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.