Chronic nicotine differentially regulates alpha6- and beta3-containing nicotinic cholinergic receptors in rat brain.
We investigated the effects of chronic nicotine on alpha6- and beta3-containing nicotinic acetylcholine receptors (nAChRs) in two rat brain regions using three methodological approaches: radioligand binding, immunoprecipitation, and nicotine-stimulated synaptosomal release of dopamine. Nicotine was administered by osmotic minipumps for 2 weeks. Quantitative autoradiography with [(125)I]alpha-conotoxin MII to selectively label alpha6(*) nAChRs showed a 28% decrease in binding in the striatum but no change in the superior colliculus. Immunoprecipitation of nAChRs labeled by [(3)H]epibatidine in these two regions showed that chronic nicotine increased alpha4- and beta2-containing nAChRs by 39 to 67%. In contrast, chronic nicotine caused a 39% decrease in alpha6-containing nAChRs in striatum but no change in superior colliculus. No changes in beta3-containing nAChRs were seen in either region after chronic nicotine. The decreased expression of alpha6-containing nAChRs persisted for at least 3 days, recovering to baseline by 7 days after removal of the pumps. There was a small but significant decrease in total nicotine-stimulated dopamine release in striatal synaptosomes after nicotine exposure. However, the component of dopamine release that was resistant to alpha-conotoxin MII blockade was unaffected, whereas dopamine release that was sensitive to blockade by alpha-conotoxin MII was decreased by 56%. These findings indicate that the alpha6(*) nAChR is regulated differently from other nAChR subtypes, and they suggest that the inclusion of a beta3 subunit with alpha6 may serve to inhibit nicotine-induced down-regulation of these receptors.
Perry
David C
DC
Department of Pharmacology and Physiology, George Washington University, Washington, DC, USA.
Mao
Danyan
D
Gold
Allison B
AB
McIntosh
J Michael
JM
Pezzullo
John C
JC
Kellar
Kenneth J
KJ
D000595:Amino Acid Sequence; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects*; D020916:Conotoxins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D047468:Immunoprecipitation; D008297:Male; D008969:Molecular Sequence Data; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000032:analysis / Q000187:drug effects*
D020916:Conotoxins; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6; C509815:nicotinic receptor beta3, rat; D009538:Nicotine; D004298:Dopamine