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Abstract: Parkinson''s disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson''s disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson''s disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson''s disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson''s disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson''s disease is therefore critical for the development of targeted therapies. Results show that striatal α6β2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, α4β2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to α6β2-containing nAChRs may represent a particularly relevant target for Parkinson''s disease therapeutics. [Copyright &y& Elsevier]

Epidemiological studies indicate that smoking is a negative, and exposure to pesticides, a positive risk factor for Parkinson's disease (PD). The purpose of this study was to assess the interplay between these two factors in a rodent model of nigrostriatal damage. To approach this, mice were administered nicotine, the agent in smoke implicated in neuroprotection. They were then treated for 3 weeks with the pesticide, paraquat, while nicotine was continued. Paraquat treatment decreased (25%) nigral dopaminergic neurons, consistent with previous results. Chronic nicotine administration significantly protected against nigral cell damage, with only a 16% decline in mice treated with both nicotine and paraquat. Paraquat treatment also decreased (14%) the striatal dopamine transporter, an effect that was partially prevented by nicotine. These changes in the striatal dopamine transporter paralleled those in a select striatal α6β2* nicotinic receptor (nAChR) subtype. In contrast, striatal α4β2* nAChRs were not decreased with paraquat treatment, suggesting they are on a differential subset of dopaminergic terminals. The results show that nicotine treatment partially protects against paraquat-induced declines in nigrostriatal dopaminergic neurons to which a select population of α6β2* nAChRs are localized. Moreover, these data support epidemiological findings that environmental influences can elicit opposing effects on nigrostriatal dopaminergic integrity. [ABSTRACT FROM AUTHOR]

Evidence suggests that nicotinic receptors play a role in nigrostriatal function, a finding that may be relevant to Parkinson''s disease. Knowledge of the conditions that regulate nicotinic receptor expression is therefore important. Previous studies showed that several different nicotinic receptors, including α-conotoxinMII (α-CtxMII)-sensitive receptors, are decreased after nigrostriatal damage. Nigrostriatal dopaminergic terminals also demonstrate a capacity for recovery after lesioning. The present experiments were therefore done to determine whether there were changes in striatal nicotinic receptors with recovery. To address this, we used two well-characterized animal models of nigrostriatal damage produced using the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Studies in mice showed that striatal 125I-α-CtxMII, as well as 125I-epibatidine and 125I-A85380 binding sites significantly recovered 1 month after lesioning, suggesting that α6* and most likely α4* receptors are increased. Experiments were next done in monkeys since striatal 125I-α-CtxMII receptors constitute a large percentage of nicotinic receptors and are more vulnerable to nigrostriatal damage in this model that closely mirrors Parkinson''s disease. In monkeys allowed to recover from the toxic effects of MPTP for a 1–2 year period, there was a significant improvement in the Parkinson disability score. There was also a reversal in lesion-induced declines in striatal α-CtxMII-sensitive receptors, but no significant change in 125I-epibatidine and 125I-A85380 receptors. These findings suggest that α3*/α6* sites are selectively increased in monkey striatum with recovery. The present data show that recovery of 125I-α-CtxMII receptors occurs in parallel with the dopamine transporter, indicating that these nicotinic receptors sites are localized to presynaptic dopamine terminals in both species. [Copyright &y& Elsevier]

Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve L-dopa-induced dyskinesias, a debilitating side effect of L-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in L-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with β2 and α6 nAChR knockout mice has shown that α6β2* nAChRs were necessary for the development/maintenance of L-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian α4 nAChR knockout mice indicate that α4β2* nAChRs also play an essential role since nicotine did not reduce L-dopa-induced AIMs in such mice. Combined analyses of the data from α4 and α6 knockout mice suggest that the α6α4β2β3 subtype may be critical. In contrast to the studies with α4 and α6 knockout mice, nicotine treatment did reduce L-dopa-induced AIMs in parkinsonian α7 nAChR knockout mice. However, α7 nAChR subunit deletion alone increased baseline AIMs, suggesting that α7 receptors exert an inhibitory influence on L-dopa-induced AIMs. In conclusion, α6β2*, α4β2* and α7 nAChRs all modulate L-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing L-dopa-induced dyskinesias in Parkinson's disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)