α6β2*and α4β2*Nicotinic Receptors Both Regulate Dopamine Signaling with Increased Nigrostriatal Damage: Relevance to Parkinson's Disease

Nicotinic receptors (nAChRs) are important modulators of dopaminergic transmission in striatum, a region critical to Parkinson's disease. The nAChRs mainly involved are the alpha 6 beta 2* and alpha 4 beta 2* subtypes. Lesion studies show that the alpha 6 beta 2* receptor is decreased to a much greater extent with nigrostriatal damage than the alpha 4 beta 2* subtype raising the question whether this latter nAChR population is more important with increased nigrostriatal damage. To address this, we investigated the effect of varying nigrostriatal damage on alpha 6 beta 2* and alpha 4 beta 2* receptor-modulated dopamine signaling using cyclic voltammetry. This approach offers the advantage that changes in dopamine release can be observed under different neuronal firing conditions. Total single-pulse-evoked dopamine release decreased in direct proportion to declines in the dopamine transporter and dopamine uptake. We next used alpha-conotoxinMII and mecamylamine to understand the role of the alpha 4 beta 2* and alpha 6 beta 2* subtypes in release. Single-pulse-stimulated alpha 6 beta 2* and alpha 4 beta 2* receptor dopamine release decreased to a similar extent with increasing nigrostriatal damage, indicating that both subtypes contribute to the control of dopaminergic transmission with lesioning. Total burst-stimulated dopamine release also decreased proportionately with nigrostriatal damage. However, the role of the alpha 4 beta 2* and alpha 6 beta 2* nAChRs varied with different degrees of lesioning, suggesting that the two subtypes play a unique function with burst firing, with a somewhat more prominent and possibly more selective role for the alpha 6 beta 2* subtype. These data have important therapeutic implications because they suggest that drugs directed to both alpha 4 beta 2* and alpha 6 beta 2* nAChRs may be useful in the treatment of neurological disorders such as Parkinson's disease.