@article {Marks1268, author = {M J Marks and S R Grady and A C Collins}, title = {Downregulation of nicotinic receptor function after chronic nicotine infusion.}, volume = {266}, number = {3}, pages = {1268--1276}, year = {1993}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Chronic nicotine treatment generally results in tolerance to several actions of nicotine and a paradoxical increase in brain nicotinic receptor numbers. Receptor upregulation, it has been argued, arises as a consequence of functional desensitization. In the studies reported here, mice were chronically infused with saline (control) or one of five doses of nicotine (0.25-4.0 mg/kg/hr) for 10 days. This treatment resulted 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 [3H]nicotine binding was also observed. To assess functional status of the nicotinic receptors, nicotine-stimulated release of [3H]dopamine from striatal synaptosomes and 86Rb+ efflux from cortical and midbrain synaptosomes were also measured. Chronic nicotine infusion resulted in an infusion dose-dependent decrease in [3H]dopamine release from striatum and 86Rb+ efflux from midbrain; cortical 86Rb+ efflux was not affected by chronic nicotine treatment. Dose-response analyses of the release and efflux assays demonstrated that chronic nicotine infusion evoked decreases in the maximal effects of nicotine on the functional assays; potency was not altered by chronic drug treatment. These results are consistent with the hypothesis that behavioral tolerance to nicotine is a consequence of down-regulation of brain nicotinic receptor function.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/266/3/1268}, eprint = {https://jpet.aspetjournals.org/content/266/3/1268.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }