Downregulation of nicotinic receptor function after chronic nicotine infusion.
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.
Institute for Behavioral Genetics, University of Colorado, Boulder.
M J
MJ
Marks
S R
SR
Grady
A C
AC
Collins
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004361:Drug Tolerance; D005260:Female; D007262:Infusions, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D012413:Rubidium / Q000493:pharmacokinetics; D012414:Rubidium Radioisotopes; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D014316:Tritium; D009538:Nicotine; D012413:Rubidium; D004298:Dopamine