RT Journal Article
SR Electronic
T1 α6β2* and α4β2* nicotinic receptors both regulate dopamine signaling with increased nigrostriatal damage; relevance to Parkinson's disease
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.067561
DO 10.1124/mol.110.067561
A1 Xiomara Perez
A1 Tanuja Bordia
A1 J. Michael McIntosh
A1 Maryka Quik
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/08/23/mol.110.067561.abstract
AB Nicotinic receptors (nAChRs) are important modulators of dopaminergic transmission in striatum, a region critical to Parkinson's disease. The nAChRs mainly involved are the α6β2* and α4β2* subtypes. Lesion studies show that the α6β2* receptor is decreased to a much greater extent with nigrostriatal damage than the α4β2* 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 α6β2* and α4β2* 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 α-conotoxinMII and mecamylamine to understand the role of the α4β2* and α6β2* subtypes in release. Single-pulse-stimulated α6β2* and α4β2* 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 α4β2* and α6β2* 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 α6β2* subtype. These data have important therapeutic implications as they suggest that drugs directed to both α4β2* and α6β2* nAChRs may be useful in the treatment of neurological disorders such as Parkinson's disease.