MODULATION OF THE ACTION OF PCP BY MG2+ AND POLYAMINES

广泛滥用的药物PCP（苯环己哌啶， “天使尘”）与N-甲基-D- 天冬氨酸（NMDA）选择性谷氨酸受体亚型。 PCP类药物 结合到位于NMDA操纵的离子通道内的位点，并且只能 如果受体被激活，则结合。 NMDA受体的激活是 受到许多内源性因素的调节，包括Mg 2+和 多胺亚精胺和精胺。 了解这些影响 调节剂对NMDA受体的激活是至关重要的 阐明PCP样药物作用的分子机制。 该项目的具体目标是： i）了解Mg 2+和多胺对放射性配体结合的影响 连接到NMDA受体上的PCP位点; ii）研究Mg 2+和多胺对使用依赖性 PCP对NMDA受体的阻断和从阻断中恢复以及相关的 毒品; （三）确定膜电位对五氯苯酚作用的影响， 像毒品一样;以及 iv）研究Mg ~（2+）和多胺对 新型卤代PCP样药物。 该项目将利用一系列成熟的生物化学， 生理学和生物物理学方法来研究这些问题， 包括[3 H]地佐环平结合、细胞内Ca 2+测量和 大鼠皮层神经元膜片钳电生理学研究 这些研究将 大大增加了对造成这种情况的因素的了解， 五氯苯酚和相关药物的结合。 此外，通过鉴定 可能会增加PCP的作用，并开发这些拮抗剂 调节剂，这可能是可能的开发新的方法，以急性 五氯苯酚中毒和长期滥用五氯苯酚的治疗。

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.