要作用。与此相一致的是，迅速 越来越多的文献支持有机阳离子转运蛋白 3 (OCT3) 在调节多巴胺能方面发挥着重要作用 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)， 抑制安非他明引起的体内过度运动和 DA 释放，这些作用在本构型 OCT3 中消失 基因敲除（KO，-/-）小鼠。此外，D22 可以以某种方式抑制苯丙胺诱导的底物流出 独立于可卡因敏感转运蛋白。这些数据提出了令人兴奋的可能性：OCT3 是一个关键的 苯丙胺作用的参与者，这可能有助于解释为什么基于 DAT 的疗法尚未被广泛应用 成功治疗安非他明滥用。我们的目的是提交 R01 以建立这些令人兴奋的发现， 但在此之前，需要额外的初步数据。首先，我们需要确定是否有潜在的补偿 在组成型 OCT3-/- 小鼠中，它们的运动和 DA 释放反应缺乏差异 安非他明与野生型 (OCT3+/+) 小鼠的比较。为此，OCT3 floxed 小鼠最近被 由德克萨斯大学圣安东尼奥健康科学中心 (UTHSCSA) 生成。我们将与这些老鼠杂交 使用市售的 Cre 细胞系生成他莫昔芬诱导型全局 OCT3 KO。这样，我们就可以 暂时控制 OCT3 KO，并在未来的研究中，使用不同的 Cre 系来创建大脑区域特异性诱导细胞 KO。我们将使用这些小鼠来检验安非他明诱导的 DA 释放、运动和运动的假设。 与对照小鼠相比，诱导型 OCT3 KO 小鼠的刻板印象会减弱。此外，如果 OCT3 是 作为治疗安非他明滥用的有用靶点，我们需要证明 OCT3 在调解中很重要 安非他明的奖励和强化作用。为此，我们将使用条件位置偏好（CPP）， 以及小鼠的自我给药，以测试安非他明的奖励和强化作用的假设 诱导型 OCT3 KO 小鼠中的 D22 含量低于对照小鼠，并且 D22 会减弱 CPP 的发育，从而 安非他明和安非他明在对照小鼠中自我给药，但在诱导型 OCT3 KO 中则不然。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。