In a postmortem study of nicotinic receptors in human brain, cigarette smoking was found to be associated with increased (-)-[3H]nicotine binding to membranes prepared from gyrus rectus (Brodmann area 11) (p less than 0.001), hippocampal neocortex (Brodmann area 27), cerebellar cortex (p less than 0.01), hippocampal formation (Ammon's horn + subiculum), and the median raphe nuclei of the midbrain (p less than 0.05) but not the medulla oblongata. Analysis of the binding data suggested that the increased binding reflected an increase in the density of the receptors rather than a change in their affinity for (-)-nicotine. The effects of smoking were not influenced significantly by either the sex or age of the subject. It is concluded that smoking evokes an increase in high-affinity nicotine binding similar to that observed previously in animals treated chronically with nicotine and that the effect of smoking on these sites is probably caused by the nicotine present in the tobacco smoke.

1 The effects of acute and subchronic nicotine and (+)-amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely-moving rats by use of in vivo microdialysis. 2 In rats which had been habituated to the test apparatus for approximately 80min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4mgkg-') caused a dose-dependent increase (P<0.01) in spontaneous activity and evoked significant increases (P<0.05) in the extracellular levels of DOPAC and HVA. 3 Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg-') resulted in increased basal levels of dopamine (P <0.01) and decreased basal levels of DOPAC (P <0.05) in the NAc dialysates. 4 Pretreatment with nicotine (0.1 or 0.4 mg kg-' daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P <0.05). 5 If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg-') resulted in significant increases (P < 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P<0.05) the dopamine response to a challenge dose of nicotine.6 Subcutaneous injections of (+)-amphetamine (0.2 or 0.5 mg kg-') evoked dose-dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug. 7 The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.

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1 The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg-day-') on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4mgkg-' day-' 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 (0.4mgkg-', 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 (2.0mgkg-', s.c.) but not by hexamethonium (2.0mgkg-', s.c.). 4 The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg' day' 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' day-' 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-', s.c.), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg-' day-' 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.