Methamphetamine and the Striatal NK-1 Receptors

描述（由申请人提供）：甲基苯丙胺（冰毒）的使用在美国正在增加。甲基苯丙胺引起的纹状体缺陷在解毒和长期戒断后持续存在，并与运动任务和学习障碍有关。我们的实验室发现药理学。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甲基苯丙胺的影响。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一个治疗靶点。我们的工作假设是，过量的DA在甲基安非他明的反应中释放，与含有p物质的纹状体神经元相互作用。这反过来导致P物质（SP）的过度释放，然后通过NK-1Rs作用于胆碱能和生长抑素/NOS中间神经元。在后一种神经元中，nNOS被上调，并产生过多的NO。我们认为过量的一氧化氮是导致纹状体da末端缺失和神经元细胞死亡的原因。这一假设将通过以下具体目的进行验证：目的1：该目的的目的是验证SP在冰毒存在下诱导纹状体损伤的假设。为此，我们将利用选择性SP激动剂GR73632加重甲基苯丙胺诱导的纹状体神经损伤。目的2：本目的目的是验证纹状体NK-1 Rs在甲基苯丙胺存在下信号神经损伤的假设。为此，纹状体表达nk - 1r的细胞将被选择性毒素ssp -皂苷破坏。目的3：本目的目的是检验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-1Rs与谷氨酸/一氧化氮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-1Rs在甲基苯丙胺诱导的纹状体损伤中的作用。这一信息可能对治疗冰毒滥用有价值，也可能描述纹状体中这种受体的新作用。

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.