Uptake2 transporters: Novel sex-dependent molecular targets to treat stimulant use disorder

Uptake2转运蛋白：治疗兴奋剂使用障碍的新型性别依赖性分子靶标

基本信息

批准号：
10595444
负责人：
LYNETTE C DAWS
金额：
$ 67.43万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595444
关键词：
Affinity Age Amphetamine Addiction Amphetamines Astrocytes Attenuated Behavior Behavioral Brain region Chronic Cocaine Compensation Complex Corpus striatum structure Data Development Disease Dopamine Dopamine Receptor Dorsal Dose Drug Design Elements Female Gene Expression Goals Histologic In Vitro Knock-out Knockout Mice Knowledge Legal Light Literature Locomotion LoxP-flanked allele Measures Mediating Methamphetamine Modeling Molecular Target Motor Activity Mus Neuroglia Nucleus Accumbens Organic Cation Transporter Pathway interactions Persons Pharmaceutical Preparations Pharmacology Presynaptic Terminals Property Public Health Rewards Role Self Administration Sex Differences Signal Transduction Stimulant Substance Use Disorder Tamoxifen Testing Therapeutic Time Transgenic Mice Tyrosine 3-Monooxygenase Viral Wild Type Mouse addiction amphetamine use attenuation bath salts conditional knockout conditioned place preference dopamine transporter dopaminergic neuron drug of abuse effective therapy in vivo inhibitor insight knock-down male mephedrone monoamine mouse model neurotransmission nigrostriatal pathway novel presynaptic prevent protein expression psychostimulant response sex stereotypy stimulant abuse stimulant dependence stimulant use disorder synthetic drug therapeutic target treatment strategy uptake vesicular monoamine transporter

项目摘要

Medications to treat substance use disorders (SUD) exist for many drugs of abuse, but not for psychostimulants, such as amphetamine (AMPH), and methamphetamine. 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 better 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 decynium-22 (D22), an inhibitor of OCT3, inhibits DA release in vivo in male OCT3 wild-type (WT) mice, an effect lost in constitutive OCT3 knockout (KO) mice. Furthermore, in vitro studies showed that AMPH-induced substrate efflux could be inhibited by D22 in a manner independent of cocaine-sensitive transporters. These finding were paralleled by a loss of conditioned place preference (CPP) for AMPH in male mice, and an attenuation in female OCT3 KO, with D22 preventing CPP in both WT sexes. Preliminary data in male mice show that the dose-response curve for self-administration of AMPH is dramatically downward and rightward shifted in male OCT3 KO mice relative to their WT counterpart. In light of these findings, we have established and validated OCT3 floxed mice so as to examine the role of OCT3 in the absence of any developmental compensation that may occur in germline KOs. Harnessing the power of these mice, new data show that tamoxifen inducible or viral KO of OCT3 robustly attenuates AMPH- evoked DA release and CPP. Proposed studies will interrogate OCT3’s role in the ability of AMPH to impact behavior and DA efflux by testing the novel and potentially transformative hypothesis that AMPH driven DA release is not mediated solely by DAT but by reverse transport via OCT3 as well. Thus, DAT-OCT3 redundancy may explain why DAT-based therapeutics have been unsuccessful in treating AMPH use disorders. We will use a combination of pharmacology, novel and established transgenic mouse models (DA neuron-specific vs glia- specific), and brain-region specific viral knockdown, to determine the role of OCT3 in AMPH-induced behavioral effects (locomotion, rearing, stereotypy, sensitization, CPP, self-administration) (Aim 1), and AMPH-induced DA efflux and clearance in vivo (Aim 2). In Aim 3 we will determine how tamoxifen inducible KO or viral KO of OCT3 impacts key elements in DA signaling and how OCT3 adapts to chronic AMPH self-administration. These studies will fill fundamental knowledge gaps about the importance of OCT3 in abuse-related effects of AMPH, and its congeners, which will help identify novel molecular targets for medications to treat AMPH addiction.

治疗物质使用障碍 (SUD) 的药物适用于许多滥用药物，但不适用于精神兴奋剂，例如安非他明 (AMPH) 和甲基安非他明，它们也缺乏日益使用的合成药物。旨在模仿已知的精神兴奋剂的作用，包括已知的和新的精神活性物质。继续对公共卫生构成重大且日益严重的威胁。需要更好地了解这些兴奋剂产生的滥用相关影响。许多兴奋剂会相互作用。与多巴胺 (DA) 转运蛋白 (DAT) 结合，这被认为可以调节其滥用相关的影响。针对 DAT 的策略在治疗精神兴奋剂成瘾方面几乎没有产生任何效果，从而提高了这些兴奋剂可能在其他地方具有调节多巴胺能神经传递的显着作用。与此相一致的是，快速增长的文献支持有机阳离子转运蛋白 3 (OCT3) 的重要作用我们的初步数据支持这一观点，表明 decynium-22 具有调节多巴胺能神经传递的作用。 (D22) 是一种 OCT3 抑制剂，可抑制雄性 OCT3 野生型 (WT) 小鼠体内 DA 的释放，但在此外，体外研究表明 AMPH 诱导底物流出。 D22 可以以独立于可卡因敏感转运蛋白的方式抑制这些发现。雄性小鼠 AMPH 条件性位置偏好 (CPP) 丧失，雌性 OCT3 KO 减弱，在雄性小鼠中使用 D22 预防 CPP 的初步数据显示，剂量反应曲线相对于雄性 OCT3 KO 小鼠，AMPH 的自我给药显着向下和向右移动。根据这些发现，我们建立并验证了 OCT3 floxed 小鼠以进行检查。在种系 KO 中没有任何发育补偿的情况下 OCT3 的作用。凭借这些小鼠的力量，新数据表明 OCT3 的他莫昔芬诱导型或病毒型 KO 可显着减弱 AMPH- 诱发的 DA 释放和 CPP 拟议的研究将探讨 OCT3 在 AMPH 影响能力中的作用。通过测试 AMPH 驱动 DA 释放的新颖且具有潜在变革性的假设来研究行为和 DA 流出不仅仅由 DAT 介导，还通过 OCT3 的反向传输介导，因此，DAT-OCT3 冗余可能。解释为什么基于 DAT 的疗法在治疗 AMPH 使用障碍方面不成功。药理学、新型和已建立的转基因小鼠模型（DA 神经元特异性与神经胶质细胞特异性）的结合特异性）和脑区域特异性病毒敲低，以确定 OCT3 在 AMPH 诱导的行为中的作用效应（运动、站立、定型、敏化、CPP、自我给药）（目标 1）和 AMPH 诱导的 DA 体内外排和清除（目标 2）在目标 3 中，我们将确定他莫昔芬如何诱导 OCT3 KO 或病毒 KO。这些研究影响 DA 信号转导的关键要素以及 OCT3 如何适应慢性 AMPH 自我管理。将填补关于 OCT3 在 AMPH 滥用相关影响中的重要性及其重要性的基础知识空白同系物，这将有助于确定治疗 AMPH 成瘾药物的新分子靶标。