The results depict changes in nAChR subtypes in human putamen with ~50% (mod - moderate) and ~90% (sev - severe) declines in the striatal dopamine transporter measured using ¹²⁵I-RTI-121, as shown in A. ¹²⁵I-α-CtxMII binding studies in the absence and presence of the α-CtxMII analog E11A distinguished between at least two E11A sensitive α6β2* nAChR populations, the α6α4β2* (B) and the α6(nonα4)β2* (C) nAChR subtype [72]. With 50% declines in the dopamine transporter, there is almost complete loss of the α6α4β2* subtype, with no significant reduction in the α6(nonα4)β2* nAChR subtype. By contrast, there are major deficits in α6(nonα4)β2* receptors with a ~90% decline in the dopamine transporter. α4β2* nAChRs, determined using ¹²⁵I-epibatidine binding in the presence of 100 nM α-CtxMII (D), are much less affected than the α6β2* nAChR subtypes with a small nonsignificant decline with 50% decrease and an ~40% loss with a near complete loss in dopamine transporter. Thus, the α6α4β2* subtype appears to be the most vulnerable to nigrostriatal damage, the α6(nonα4)β2* receptor is next affected, and the α4β2* nAChR is the most resistant to nigrostriatal damage. Each value is the mean ± SEM of 4-6 control (Con) or 4-6 Parkinson’s disease cases (Mod or Sev). Significance of difference from control using one-way ANOVA followed by a Bonferroni post hoc test; ***p < 0.001, **p < 0.01; from a moderate lesion, ^##p < 0.01, ^#p < 0.05. Reproduced in modified form with permission from reference [72, 105].

In the top panels (A, B), nicotine (50 μg/ml) was administered to unlesioned rats in saccharin-containing drinking water, as previously described [41]. Two weeks later, the rats received intracranial injections of 6-OHDA or vehicle into the right medial forebrain bundle. To assess the effect of nicotine treatment on motor deficits that arise with nigrostriatal damage, amphetamine-induced ipsiversive rotation was assessed 2-3 weeks after lesioning, with the nicotine [41]. The rats were placed in the chamber for 30 min for acclimatization, after which amphetamine (4.0 mg/kg ip) was administered. Circling behavior was assessed between 85 to 120 min after amphetamine administration when effects of nicotine on circling had returned to control levels. The rats were then killed and dopamine transporter levels measured using autoradiography. This treatment regimen resulted in an improvement in aberrant motor behavior and in striatal dopamine transporter levels. In the nicotine post-treatment only study (C, D), rats were first lesioned with 6-OHDA, as described above. Two to 3 weeks later, nicotine (50 μg/ml) treatment was initiated and maintained throughout. Ipsiversive rotation was evaluated after 3-4 weeks on nicotine. The rats were then killed and dopamine transporter levels evaluated. By contrast, there was no improvement in aberrant turning behavior or striatal dopamine transporter levels when nicotine was administered after nigrostriatal damage was complete. Results are the mean ± SEM of 6-9 rats per group. With nicotine pre-treatment (A), there was a significant (p < 0.001) main effect of 6-OHDA lesioning on rotations assessed using three-way ANOVA and a significant (p < 0.05) interaction between nicotine treatment and 6-OHDA lesioning. By contrast, nicotine post-treatment (C) yielded a significant main effect of 6-OHDA lesioning (p < 0.001) but no interaction, by three-way ANOVA, suggesting no neuroprotection. Significance of difference from unlesioned group (B,D) using two-way ANOVA followed by a Bonferroni post hoc test; ***p < 0.001, from lesioned ^#p < 0.05. Reproduced in modified form with permission from reference [41].

In A, rats were lesioned by injection of 6-OHDA into the right medial forebrain bundle. When the lesion was complete, they were given nicotine in the drinking water for several weeks. Forelimb use (cylinder test) was then evaluated before and 1 h after administration of 8 mg/kg L-dopa methyl ester plus 15 mg/kg benserazide. There were no significant differences in motor performance with nicotine treatment as compared to vehicle either OFF or ON L-dopa. Each value represents the mean ± SEM of 6-8 rats. In B, parkinsonism was assessed in MPTP-treated monkeys immediately prior 5 mg/kg L-dopa plus carbidopa dose, as well as ~2 hours after L-dopa treatment when a maximal antiparkinsonian effect is observed. L-dopa treatment alone resulted in significant declines in parkinsonism, as expected. However, nicotine resulted in no appreciable effect on motor behavior either ON or OFF L-dopa. Each value is the mean ± SEM of 5 monkeys. Significance of difference from the same group with no L-dopa treatment using two-way ANOVA followed by a Bonferroni post hoc test; **p < 0.01, *p < 0.05. Reproduced in modified form with permission from reference [28, 29].

In A, unilateral 6-OHDA-lesioned rats were given saccharin containing drinking water without or with nicotine (25 μg/ml) for several weeks as described [28]. They were then given 8 mg/kg L-dopa methyl ester plus 15 mg/kg benserazide, and the AIMs scores evaluated over a 3-hour period. Nicotine treatment significantly reduced AIMs compared to the vehicle-treated group (p < 0.05 using repeated measures ANOVA). Each symbol is the mean ± SEM of 9-10 rats. In B, MPTP-lesioned monkeys were given either nicotine or vehicle in drinking water, as described [29]. They were then gavaged with L-dopa 5 mg/kg plus carbidopa and dyskinesias rated over a 3-hour interval. Each symbol is the mean ± SEM of 3 to 4 monkeys. Dyskinesias were significantly reduced in nicotine-treated animals compared to monkeys not receiving nicotine (p < 0.05 using repeated measures ANOVA). Reproduced in modified form with permission from reference [28, 29].

Traces of evoked dopamine release in slices of rat dorsal striatum (A) in the absence (Total) and presence of the α3/α6β2* antagonist α-CtxMII (100 nM), or the general nAChR blocker mecamylamine (mec, 100 μM). Quantitative analyses (B) of peak striatal dopamine release show that ~75% nAChR-modulated dopamine release occurs through α6β2* nAChRs and ~25% by α4β2* nAChRs in the rat [68]. The values represent the mean ± SEM of 4-6 rats. Traces of evoked dopamine release in slices of monkey dorsal putamen (C) in the absence (Total) and presence of α-CtxMII (100 nM), or mecamylamine (100 μM). Quantitative analyses of peak dopamine release show that almost all of the nAChR-modulated dopamine release in monkey dorsal striatum is modulated by α3/α6β2* nAChRs. Insets are typical voltammograms for dopamine with an oxidation peak at 500-600 mV and a reduction peak around -200 mV. The values represent the mean ± SEM of 3-7 monkeys. Significance of difference from control using one-way ANOVA followed by a Bonferroni post hoc test, after a 1 pulse stimulus, ***p < 0.001; from α-CtxMII, ^#p < 0.05. Reproduced in modified form with permission from reference [68].