Methamphetamine and the Striatal NK-1 Receptors

描述（由申请人提供）：甲基苯丙胺（METH）的使用在美国正在增加。甲基苯丙胺引起的人类纹状体缺陷在脱毒和长期禁欲后持续存在，并与运动任务和学习障碍有关。我们的实验室发现，纹状体神经激肽-1受体（NK-1 R）的药理学阻断可保护多巴胺（DA）终末和纹状体神经元免受METH的侵害。这一有趣而新颖的发现需要进一步研究，因为它为METH滥用的治疗提供了一个治疗靶点。我们的工作假设是，过量的DA释放在响应METH，与P物质的纹状体神经元相互作用。这反过来又导致P物质（SP）的过度释放，然后通过NK-1 R作用于胆碱能和生长抑素/NOS中间神经元。在后者神经元中，nNOS上调，产生过量的NO。我们认为过量的NO是导致纹状体DA-末端丢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检验：目的1：这一目的的目的是检验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GR 73632将被用于加重METH诱导的纹状体神经损伤。目的2：本目的的目的是检验纹状体NK-1 Rs在METH存在下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-1 R表达细胞。目的3：本研究的目的是验证SP调节纹状体NO产生的假说。为此，将利用神经化学和组织学方法来建立纹状体NK-1 Rs和谷氨酸/NO神经毒性级联反应之间的联系。这些研究的总体长期目标是确定NK-1 R在METH诱导的纹状体损伤中的作用。这一信息可能被证明是有价值的甲基滥用的治疗，也可能描述一个新的作用，这种受体在纹状体。

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.