BIOCHEMISTRY OF LIGAND GATED ION CHANNELS IMPORTANT TO DRUG ABUSE

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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.