Methamphetamine and the Striatal NK-1 Receptors

甲基苯丙胺和纹状体 NK-1 受体

• 批准号: 7393258
• 负责人: Jesus A Angulo
• 金额: $ 21.77万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393258
• 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; Cholinergic Agents; 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; Purpose; Receptor Signaling; Reporting; Role; Signal Transduction; Societies; Somatostatin; Somatostatin Receptor; Substance P; Substance P Receptor; Synapses; Testing; Thalamic structure; Thinking; Time; Toxic effect; Toxin; Tyrosine 3-Monooxygenase; United States; Western Blotting; Work; cholinergic; dopamine toxicity; dopamine transporter; drug of abuse; interest; motor impairment; neurochemistry; neuron loss; neurotoxic; novel; postsynaptic; prevent; receptor; relating to nervous system; response; therapeutic target

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（甲基苯丙胺）使用正在增加。解毒后，由甲基毒素引起的人类中的纹状体缺陷和持久性持续性，并与运动任务和学习的损害有关。我们的实验室发现，纹状体神经蛋白-1受体（NK-1R）的药理学。块赋予了甲基甲基甲基甲基甲基（DA）末端和纹状体神经元的保护。这一有趣而新颖的发现需要进一步研究，因为它为治疗滥用甲基苯丙胺的治疗提供了一个治疗靶标。我们的工作假设是，响应于甲基的释放的过多DA与物质含有P的纹状体神经元相互作用。反过来，这会导致P（SP）的过度释放，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被上调并且没有产生过多。我们建议过多的NO是导致纹状体中DA末端和神经元细胞死亡丧失的原因。该假设将通过以下特定目的进行检验：目标1：该目的的目的是检验SP在甲基甲基存在下诱导纹状体损伤的假设。为此，选择性的SP激动剂GR73632将用于加剧甲基甲基甲基甲基甲基诱导的纹状体神经损伤。目的2：此目的的目的是检验以下假设：冰含量在甲基苯酚存在下的纹状体NK-1 RS信号神经损伤。为此，纹状体表达NK-1R的细胞将用选择性毒素SSP-糖粉破坏。目的3：此目的的目的是测试SP调节纹状体无生产的假设。为此，将利用神经化学方法和组织学方法在纹状体NK-1RS与谷氨酸/无神经毒性级联反应之间建立联系。这些研究的总体长期目标是定义NK-1R在甲基菌引起的纹状体损伤中的作用。该信息可能被证明对于治疗甲基苯丙胺的滥用有价值，也可能描述了该受体在纹状体中的新作用。