The effects of acute nicotine (0.5 mg/kg, s.c.) on dopamine (DA) metabolism and Fos protein expression in striatal and limbic areas of rats on the seventh day of chronic nicotine infusion (4 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) and after 24 or 72 hr withdrawal were investigated. In saline-infused rats, acute nicotine elevated striatal and limbic 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly. During the nicotine infusion, no such increases were seen in the striatum, but limbic HVA was somewhat elevated. After 24 hr withdrawal when no nicotine was found in the plasma, acute nicotine elevated striatal DOPAC and HVA and limbic HVA. However, the limbic DOPAC was unaffected. Acute nicotine increased Fos immunostaining (IS) in the caudate-putamen (CPU), the core of nucleus accumbens (NAcc), the cingulate cortex (Cg), and the central nucleus of amygdala (ACe) significantly. During nicotine infusion the nicotine-induced responses were attenuated in CPU and NAcc, whereas in ACe and Cg Fos immunostaining was increased as in saline-infused rats. After 24 hr withdrawal, acute nicotine did not increase Fos immunostaining in CPU, NAcc, and Cg, but increased it clearly in ACe. After 72 hr withdrawal, nicotine's effects were restored. Our findings suggest that the nicotinic receptors in the striatal areas are desensitized more easily than those in the limbic areas. Furthermore, the effects of nicotine on various DA metabolites differ. We also found evidence for long-lasting inactivation of nicotinic receptors in vivo regulating limbic dopamine metabolism and Fos expression in striatal and limbic areas. These findings might be important for the protective effects of nicotine in Parkinson's disease and in its dependence-producing properties. Key words: nicotine; constant infusion; striatal dopamine metabolism; limbic dopamine metabolism; Fos protein; desensitization; toleranceAcute nicotine enhances striatal and limbic dopamine (DA) turnover and metabolism (Nose and Takemoto, 1974;Haikala et al., 1986;Grenhoff and Svensson, 1988). Nicotine increases 3 H-DA release in vitro from striatal slices and synaptosomes (Westfall, 1974;Rapier et al., 1988;Grady et al., 1992) and from the nucleus accumbens (NAcc) (Rowell et al., 1987). Nicotine also elevates extracellular DA in the striatum (Imperato et al., 1986) and in the NAcc (Imperato et al., 1986;Benwell and Balfour, 1992). There is evidence that nicotine activates the limbic DA system more easily than the striatal one (Imperato et al., 1986;Grenhoff and Svensson, 1988;Benwell and Balfour, 1997). We recently found that in mice tolerance develops to the nicotine-induced increase of striatal dopamine metabolism at 24 hr after withdrawal from 7 week oral nicotine administration (Pietilä et al., 1996). The effect of chronic nicotine treatment seems to depend on the method of administration. During prolonged constant nicotine infusion the acute nicotine-evoked increase of extracellular DA in the NAcc and dorsal striatum was inhibited, and the elevation of acc...

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1 The eect of ambient temperature on the nicotine-induced (0.3, 0.5 or 0.8 mg kg 71 s.c.) changes of the striatal concentrations of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was studied in freely-moving rats by in vivo microdialysis. 2 At the ambient temperature of 30 ± 338C, but not at 20 ± 238C, nicotine doses of 0.5 (P50.01) and 0.8 mg kg 71 (P50.05) signi®cantly increased the extracellular DA concentration. The nicotine doses of 0.5 and 0.8 mg kg 71 increased the DA metabolite levels similarly at both ambient temperatures studied (P40.0001), but the dose of 0.3 mg kg 71 only at 30 ± 338C (DOPAC: P50.05; HVA: P50.01).3 At 30 ± 338C, dihydro-b-erythroidine (DHbE 2.8 mg kg 71 i.p.) blocked the nicotine-induced (0.5 or 0.8 mg kg 71 ) increases of extracellular DA concentration but only tended to antagonize the increases of DA metabolites. Mecamylamine (5.0 mg kg 71 i.p.) blocked the increase of DA output induced by 0.5 mg kg 71 but not that induced by 0.8 mg kg 71 of nicotine and fully prevented the nicotine-induced elevations of DOPAC and HVA. 4 Elevation of ambient temperature did not aect the cerebral concentration of nicotine or the nicotine-induced elevation of serum corticosteroids. Also, the rectal temperatures of rats given nicotine at either ambient temperature did not signi®cantly change. 5 Our results show that the nicotine-induced output of striatal DA is enhanced at high ambient temperature. Further, our ®ndings suggest that the nicotinic cholinoceptors mediating the eects of nicotine on striatal DA release are dierent from those mediating nicotine's eects on DA metabolism.