Trends in Neurosciences
Smoking, nicotine and Parkinson's disease
Section snippets
Presence of specific nACh receptor subtypes in the nigrostriatal system
Neuronal nACh receptors are pentameric ligand-gated ion channels composed of α subunits (homomeric receptors) or of α and β subunits (heteromeric receptors) [11]. Identification of receptor composition is proving challenging, with six different α subunits (α2–α7) and three different β subunits (β2–β4) expressed in mammalian brain [11]. mRNA encoding α2–α7 and β2–β4 subunits is present in the nigrostriatal system, with a very restricted localization of α6 and β3 mRNA in the substantia nigra, the
Nigrostriatal damage reduces expression of specific nACh receptor subtypes
In PD there is a loss of nigrostriatal dopaminergic neurons. Thus, a crucial question is whether nACh receptors are affected by denervation, as this would have an impact on subsequent actions of administered nicotine. Results from animal models with selective lesion of nigrostriatal dopaminergic neurons and in PD (Figure 2 and Table 1) demonstrate significant declines in select nACh receptor populations 5, 19, 20, 21, 22, 23, 24, 25. In rodent and monkey striatum, both nicotine-binding sites
Role of nACh receptors in modulating dopamine release
One important action of nicotine is modulation of dopamine release from nigrostriatal dopaminergic terminals 26, 27, 28, 29. The finding that nACh receptors are decreased with nigrostriatal damage suggests that nicotine-evoked dopamine release might also be reduced. Indeed, studies in mice [23] show that there is a decrease in nicotine-evoked dopamine release with nigrostriatal damage that parallels the nACh receptor decline (Figure 4). Drugs that target the subtypes of nACh receptor that
How nicotine-evoked dopamine release might benefit PD
The modulatory effect of nicotine on nigrostriatal dopamine release 26, 27, 28, 29 is most likely of direct relevance to PD because there are major deficits in nigrostriatal function in this disorder. Conceivably, enhanced nicotine-evoked dopamine release could benefit PD (i) from an immediate symptomatic standpoint, by alleviating the motor symptoms, and (ii) by protecting against nigrostriatal damage in the long term.
Other mechanisms whereby nicotine could protect against PD
Extensive literature suggests that nicotine protects against different toxic insults in culture systems 5, 35, including against MPTP-induced toxicity in nigral neurons [36]. These in vitro results extend to the in vivo situation. Smoking and/or nicotine exposure protect against nigrostriatal damage in several rodent models. However, reproducibility is an issue (Box 1), with only some studies showing protection 5, 35. Identification of the biological bases for these inconsistencies is important
Does nicotine therapy benefit PD?
The finding that smoking protects against PD raises the question whether nicotine treatment is beneficial either to relieve PD symptoms or for neuroprotection. With regard to use of nicotine in symptomatic treatment, initial reports had suggested that smoking, nicotine patches or nicotine gum alleviate some movement disabilities 58, 59. More recently, several small-scale clinical trials tested the effect of short-term nicotine therapy on motor and cognitive deficits in PD. Overall, these
What about other chemicals in tobacco products?
In addition to nicotine, numerous agents in tobacco products could modulate biological functions and, thus, the development of PD. Cigarette smoking is associated with decreased (40%) brain monoamine oxidase B activity, an effect not mediated by nicotine (at least not acutely) [64]. This could contribute to a lower incidence of PD by decreasing levels of hydrogen peroxide, a by-product of dopamine metabolism, or by reducing enzymatic conversion of endogenous or exogenous compounds to toxic
Concluding remarks and future challenges
A systematic review of the existing literature shows that there is an undoubted inverse correlation between smoking and PD; that is, disease incidence is unexpectedly reduced in smokers. The challenge at present is to identify the active component(s) in smoke that contributes to this beneficial effect. This is no easy task because exposure to the agent(s) of interest could occur many years before the onset of symptoms. Some of the key issues for future research are outlined in Box 2. Although a
Acknowledgements
Research support is gratefully acknowledged from the TRDRP and NIH. Thanks to T. Bordia, A. Collins, B. Collier, D. Di Monte, A. Lai and S. McCallum for helpful comments and discussion.
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