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Does neurokinin-1 modulate amphetamine reward via catecholamine transport?

Neurokinin-1 是否通过儿茶酚胺转运调节安非他明奖赏？

基本信息

批准号：
9348614
负责人：
LANKUPALLE D JAYANTHI
金额：
$ 19.06万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9348614
关键词：
Acute Address Affect Affinity Agonist Amination Amines Amphetamine Abuse Amphetamines Animal Behavior Attention deficit hyperactivity disorder Attenuated Behavior Behavioral Biochemical Brain Catecholamines Cell Culture System Cell Nucleus Cells Cocaine Conserved Sequence Corpus striatum structure Coupled Data Down-Regulation Drug Addiction Exhibits FDA approved Goals Grant Human In Vitro Injectable Knockout Mice Knowledge Link Measures Mediating Membrane Mental Depression Microinjections Molecular Mus Neurons Outcome Pathway interactions Peptides Permeability Pharmaceutical Preparations Phenotype Phosphorylation Physiological Play Process Publishing Rattus Receptor Activation Regulation Relapse Rewards Role Sequence Homology Series Substance P Substance P Receptor Surface Synapses Testing Therapeutic Therapeutic Agents Treatment Efficacy Ventral Striatum addiction aprepitant dopamine transporter drug reward in vivo monoamine neurobiological mechanism neuropsychiatry noradrenaline transporter noradrenergic novel preference presynaptic prevent protein protein interaction psychostimulant public health relevance stimulant abuse therapeutic target trafficking transmission process

项目摘要

DESCRIPTION (provided by applicant): Currently, there are no proven medications to treat stimulant abuse, addiction or relapse. Therefore, new knowledge on the neuronal substrates that are modified by psychostimulant drugs will greatly aid in identifying novel targets for developing therapeutic strategies to intervene in these processes. Altered noradrenergic transmission and presynaptic norepinephrine transporter (NET) expression have long been associated with depression and drug-addiction. Indeed, amphetamine (AMPH) targets NET and downregulates its function. We have shown that AMPH downregulates NET function and surface expression via transporter T258/S259 trafficking motif. We have also shown that activation of the neurokinin-1 receptor (NK1R) negatively regulates NET via PKC phosphorylation of the same motif. These findings are of physiological significance because (i) Substance P, the endogenous NK1R agonist, is released following AMPH treatment. SP enhances AMPH stimulant effects, whereas NK1R antagonists block this effect; (ii) NK1R knockout mice exhibit ADHD-like phenotype; and (iii) AMPH is a therapeutic agent for treating ADHD in the human. Thus, there is, apparently a physiologically relevant relationship between NET, NK1R and AMPH. In this regard, our discovery that both NK1R and AMPH mediate NET downregulation and that both are linked to the T258/S259 motif suggests that this pathway may play a significant role in regulating AMPH-elicited behaviors. In support, our preliminary in vivo studies suggest that AMPH-induced NET downregulation and locomotor activation are sensitive to NK1R antagonists and to manipulations targeting the T258/S259 motif. We propose two specific aims to test our hypothesis that the NK1R-mediated T258/S259-specific NET downregulation contributes to AMPH behavioral effects. Aim 1 will test the hypothesis that NK1R mediates AMPH-induced NET regulation and reward-like behavior in mice. We will identify the role of ventral striatal NK1R in modulating AMPH-induced synaptic NET regulation and conditioned place preference by brain nuclei-specific microinjections of agonists and antagonists alone or in combination. Aim 2 will test the hypothesis that NET T258/S259 motif is required for AMPH-mediated reward-like behavior and NET downregulation in mice. We will study the role of the T258/S269 motif by ventral striatal microinjections of cell permeable TAT-NET peptides that interfere with the AMPH-dependent trafficking of NET. Since dopamine transporter (DAT) is also downregulated by both NK1R and AMPH, and both NET and DAT share highly conserved sequence homology at the T258/S259 region, DAT-KO mice will also be utilized in both aims to dissociate the role of NET regulation from that of DAT. Thus, understanding how NK1R regulates amine transporters may help us identify the specific mechanisms (which could be therapeutic targets) whereby AMPH disrupts catecholamine transporter function and hence animal behavior.

描述（由申请人提供）：目前，还没有经过验证的药物可以治疗兴奋剂滥用、成瘾或复发。因此，关于精神兴奋药物修饰的神经元底物的新知识将极大地有助于确定新的靶标，以制定干预这些过程的治疗策略。去甲肾上腺素能传递和突触前去甲肾上腺素转运蛋白（NET）表达的改变长期以来一直与抑郁症和药物成瘾有关。事实上，安非他明 (AMPH) 以 NET 为目标并下调其功能。我们已经证明 AMPH 通过转运蛋白 T258/S259 运输基序下调 NET 功能和表面表达。我们还表明，神经激肽-1 受体 (NK1R) 的激活通过同一基序的 PKC 磷酸化负向调节 NET。这些发现具有生理意义，因为 (i) P 物质（内源性 NK1R 激动剂）在 AMPH 治疗后释放。 SP 增强 AMPH 刺激作用，而 NK1R 拮抗剂则阻断这种作用； (ii) NK1R 基因敲除小鼠表现出 ADHD 样表型； (iii) AMPH是用于治疗人类ADHD的治疗剂。因此，NET、NK1R 和 AMPH 之间显然存在生理学相关关系。在这方面，我们发现 NK1R 和 AMPH 均介导 NET 下调，并且两者都与 T258/S259 基序相关，这表明该途径可能在调节 AMPH 引发的行为中发挥重要作用。作为支持，我们的初步体内研究表明 AMPH 诱导的 NET 下调和运动激活对 NK1R 拮抗剂和针对 T258/S259 基序的操作敏感。我们提出了两个具体目标来检验我们的假设，即 NK1R 介导的 T258/S259 特异性 NET 下调有助于 AMPH 行为效应。目标 1 将检验 NK1R 介导 AMPH 诱导的小鼠 NET 调节和奖励样行为的假设。我们将通过脑核特异性显微注射单独或组合的激动剂和拮抗剂来确定腹侧纹状体 NK1R 在调节 AMPH 诱导的突触 NET 调节和条件性位置偏好中的作用。目标 2 将测试以下假设：NET T258/S259 基序是 AMPH 介导的奖励样行为和小鼠 NET 下调所必需的。我们将通过腹侧纹状体显微注射细胞可渗透的 TAT-NET 肽来研究 T258/S269 基序的作用，这些肽干扰 AMPH 依赖性的 NET 运输。由于多巴胺转运蛋白（DAT）也被 NK1R 和 AMPH 下调，并且 NET 和 DAT 在 T258/S259 区域具有高度保守的序列同源性，因此 DAT-KO 小鼠也将用于这两个目的，以将 NET 调节的作用与 DAT 的作用分开。因此，了解 NK1R 如何调节胺转运蛋白可能有助于我们确定 AMPH 扰乱儿茶酚胺转运蛋白功能并进而扰乱动物行为的具体机制（可能是治疗靶点）。