The nicotinic acetylcholine receptors (nAChR) assembled from alpha4 and beta2 subunits are the most densely expressed subtype in the brain. Concentration-effect curves for agonist activation of alpha4beta2*-nAChR are biphasic. This biphasic agonist sensitivity is ascribed to differences in subunit stoichiometry. The studies described here evaluated desensitization elicited by low concentrations of epibatidine, nicotine, cytisine or methylcarbachol of brain alpha4beta2-nAChR function measured with acetylcholine-stimulated (86)Rb(+) efflux from mouse thalamic synaptosomes. Each agonist elicited concentration-dependent desensitization. The agonists differed in potency. However, IC(50) values for each agonist for desensitization of (86)Rb(+) efflux both with high (EC(50) approximately 3 microM) and low (EC(50) approximately 150 microM) acetylcholine sensitivity were not significantly different. Concentrations required to elicit desensitization were higher that their respective K(D) values for receptor binding. Even though the two components of alpha4beta2*-nAChR-mediated (86)Rb(+) efflux from mouse brain differ markedly in EC(50) values for agonist activation, they are equally sensitive to desensitization by exposure to low agonist concentrations. Mice were also chronically treated with nicotine by continuous infusion of 0, 0.5 or 4.0mg/kg/h and desensitization induced by nicotine was evaluated. Consistent with previous results, chronic nicotine treatment increased the density of epibatidine binding sites. Acute exposure to nicotine also elicited concentration-dependent desensitization of both high-sensitivity and low-sensitivity acetylcholine-stimulated (86)Rb(+) efflux from cortical and thalamic synaptosomes. Although chronic nicotine treatment reduced maximal (86)Rb(+) efflux from thalamus, IC(50) values in both brain regions were unaffected by chronic nicotine treatment.