Levodopa is one of the most effective therapies for Parkinson’s disease. However, its use is associated with the development of abnormal involuntary movements or dyskinesias that may be as debilitating as the disease itself. Although there is consensus that antidyskinetic therapy would greatly benefit Parkinson's disease patients, treatment is currently restricted to amantadine, which is only modestly effective. The central hypothesis underlying this proposal is that drugs targeting CNS nicotinic acetylcholine receptors (nAChRs) may be of therapeutic value for the treatment of levodopa-induced dyskinesias in Parkinson's disease.
The idea that nicotinic drugs may be useful for the treatment of dyskinesias is based on our studies, which show that nicotine reduces levodopa-induced abnormal involuntary movements in a non-human primate parkinsonian model and in hemi-parkinsonian rats. This well-validated pre-clinical model is predictive of changes in PD, and is thus a very useful and economical model for initial studies to evaluate the antidyskinetic potential of nicotinic drugs. Nicotine most likely exerts its effects by interacting with nAChRs. However, nicotine activates all nAChRs in the peripheral and central nervous system. Interestingly, the nAChRs in the brain are distinct from those in the peripheral nervous system. We therefore propose to test the effect of nAChR agonists that preferentially stimulate brain nAChRs and not those in the peripheral nervous system. The results will allow for the development of selective nicotinic drugs against levodopa-induced dyskinesias with optimal therapeutic efficacy and a minimum of adverse effects.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The proposed studies represent a new research direction for the treatment of levodopa-induced dyskinesias using nicotine or nicotinic receptor agonists. This research may lead to novel therapeutic strategies to reduce dyskinesias that develop with levodopa treatment in Parkinson's disease patients.
We anticipate that these studies will increase our basic understanding of the role of the nigrostriatal nicotinic cholinergic system in the development of levodopa-induced dyskinesias. It will also help determine whether nicotine and/or nicotinic agonists are of benefit in the treatment of dyskinesias that occur with levodopa treatment for Parkinson’s disease.
Dr. Quik found that the targeted nAChR agonist varenicline resulted in significant declines in levodopa-induced AIMs at a relatively low dose of the agonist, with no worsening of parkinsonism. These data suggest that this compound may be useful for the treatment of levodopa-induced abnormal involuntary movements in Parkinson's disease. Further studies in non-human primates are important to evaluate this possibility. Dr. Quik is currently doing further work to identify the optimal agonists for reducing dyskinesias.