Takayama_1989_J.Pharmacol.Exp.Ther_251_1083

This study was performed to determine how drugs that inhibit the function of peripheral nicotinic receptors (noncompetitive inhibitors), interact with nicotinic receptors in the brain. By using [3H]MCC (methylcarbamylcholine ) as a ligand for nicotinic receptors, competition studies at a fixed concentration of radioligand and saturation studies were performed with various noncompetitive inhibitors. [3H]MCC labeled high affinity nicotinic receptor sites in the rat brain at equilibrium. The sites appeared to represent desensitized nicotinic receptors, comprising a fraction of the total pool of these receptors. At micromolar concentrations, noncompetitive inhibitors interacted distinctively with [3H]MCC binding sites. Mecamylamine behaved as an allosteric inhibitor, as it decreased the apparent density of [3H]MCC binding sites. Tetracaine had mixed allosteric/competitive properties, reducing both the density and the affinity of binding. Chlorpromazine manifested a biphasic effect, increasing receptor density at concentrations of approximately 50 to 500 microM and reducing the affinity at higher concentrations. The results suggest that noncompetitive inhibitors bind to different, but interacting sites associated with desensitized nicotinic receptors in the brain, as well as to recognition sites for acetylcholine.