Striatal α6*Nicotinic Acetylcholine Receptors: Potential Targets for Parkinson's Disease Therapy

Abstract

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. α6-containing nAChRs (designated α6^*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 α-conotoxinMII, a toxin key in its identification and characterization. α6^* nAChRs are also regulated in a novel manner, with a decrease in their number after nicotine treatment rather than the increase observed for α4^* nAChRs. Striatal α6^* receptors were functional and mediate dopamine release, suggesting that they have a presynaptic localization. This is further supported by lesion studies showing that both α6^* nAChR sites and their functions are dramatically decreased with dopaminergic nerve terminal loss, in contrast to only small declines in α4^* and no change in α7^* receptors. Although the role of nigrostriatal α6^* 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 α6^* nAChRs may represent unique targets for neurodegenerative disorders linked to the nigrostriatal system such as Parkinson's disease.