DOWN-REGULATION OF NICOTINIC RECEPTOR FUNCTION AFTER CHRONIC NICOTINEINFUSION

Chronic nicotine treatment generally results in tolerance to several a ctions of nicotine and a paradoxical increase in brain nicotinic recep tor numbers. Receptor upregulation, it has been argued, arises as a co nsequence of functional desensitization. In the studies reported here, mice were chronically infused with saline (control) or one of five do ses of nicotine (0.25-4.0 mg/kg/hr) for 10 days. This treatment result ed in a dose-dependent tolerance to nicotine-induced decreases in body temperature as well as decreases in locomotor and rearing activities in a Y-maze. The anticipated increase in [H-3]nicotine binding was als o observed. To assess functional status of the nicotinic receptors, ni cotine-stimulated release of [H-3]dopamine from striatal synaptosomes and Rb-86+ efflux from cortical and midbrain synaptosomes were also me asured. Chronic nicotine infusion resulted in an infusion dose-depende nt decrease in [H-3]dopamine release from striatum and Rb-86+ efflux f rom midbrain; cortical Rb-86+ efflux was not affected by chronic nicot ine treatment. Dose-response analyses of the release and efflux assays demonstrated that chronic nicotine infusion evoked decreases in the m aximal effects of nicotine on the functional assays; potency was not a ltered by chronic drug treatment. These results are consistent with th e hypothesis that behavioral tolerance to nicotine is a consequence of down-regulation of brain nicotinic receptor function.