Methamphetamine and the Striatal NK-1 Receptors

甲基苯丙胺和纹状体 NK-1 受体

基本信息

批准号：
7797580
负责人：
Jesus A Angulo
金额：
$ 21.55万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7797580
关键词：
3-nitrotyrosine Ablation Abstinence Address Affect Agonist Amygdaloid structure Animals Apoptosis Autoradiography Biological Assay Brain Injuries Cell Death Cells Choline O-Acetyltransferase Corpus striatum structure Detection Doctor of Philosophy Dopamine Drug Metabolic Detoxication Excision Glutamates Goals High Pressure Liquid Chromatography Human Immunohistochemistry In Situ Nick-End Labeling Infusion procedures Injection of therapeutic agent Injury Interneurons Investigation Learning Magnetic Resonance Imaging Marshal Mediating Methamphetamine Methods Monitor N-Methylaspartate Neuronal Injury Neurons Nitric Oxide Nitric Oxide Synthase Parvalbumins Pharmaceutical Preparations Positron-Emission Tomography Production Proteins Receptor Signaling Reporting Role Signal Transduction Societies Somatostatin Substance P Substance P Receptor Synapses Testing Thalamic structure Time Toxic effect Toxin Tyrosine 3-Monooxygenase United States Western Blotting Work cholinergic dopamine toxicity dopamine transporter drug of abuse interest methamphetamine abuse motor impairment neurochemistry neuron loss neurotoxic novel postsynaptic prevent receptor relating to nervous system response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine (METH) use is increasing in the United States. Striatal deficits in humans induced by METH persist after detoxification and protracted abstinence and have been associated with impairment of motor tasks and learning. Our lab discovered that pharmacological .blockade of the striatal neurokinin-1 receptor (NK-1R) confers protection from METH to both dopamine (DA) terminals and striatal neurons. This interesting and novel finding needs further investigation because it provides a therapeutic target for the treatment of METH abuse. Our working hypothesis is that the excessive DA released in response to METH, interacts with substance P-containing striatal neurons. This in turn causes excessive release of substance P (SP), which then acts through NK-1Rs on cholinergic and somatostatin/NOS interneurons. In the latter neurons, nNOS is up-regulated and excessive NO produced. We suggest that the excessive NO is what is causing the loss of DA-terminals and neuronal cell death in the striatum. This hypothesis will be tested by the following specific aims: Aim 1: The purpose of this aim is to test the hypothesis that SP induces striatal injury in the presence of METH. To this end, the selective SP agonist GR73632 will be utilized to exacerbate METH-induced striatal neural damage. Aim 2: The purpose of this aim is to test the hypothesis that the striatal NK-1 Rs signal neural damage in the presence of METH. To this end, the striatal NK-1R-expressing cells will be destroyed with the selective toxin SSP-saporin. Aim 3: The purpose of this aim is to test the hypothesis that SP modulates striatal NO production. To this end, neurochemical and histological methods will be utilized to establish a connection between the striatal NK-1Rs and the glutamate/NO neurotoxic cascade. The overall, long-term goal of these studies is to define the role of the NK-1Rs in the striatal injury induced by METH. This information may prove valuable for the treatment of METH abuse and may also describe a new role for this receptor in the striatum.

描述（由申请人提供）：美国的甲基苯丙胺 (METH) 使用量正在增加。人类由冰毒引起的纹状体缺陷在戒毒和长期戒酒后仍然存在，并与运动任务和学习障碍有关。我们的实验室发现，通过药理学阻断纹状体神经激肽-1 受体 (NK-1R)，可以保护多巴胺 (DA) 末端和纹状体神经元免受冰毒侵害。这一有趣而新颖的发现需要进一步研究，因为它为治疗冰毒滥用提供了治疗靶点。我们的工作假设是，METH 释放的过量 DA 与含有 P 物质的纹状体神经元相互作用。这反过来会导致 P 物质 (SP) 过度释放，然后通过 NK-1R 作用于胆碱能和生长抑素/NOS 中间神经元。在后者的神经元中，nNOS 上调并产生过量的 NO。我们认为过量的 NO 是导致纹状体中 DA 末端丢失和神经元细胞死亡的原因。该假设将通过以下具体目标进行检验：目标 1：该目标的目的是检验 SP 在 METH 存在下诱导纹状体损伤的假设。为此，选择性 SP 激动剂 GR73632 将用于加剧 METH 诱导的纹状体神经损伤。目标 2：该目标的目的是检验纹状体 NK-1 Rs 在 METH 存在时发出神经损伤信号的假设。为此，将用选择性毒素 SSP-皂草素破坏纹状体 NK-1R 表达细胞。目标 3：该目标的目的是检验 SP 调节纹状体 NO 产生的假设。为此，将利用神经化学和组织学方法来建立纹状体 NK-1R 和谷氨酸/NO 神经毒性级联之间的联系。这些研究的总体长期目标是确定 NK-1R 在 METH 引起的纹状体损伤中的作用。这些信息可能对治疗冰毒滥用很有价值，也可能描述这种受体在纹状体中的新作用。