BIOCHEMISTRY OF LIGAND GATED ION CHANNELS IMPORTANT TO DRUG ABUSE

烟碱型乙酰胆碱受体(NAChRs)是尼古丁作用的配基门控离子通道，在药物滥用中发挥重要作用，可能是开发合理的药物滥用治疗方法的核心。用2-脱氧-D-[1-C-14]葡萄糖技术测定大脑局部葡萄糖代谢率，以阐明烟碱拮抗剂甲戊胺对慢性尼古丁大鼠脑功能的影响。虽然甲戊胺逆转了在接受尼古丁的动物中观察到的大脑葡萄糖代谢的增加，但它没有产生戒断迹象，支持甲乙胺与尼古丁相结合在治疗尼古丁依赖方面有效的观点。对[H-3]-胱氨酸、[H-3]-表巴替丁和本实验室开发的两个新的放射性配体[I-125]-5-I-A-85380(5-碘-3-(2(S)-氮杂二基甲氧基)吡啶和[F-18]-2-F-A-85380)的研究表明，5-I-A-85380和2-F-A-85380选择性地与α4beta2亚型的nAChRs结合。[H-3]-epbatidine和[I-125]-5-I-A-85380在缺乏nAChRsβ2亚基的小鼠(“基因敲除”小鼠)脑内的饱和度、动力学和竞争研究结果表明，这些配体与α4β2 nAChRs亚型的相互作用具有高亲和力。

Nicotinic acetylcholine receptors (nAChRs), which are the ligand gated ion channels at which nicotine acts, play an important role in drug abuse and may be central to developing rational approaches for substance abuse treatments. 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, on brain function in rats receiving chronic nicotine. Although mecamylamine reversed the increase in cerebral glucose metabolism observed in animals that received nicotine, it did not produce withdrawal signs, supporting to the view that mecamylamine in combination with nicotine, is efficacious in treating nicotine dependence. Studies with [H-3]-cytisine, [H-3]-epibatidine and two novel radioactive ligands developed in our lab, [I-125]-5-I-A-85380 (5-iodo-3-(2(S)-azetidinylmethoxy)pyridine and [F-18]-2-F-A-85380 indicate that 5-I-A-85380 and 2-F-A-85380 binds specifically and selectively to the alpha4beta2 subtype of nAChRs. The results of saturation, kinetic and competition studies performed with [H-3]-epibatidine and [I-125]-5-I-A-85380 in brains of mice lacking beta2 subunits of nAChRs ("knockout" mice) suggest that the high affinity population of [H-3]-epibatidine binding sites characterizes the interaction of these ligands with alpha4beta2 nAChRs subtype.