Regulation of nicotinic receptors in the brain of mice withdrawn from chronic oral nicotine treatment.

Abstract

The effect of nicotine withdrawal on regional regulation of brain nicotinic receptors was studied in mice after chronic administration of nicotine in the drinking water for 2, 4 or 7 weeks. Two weeks of chronic nicotine administration did not alter the binding of [3H]-nicotine in the midbrain, cortex or cerebellum of the mice, while after both 4-and 7-week treatments a significant increase in the specific [3H]-nicotine binding was observed in cortical and midbrain membranes. In the midbrain, the [3H]-nicotine binding was increased by about 40% in mice withdrawn for 48-72 h from the 4-week chronic nicotine treatment and in mice withdrawn for 48 h from the 7-week treatment. The [3H]-nicotine binding was significantly increased (by 55-65%) in the cortex at 48 h and 72 h after withdrawal from 4-week chronic nicotine and it was even somewhat more increased (by 72-66%) after 7-week treatment. The cortical [3H]-nicotine binding was not altered at 24 h after the 4-week treatment, but in mice withdrawn for 24 h from the 7-week treatment it was increased by 116%. The increases in [3H]-nicotine binding returned to control levels within 1 week after withdrawal. None of the studied treatments affected the [3H]-nicotine binding in the cerebellum. Tolerance towards nicotine-induced locomotor depression was only found in mice withdrawn for 24 h from the 7-week chronic nicotine administration. These findings suggest that at least 4-week chronic nicotine administration in the drinking water is needed before any upregulation of nicotinic receptors can be observed. Furthermore, in our experiments the increase in the [3H]-nicotine binding was seen before behavioural tolerance could be demonstrated. The differences between brain regions in the time course of nicotinic receptor upregulation may reflect variations in nicotinic receptor subunits and their sensitivity to chronic nicotine treatment.