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

帮助治疗成瘾的药物存在于许多主要的滥用药物中，但不适用于精神兴奋剂，如 安非他明及其同类物。他们也缺乏越来越多使用的合成药物， 已知精神兴奋剂的作用已知的和新的精神活性物质继续构成一个主要的 增加公共卫生威胁。为了开发有效的治疗方法，这些兴奋剂 产生与滥用有关的影响。许多兴奋剂与多巴胺（DA）相互作用 转运蛋白（DAT），这被认为是介导其滥用相关的影响。然而，针对DAT的策略 在治疗精神兴奋剂成瘾方面几乎没有任何益处，这增加了这些兴奋剂 在调节多巴胺能神经传递方面具有重要作用。与此同时，一个快速 越来越多的文献支持有机阳离子转运蛋白3（OCT 3）在调节多巴胺能神经元中的重要作用。 神经传递我们的初步数据支持这一观点，显示OCT 3抑制剂decyloxide-22（D22）， 抑制安非他明诱发的过度运动和体内DA释放，这种作用在组成性OCT 3中丧失， 敲除（KO，-/-）小鼠。此外，D22可抑制苯丙胺诱导的底物外排， 与可卡因敏感的转运蛋白无关。这些数据提出了一种令人兴奋的可能性，即OCT 3是一种关键的 这可能有助于解释为什么基于DAT的治疗方法没有被广泛应用。 成功治疗安非他明滥用我们的目的是提交一份R 01，以这些令人兴奋的发现为基础， 但在此之前，还需要更多的初步数据。首先，我们需要确定潜在的补偿 在组成型OCT 3-/-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（OCT 3 +/+）小鼠相比。为了做到这一点，OCT 3 floxed小鼠最近被 由位于圣安东尼奥的德克萨斯大学健康科学中心（UTHSCSA）生成。我们会让这些老鼠 与市售Cre系杂交以产生他莫昔芬诱导的全局OCT 3 KO。这样才能 暂时控制OCT 3 KO，并在未来研究中，使用不同的Cre细胞系来产生脑区域特异性诱导型 科斯。我们将使用这些小鼠来检验安非他明诱导的DA释放、运动和神经元损伤的假设。 与对照小鼠相比，在诱导型OCT 3 KO小鼠中刻板性将减弱。此外，如果OCT 3是 作为治疗安非他明滥用的有用靶点，我们需要证明OCT 3在介导 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）， 和自我管理的小鼠，以测试的假设，奖励和加强作用的安非他明 在诱导型OCT 3 KO小鼠中的CPP比对照小鼠少，并且D22将减弱CPP的发展， 对照小鼠中的安非他明和安非他明自我给药，但在诱导型OCT 3 KO中没有。这些 拟议中的研究将为R 01申报提供必要的数据，并将开始填补关键的知识空白 OCT 3在苯丙胺滥用相关效应中的作用。

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.