Nicotinic agonists differ in activation and desensitization of 86Rb+ efflux from mouse thalamic synaptosomes

The effects of the nicotinic agonists acetylcholine, (+)-anatox in-a, carbachol, cytisine, dimethylphenylpiperazinum, (+)-epibatidine, (-)-epibatidine, methylcarbachol, D-nicotine, L-nicotine, and tetramethylammonium on 86Rb+ efflux from mouse thalamic synaptosomes were investigated. All 11 agonists evoked a concentration-dependent stimulation of 86Rb+ efflux as well as a time- and concentration-dependent reduction of response (desensitization). The agonists varied widely in potency, efficacy and rate of desensitization. (+)-Epibatidine was the most potent agonist (EC50 = 10 nM), whereas tetramethylammonium was the least potent (EC50 = 65 microM). The agonists containing a quaternary ammonium group were generally more efficacious than the other agonists, except for both of the enantiomers of epibatidine, which stimulated 86Rb+ efflux at least as well as acetylcholine. Cytisine was the least efficacious compound tested with a maximal response approximately 10% that of (-)-epibatidine. Exposure of the thalamic synaptosomes to agonist concentrations that generally stimulated little or no efflux reduced in a concentration-dependent manner a subsequent response to 10 microM nicotine. The IC50 values for this functional blockade (desensitization) were highly correlated with the Ki values for the inhibition of [3H]nicotine binding. Furthermore, exposure of the thalamic synaptosomes to 300 nM L-nicotine reduced the responses evoked by a subsequent exposure to a stimulating concentration of all 11 agonists. The observation of desensitization by both stimulating and substimulating concentrations of each agonist is consistent with the predictions of the two-state model of Katz and Thesleff.