Binding and functional activity of nicotinic cholinergic receptors in selected rat brain regions are increased following long-term but not short-term nicotine treatment.
Chronic nicotine exposure up-regulates neuronal nicotinic receptors, but the functional consequences for these receptors is less well understood. Following 2 weeks of nicotine or saline treatment by osmotic minipump, the functional activity of nicotinic receptors was measured by concentration-response curves for epibatidine-stimulated (86)Rb efflux. Nicotine-treated animals had a significantly higher maximal efflux in cerebral cortex and superior colliculus, but not in thalamus or interpeduncular nucleus plus medial habenula. This increase was confirmed in a separate experiment with stimulation by single concentrations of epibatidine (cortex, superior colliculus) or nicotine (cortex only). Chronic nicotine did not alter (86)Rb efflux stimulated by cytisine, an alpha3beta4-selective agonist, or by potassium chloride, in any region. Short-term (16 h) nicotine exposure caused no changes in either (86)Rb efflux or receptor binding measured with [(3)H]epibatidine. Binding was significantly increased after 2 weeks nicotine exposure in cortex, superior colliculus and thalamus, but not in interpeduncular nucleus plus medial habenula. The increases in epibatidine-stimulated (86)Rb efflux in the four regions tested was linearly correlated with the increases in [(3)H]epibatidine binding in these regions (R(2) = 0.91), suggesting that rat brain receptors up-regulated by chronic nicotine are active. These results have important consequences for understanding nicotinic receptor neurobiology in smokers and users of nicotine replacement therapy.
Nguyen
Henry N
HN
Department of Pharmacology and Physiology, and Institute for Biomedical Sciences, George Washington University, Washington, DC, USA.
Rasmussen
Bruce A
BA
Perry
David C
DC
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003367:Cotinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015918:Infusion Pumps, Implantable; D008024:Ligands; D008297:Male; D009538:Nicotine / Q000097:blood / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D012414:Rubidium Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D009538:Nicotine; D003367:Cotinine; C082748:epibatidine