Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels.
It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increase the number of [3H]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after cotreatment with the two drugs. The studies reported here extend these findings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of resolution. DBA/2 mice were chronically infused (i.v.) with saline, 4.0 mg/ kg/hr nicotine, 4.0 mg/kg/hr mecamylamine or both drugs for 7 days. The brains of these mice were subsequently analyzed to determine the effects of chronic drug treatment on [3H]-nicotine binding and on the levels of mRNA encoding the nicotinic receptor subunits, alpha 4 and beta 2. [3H]-Nicotine binding was increased in 37 of 46 brain regions after chronic nicotine treatment (average increase = 66.5%), in 41 of 46 regions after chronic mecamylamine treatment (average increase = 56.5%), and in 45 of 46 brain regions after chronic treatment with both drugs (average increase = 107.1%). The changes in [3H]-nicotine binding produced by the two drugs across brain regions were highly (r = 0.98) and significantly correlated. These results are consistent with the proposal that the same receptors are affected by agonist or antagonist treatment. Chronic treatment had no significant effect on the levels of alpha 4 or beta 2 mRNA as measured by in situ hybridization. Therefore, the increases in [3H]-nicotine binding do not arise from changes in the steady-state levels of either alpha 4 or beta 2 mRNA which are believed to encode the subunits of this nicotinic receptor subtype.
Pauly
J R
JR
Department of Pharmacology, Medical College of Georgia, Augusta, Georgia, USA.
Marks
M J
MJ
Robinson
S F
SF
van de Kamp
J L
JL
Collins
A C
AC
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D008464:Mecamylamine / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D009538:Nicotine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D008464:Mecamylamine; D009538:Nicotine