Dissociation of the apparent relationship between nicotine tolerance and up-regulation of nicotinic receptors

Abstract

Saline or nicotine (0.8 mg/kg/hr) was administered chronically to rats via subcutaneous infusion for 7 days. After chronic treatment, the effects of a challenge dose of nicotine, injected subcutaneously, on open-field activity and body temperature were measured. Nicotine responses were measured 2 hours after infusion had been stopped (day 0) or 1, 2, 4, 8, or 21 days after cessation of treatment. Brain nicotinic receptors were measured using nicotine binding or bungarotoxin binding in six brain regions. Tolerance to nicotine's effects on open-field activity and body temperature were observed; this tolerance was lost before the fourth day of withdrawal. Both nicotine and BTX binding were increased after chronic nicotine treatment. The return of the receptors to control values was dependent on brain region, but in general receptors were still increased at 4 days after withdrawal. The half-lives for receptors returning to normal were greater for nicotine binding compared to BTX binding. These results suggest that a relatively short-lived tolerance results from chronic nicotine infusion and that alterations in nicotinic receptors can be dissociated from behavioral tolerance.