Studies of ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs), are important in mechanisms of drug abuse and are central to developing rational approaches for substance abuse treatments. Nicotine directly affects these channels, whereas other agents (e.g., mecamylamine) 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]]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, [H-3]-epibatidine and a novel radioactive ligand developed in our lab, [I-125]-5-I-A-85380 (5-iodo-3-(2(S)- azetidinylmethoxy)pyridine). Specifically, we addressed the issue of the presence of two binding sites in rat brain tissue. The results of saturation, kinetic and competition studies performed with these ligands in rat brain tissue and in brains of mice lacking beta2 subunits of nAChR (knockout mice) suggested, that the previously observed high affinity population of binding sites characterizes the interaction of these ligands with alpha4beta2 nAChRs. The low affinity component of binding may reflect the interaction of these ligands with the alpha7 receptor subtype. The evaluation of last hypothesis requires additional experiments with new low molecular weight ligands for alpha7 nAChRs. - nicotinic receptors, cerebral glcose metabolism, binding sites

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000403-03
Application #
6289612
Study Section
Special Emphasis Panel (NRB)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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