Striatal alpha6* nicotinic acetylcholine receptors: potential targets for Parkinson's disease therapy

The presence of distinct nicotinic acetylcholine receptor (nAChR) subtypes in specific central nervous system (CNS) areas offers the possibility of developing targeted therapies for diseases involving the affected brain region. Parkinson's disease is a neurodegenerative movement disorder characterized by a progressive degeneration of the nigrostriatal system. alpha6-containing nAChRs (designated alpha6(*)1 nAChRs) have a relatively selective localization to the nigrostriatal pathway and a limited number of other CNS regions. In addition to a unique distribution, this subtype has a distinct pharmacology and specifically interacts with alpha-conotoxinMII, a toxin key in its identification and characterization. alpha6(*) nAChRs are also regulated in a novel manner, with a decrease in their number after nicotine treatment rather than the increase observed for alpha4(*) nAChRs. Striatal alpha6(*) receptors were functional and mediate dopamine release, suggesting that they have a presynaptic localization. This is further supported by lesion studies showing that both alpha6(*) nAChR sites and their functions are dramatically decreased with dopaminergic nerve terminal loss, in contrast to only small declines in alpha4(*) and no change in alpha7(*) receptors. Although the role of nigrostriatal alpha6(*) nAChRs is only beginning to be understood, an involvement in motor behavior is emerging. This latter observation coupled with the finding that nicotine protects against nigrostriatal damage suggest that alpha6(*) nAChRs may represent unique targets for neurodegenerative disorders linked to the nigrostriatal system such as Parkinson's disease.