CHRONIC NICOTINE AND MECAMYLAMINE TREATMENT INCREASE BRAIN NICOTINIC RECEPTOR-BINDING WITHOUT CHANGING ALPHA-4 OR BETA-2 MESSENGER-RNA LEVELS

It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increas e the number of [H-3]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after co treatment with the two drugs. The studies reported here extend these f indings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of reso lution. 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. T he brains of these mice were subsequently analyzed to determine the ef fects of chronic drug treatment on [H-3]-nicotine binding and on the l evels of mRNA encoding the nicotinic receptor subunits, alpha 4 and be ta 2. [H-3]-Nicotine binding was increased in 37 of 46 brain regions a fter chronic nicotine treatment (average increase = 66.5%), in 41 of 4 6 regions after chronic mecamylamine treatment (average increase = 56. 5%), and in 45 of 46 brain regions after chronic treatment with both d rugs (average increase = 107.1%). The changes in [H-3]-nicotine bindin g 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. Theref ore, the increases in [H-3]-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.