BIOCHEMISTRY OF LIGAND GATED ION CHANNELS IMPORTANT TO DRUG ABUSE

配体门控离子通道的研究，如 N-甲基-D-天冬氨酸受体与烟碱 乙酰胆碱受体(NAChR)在高血压的发病机制中起重要作用。 药物滥用，是制定合理的治疗方法的核心 药物滥用治疗。某些滥用药物，如尼古丁， 直接影响这些通道，而其他药剂(如MK-801) 能够改变慢性药物效应的药物，也通过 与他们的互动。在一项关于激动剂和拮抗剂如何 AT-nAChRs影响脑功能、局部脑代谢 葡萄糖的速率通过使用 2-脱氧-D-[1-[C-14]C]葡萄糖技术研究 烟碱拮抗剂甲戊胺对慢性阻塞性肺疾病大鼠的影响 尼古丁。甲基戊胺逆转了脑内葡萄糖的增加 在未服用尼古丁的动物中观察到的代谢 产生撤资迹象支持了这样一种观点 甲基戊胺与尼古丁相结合，对 治疗尼古丁依赖。甲基戊胺本身就增加了 大脑代谢在脚间核，一个区域 尼古丁还能促进新陈代谢。这一发现进一步证实了 甲乙胺和尼古丁相互作用的复杂性。我们有 继续我们对结构-功能组织的研究 使用[H-3]-胱氨酸的nAChRs，新的放射性配体， [H-3]-依巴替丁及其类似物[I-125]IPH， (+/-)-exo-2-(2-[I-125]iodo-5-pyridyl)-7-azabicyclo[2.2.1]庚烷， 和[I-125]-5-I-A-85380来表征 NAChR-通道复合体，我们去年发现的。未来 对这些结合位点的表征可能会为 尼古丁的作用机制及其研究进展 新的药物疗法。

Studies of ligand-gated ion channels, such as the N-methyl-D-aspartate receptor (NMDA) and the nicotinic acetylcholine receptor (nAChR), are important in mechanisms of drug abuse and are central to developing rational approaches for substance abuse treatments. Certain abused drugs, such as nicotine, directly affect these channels, whereas other agents (e.g., MK-801) that are capable of modifying chronic drug effects, also act through interactions with them. In a study of how agonists and antagonists at nAChRs influence brain function, regional cerebral metabolic rates for glucose were assayed using the 2-deoxy-D-[1-[C-14]C]glucose technique to elucidate the effect of nicotinic antagonist, mecamylamine, in rats receiving chronic nicotine. Mecamylamine reversed the increase in cerebral glucose metabolism observed in animals that received nicotine without producing withdrawal signs lending support to the view that mecamylamine in combination with nicotine, is efficacious in treating nicotine dependence. Mecamylamine, itself, increased cerebral metabolism in the interpeduncular nucleus, a region in which nicotine also increases metabolism. This finding reinforces the complexity of this mecamylamine-nicotine interaction. We have continued our studies of the structural-functional organization of nAChRs using [H-3]-cytisine, novel radioactive ligands, [H-3]-epibatidine and its analogue [I-125]IPH, (+/-)-exo-2-(2-[I-125]iodo-5-pyridyl)-7-azabicyclo[2.2.1] heptane, and [I-125]-5-I-A-85380 to characterize two binding sites on the nAChR-channel complex, which we identified last year. The future characterization of these binding sites may offer possibilities for understanding the mechanism of action of nicotine and developing new drug therapies.