ReviewMultiple roles for nicotine in Parkinson's disease
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Section snippets
Overview
The basal ganglia are key in the pathogenesis of Parkinson's disease, a movement disorder characterized by a predominant loss of nigrostriatal dopaminergic neurons [1], [2], [3]. A major component of the basal ganglia is the striatum which receives projections from dopaminergic cell bodies in the substantia nigra. In addition to dopamine, the striatum contains a wide diversity of neuroactive substances including serotonin, glutamate, GABA, noradrenaline, cannabinoids, opioids, adenosine, and
Role for nicotine in neuroprotection against nigrostriatal damage
Cigarette smoking is a well-known health hazard, and one of the leading avoidable causes of mortality and morbidity. It is associated with a risk of serious chronic disorders, including cardiovascular disorders, lung disease, and cancers. Unexpectedly, however, cigarette use appears to confer beneficial effects against Parkinson's disease. Since initial epidemiological findings in the early 1960s, numerous case-report and cohort studies report a reduced incidence of Parkinson's disease in
Nicotine is neuroprotective against nigrostriatal damage but not neurorestorative
The observation that nicotine treatment improves striatal dopaminergic integrity in animals with continuing nigrostriatal degeneration raised the question whether nicotine only protects against developing damage and/or whether it can also restore integrity of damaged dopaminergic neurons. To distinguish between these alternatives, we tested whether nicotine given before and/or after nigrostriatal damage improved striatal dopaminergic function in two well-established parkinsonian animal models,
Inconsistent effects of nicotine on Parkinson's disease symptoms
The observed inverse relationship between tobacco use and Parkinson's disease incidence also raised the question whether nicotine may directly improve motor symptoms. This is not an unreasonable assumption since nicotine is well known to modulate dopamine release from striatum [19], [20], [21]. Enhanced synaptic dopamine levels could conceivably ameliorate motor deficits that arise because of a nigrostriatal dopaminergic deficiency.
In fact, a number of studies have been done to determine
Nicotine does not improve motor deficits in parkinsonian rats or monkeys
As an alternate approach to investigate whether nicotine may reduce motor deficits that arise with nigrostriatal damage, we initiated studies in parkinsonian animal models. Such work offers the advantage that parkinsonism can be evaluated by raters blinded to the treatment status of the animals.
For the rat studies, the effect of nicotine was tested on two motor tests frequently used to evaluate parkinsonism in lesioned animals (Fig. 2A). One of these was dopaminergic drug-induced rotational
Nicotine reduces l-dopa-induced dyskinetic-like movements in parkinsonian rats and monkeys
During the course of our studies to evaluate the effect of nicotine on parkinsonism in l-dopa-treated animals, we also tested whether it influenced the occurrence of the dyskinetic-like movements that accompanied l-dopa treatment. Although l-dopa remains the most effective drug for the symptomatic treatment of Parkinson's disease, chronic therapy leads to abnormal involuntary movements (AIMs) or dyskinesias. These movements, which develop in the majority of Parkinson's disease patients with
Striatal nAChR subtypes that may mediate the effects of nicotine in the nigrostriatal system
Knowledge of the mechanism(s) whereby nicotine results in its beneficial effects in Parkinson's disease is very important because this would allow for the development of selective therapies, with a minimum of adverse side effects. Nicotine generally exerts its effects in the peripheral and central nervous system by stimulating nAChRs. These are pentameric ligand-gated ion channels composed of α and β subunits or only of α subunits [20], [59], [60], [61], [62], [63]. Importantly, the nAChRs in
Acknowledgements
This work was supported by NIH grants NS42091, NS47162 and the California TRDRP 17RT-0119. We thank Dr. Sharon Grady, University of Colorado Boulder, for helpful comments on the manuscript.
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