Future PD Therapy: Potential Role for Nicotine

New research suggests that nicotine or nicotine agonists may play an important role in the future of Parkinson's disease therapy.

Dopaminergic neurons of the striatum also bear so-called nicotinic acetylcholine receptors (nAchRs). Each nAchR is composed of five subunits, drawn from multiple possible types of alpha and beta subunits. Recent work by Drenan et al. demonstrate that one such subunit, alpha-6, appears to play a special role in the striatum.

--They showed in mice that specific stimulation of the alpha-6 subunit prompted dopamine release from striatal dopamine neurons, indicating the importance of nAchRs containing alpha-6 as modulators of dopaminergic signaling.

--Results of stimulation suggested that alpha-6 containing nAchRs do not occur on striatal GABA neurons, even though nAchRs of other subunit concentration do. This finding suggests that alpha-6-specific stimulation may be able to avoid off-target effects of less specific nicotinic receptor agonists.

--Repeated stimulation did not induce tolerance or sensitization, suggesting drugs targeting alpha-6 might have less potential for abuse, and "might avoid well known use-dependent side effects [of direct dopamine stimulation] such as dyskinesias," the authors say.

In vivo activation of midbrain dopamine neurons via sensitive, high-affinity alpha-6* nicotinic acetylcholine receptors. RM Drenan, SR Grady, P Whiteaker, et al.Neuron, 2008;60:123-136

The potential of nicotinic stimulation for PD therapy was also recently highlighted in a review by Quik et al. They outline the case for nicotine stimulation as follows:

--Nicotinic receptors are found presynaptically on nigrostriatal dopaminergic neurons, as well as on GABAergic and cholinergic neurons in the striatum, and nicotinic stimulation affects motor function in animals with nigrostriatal damage.

--alpha-6-containing dopaminergic neurons are more susceptible to damage in PD than neurons with other subtypes predominating. These receptors, therefore, "may represent promising pharmacologic targets for Parkinson's disease for neuroprotection and/or symptomatic improvement.

--Epidemiologic studies consistently show that smokers have a lower risk of developing PD. The effect is dose-dependent and wanes after smoking cessation, "consistent with a true biologic protective effect of tobacco use."

--Nicotine stimulation is neuroprotective in animal models of PD and cell culture systems.

--Nicotinic stimulation improves motor symptoms in animal models. Variable outcomes have been reported in humans from case studies and small trials.

--Nicotine reduces dyskinesias in animal models.

"These combined data indicate that nicotine or nicotinic agonists may be useful for Parkinson's disease therapy," potentially including neuroprotection, symptomatic improvement, and alleviation or prevention of dyskinesias, the authors conclude.

Nicotine and Parkinson's disease: Implications for therapy. M Quik, K O'Leary, CM Tanner. Movement Disorders 2008;23:1641-1652