Methamphetamine and the Striatal NK-1 Receptors

描述(申请人提供)：甲基苯丙胺(冰毒)在美国的使用正在增加。由冰毒引起的人类纹状体缺陷在戒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，药物阻断纹状体神经激肽-1受体(NK-1R)可以保护多巴胺(DA)终末和纹状体神经元免受冰毒的影响。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，冰毒反应释放的过量DA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/一氧化氮合酶中间神经元。在后一类神经元中，nNOS表达上调，过量产生NO。我们认为过量的NO是导致纹状体DA终末丢失和神经细胞死亡的原因。这一假说将通过以下具体目的来检验：目的1：这一目的是检验SP在冰毒存在下引起纹状体损伤的假说。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-1受体在冰毒存在时发出神经损伤信号的假说。为此，纹状体NK-1R表达细胞将被选择性毒素SSP-Saporin破坏。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在纹状体NK-1RS和谷氨酸/NO神经毒性级联反应之间建立联系。这些研究的总体和长期目标是确定NK-1RS在冰毒引起的纹状体损伤中的作用。这些信息可能被证明对治疗冰毒滥用很有价值，也可能描述这种受体在纹状体中的新作用。

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.