SNRP at Hunter College

在美国，甲基苯丙胺(冰毒)的使用正在增加。在人类中引起纹状体缺陷 冰毒在戒毒和长期戒断后仍然存在，并与 运动任务和学习。我们的实验室发现，对纹状体神经激肽-1的药物阻断 受体(NK-1R)对多巴胺(DA)终末和纹状体神经元均有保护作用。这 有趣和新颖的发现需要进一步研究，因为它为 冰毒滥用的治疗。我们的工作假设是对冰毒的反应释放了过量的DA， 与含有P物质的纹状体神经元相互作用。这又会导致P物质的过度释放 (SP)，然后通过NK-1RS作用于胆碱能和生长抑素/一氧化氮合酶中间神经元。在后者中 神经元中，nNOS表达上调，过量的NO产生。我们认为，过量的NO就是事实 导致纹状体DA终末丢失和神经细胞死亡。这一假设将由 以下是具体目标： 目的1：本研究的目的是验证SP引起纹状体损伤的假说。 冰毒。为此，选择性SP激动剂GR73632将被用来加重冰毒诱导的纹状体 神经损伤。 目的2：本研究的目的是验证纹状体NK-1Rs信号传导神经损伤的假设。 冰毒的存在。为此，纹状体NK-1R表达细胞将被选择性地破坏。 毒素SSP-Saporin。 目的3：本研究的目的是验证SP调节纹状体NO产生的假说。对这件事 最后，将利用神经化学和组织学方法在纹状体之间建立联系 NK-1受体与谷氨酸/一氧化氮神经毒性级联反应。 这些研究的总体、长期目标是确定NK-1RS在纹状体损伤中的作用 是冰毒引起的。收集的信息可能被证明对治疗冰毒滥用很有价值，并可能 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.