SNRP at Hunter College

甲基苯丙胺（METH）的使用在美国正在增加。人的纹状体缺陷 甲基在脱毒和长期戒断后持续存在，并与 运动任务和学习。我们的实验室发现药物阻断纹状体神经激肽-1 受体（NK-1 R）对多巴胺（DA）终末和纹状体神经元都具有保护作用。这 有趣和新颖的发现需要进一步的研究，因为它提供了一个治疗靶点， 治疗METH滥用。我们的工作假设是，过量的DA释放的反应甲基， 与含有P物质的纹状体神经元相互作用。这反过来又会导致P物质的过度释放 (SP)然后通过NK-1 Rs作用于胆碱能和生长抑素/NOS中间神经元。在后一 神经元nNOS表达上调，产生过量NO。我们认为过量的NO是什么 导致纹状体中DA-末端的损失和神经元细胞死亡。这一假设将由 具体目标如下： 目的1：本研究的目的是检验SP在存在下诱导纹状体损伤的假设。 METH.为此，选择性SP激动剂GR 73632将用于加重METH诱导的纹状体损伤。 神经损伤 目的2：本研究的目的是验证纹状体NK-1 Rs信号传导神经损伤的假设， METH的存在。为此，纹状体NK-1 R-表达细胞将被选择性地破坏。 毒素SSP-皂草素 目的3：本研究的目的是验证SP调节纹状体NO产生的假说。本 最后，神经化学和组织学方法将被用来建立纹状体之间的连接， NK-1 Rs和谷氨酸/NO神经毒性级联。 这些研究的总体长期目标是确定NK-1 R在纹状体损伤中的作用 由METH引起。收集的信息可能对治疗甲基苯丙胺滥用有价值， 还描述了这种受体在纹状体中的作用。

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-1 R-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-1 Rs 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. The information gathered may prove valuable for the treatment of METH abuse and may also describe a role for this receptor in the striatum.