BIOCHEMISTRY OF LIGAND GATED ION CHANNELS IMPORTANT TO DRUG ABUSE

尼古丁乙酰胆碱受体（nAChR）是尼古丁作用的配体门控离子通道，在药物滥用中起着重要作用，可能是开发合理药物滥用治疗方法的核心。 使用2-脱氧-D-[1-[C-14]C]葡萄糖技术测定局部脑葡萄糖代谢率，以阐明尼古丁拮抗剂美加明对长期接受尼古丁的大鼠脑功能的影响。 尽管美加明逆转了接受尼古丁的动物中观察到的脑葡萄糖代谢增加，但未产生戒断体征，支持美加明与尼古丁联合治疗尼古丁依赖有效的观点。用[H-3]-野靛碱、[H-3]-地棘蛙素和我们实验室开发的两种新型放射性配体[I-125]-5-I-A-85380（5-碘-3-（2（S）-氮杂环丁烷甲氧基）吡啶）和[F-18]-2-F-A-85380进行的研究表明，5-I-A-85380和2-F-A-85380特异性和选择性地结合nAChR的α 4 β 2亚型。 用[H-3]-地棘蛙素和[I-125]-5-I-A-85380在缺乏nAChR的β 2亚基的小鼠（“敲除”小鼠）的脑中进行的饱和、动力学和竞争研究的结果表明，[H-3]-地棘蛙素结合位点的高亲和力群体表征了这些配体与α 4 β 2 nAChR亚型的相互作用。

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.