Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine.

1. The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-1 day-1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg-1 day-1 for 5 days) of the drug. 2. The extracellular dopamine concentration in the NAc was significantly increased (P < 0.05) following a challenge dose of nicotine (0.4 mg kg-1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine. 3. The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P < 0.01) by the prior administration of mecamylamine (2.0 mg kg-1, s.c.) but not by hexamethonium (2.0 mg kg-1, s.c.). 4. The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg-1 day-1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine-pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg-1 day-1 was also significantly (P < 0.05) higher than that observed in the rats treated acutely with nicotine. 5. Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine(0.4 mg kg-1, s.c.), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg-1 day-1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion.6. The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.