Nicotine and nicotinic receptors; relevance to Parkinson's disease

The development of nicotinic agonists for therapy in neurodegenerative disorders such as Parkinson's disease is an area currently receiving considerable attention. The rationale for such work stems from findings that reveal a loss of nicotinic receptors in Parkinson's disease brains. These results, coupled with reports that nicotine treatment relieves some of the symptoms of this disorder, provides support for the contention that nicotine and/or nicotinic agonists may be beneficial for acute symptomatic treatment. Moreover, the observation that there is a decreased incidence of Parkinson's disease with tobacco use, possibly due to the nicotine in tobacco products, may imply that such drugs are useful for long-term neuroprotection. However, there are multiple nicotinic receptor populations in the brain with different functional properties. Identification of the subtypes involved in nigrostriatal dopaminergic activity is therefore critical for the rational use of selective therapeutic agents for symptomatic treatment and/or neuroprotection. Accumulating evidence, both in rodents and nonhuman primates now indicate that alpha6* nicotinic receptors are present on nigrostriatal dopaminergic neurons, and furthermore, that receptors containing this subunit may be most vulnerable to nigrostriatal damage, at least in nonhuman primates. These data suggest that nicotinic receptor ligands directed to alpha6* nicotinic receptors might be particularly relevant for Parkinson's disease therapeutics.