MODULATION OF THE ACTION OF PCP BY MG2+ AND POLYAMINES

广泛滥用的药物PCP(苯环利定， “天使之尘”)被认为与N-甲基-D- 谷氨酸受体的天冬氨酸(NMDA)选择性亚型。五氯苯酚类药物 结合到位于NMDA操作的离子通道内的位置，并且只能 如果受体被激活，则绑定。NMDA受体的激活是 受许多内源性因素的调节，包括镁和 多胺、亚精胺和精胺。了解这些因素的影响 激活NMDA受体的调节剂对 阐明五氯苯酚类药物的分子作用机制。 该项目的具体目标是： I)了解镁离子和多胺对放射性配基结合的影响 与NMDA受体上的PCP位点结合； Ii)研究镁离子和多胺对使用依赖性的影响 PCP及相关物质对NMDA受体的阻断和恢复 毒品； Iii)确定膜电位对五氯酚作用的影响- 像毒品一样；以及 四)研究镁离子和多胺对肌动蛋白作用的影响 新型卤代五氯苯酚类药物。 这个项目将利用一系列成熟的生化， 研究这些问题的生理学和生物物理学方法， 包括[~3H]地佐西平结合、细胞内钙离子测定和 大鼠皮层神经元的膜片钳电生理学。这些研究将 极大地增加了对影响经济增长的因素的理解 五氯苯酚与相关药物的结合。此外，通过识别调制器 可能增加PCP的作用，并开发拮抗剂 调节器，有可能开发新的方法来治疗急性 五氯酚中毒和长期滥用五氯酚的治疗。

The psychotomimetic effects of the widely abused drug PCP (phencyclidine, "angel dust") have been associated with blockade of the N-methyl-D- aspartate (NMDA) selective subtype of glutamate receptor. PCP-like drugs bind to a site located within the NMDA-operated ion channel, and can only bind if the receptor is activated. Activation of the NMDA receptor is subject to modulation by a number of endogenous factors, including Mg2+ and the polyamines spermidine and spermine. Understanding the effects of these modulators on the activation of the NMDA receptor is crucial for the elucidation of the molecular mechanism of action of PCP-like drugs. The specific aims of this project are: i) To understand the effects of Mg2+ and polyamines on radioligand binding to the PCP site on the NMDA receptor; ii) To study the effects of Mg2+ and polyamines on the use-dependent blockade and recovery from blockade of the NMDA receptor by PCP and related drugs; iii) To determine the effects of membrane potential on the action of PCP- like drugs; and iv) To investigate the effects of Mg2+ and polyamines on the action of novel halogenated PCP-like drugs. This project will utilize a series of well established biochemical, physiological and biophysical approaches to investigate these issues, including [3H] dizocilpine binding, intracellular Ca2+ measurements and patch-clamp electrophysiology in rat cortical neurons. These studies will greatly increase the understanding of the factors that contribute to the binding of PCP and related drugs. Moreover, by identifying modulators that may increase the action of PCP and developing antagonists to these modulators, it may be possible to develop novel approaches to the acute treatment of PCP intoxication and long-term PCP abuse.