DESENSITIZATION OF THE NICOTINE-INDUCED MESOLIMBIC DOPAMINE RESPONSESDURING 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 e voked 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 nicoti ne (0.4 mg kg(-1), s.c.) in animals which had been pretreated with dai ly 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 signific antly 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 m g 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 s ignificantly attenuated by the infusion of nicotine at all 3 doses, al though the nicotine induced locomotor activity, in the rats infused wi th 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 Significant ly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge inj ection of nicotine (0.4 mg kg(-1), s.c.), were observed 2 and 7 days a fter 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 a fter termination of the infusion. 6 The results suggest that sensitize d mesolimbic dopamine responses to nicotine occur as a result of stimu lation of centrally located nicotinic receptors but that these recepto rs may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.