PT  - JOURNAL ARTICLE
AU  - Perez, Xiomara A.
AU  - Bordia, Tanuja
AU  - McIntosh, J. Michael
AU  - Quik, Maryka
TI  - α6β2* and α4β2* Nicotinic Receptors Both Regulate Dopamine Signaling with Increased Nigrostriatal Damage: Relevance to Parkinson's Disease
AID  - 10.1124/mol.110.067561
DP  - 2010 Nov 01
TA  - Molecular Pharmacology
PG  - 971--980
VI  - 78
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/78/5/971.short
4100  - http://molpharm.aspetjournals.org/content/78/5/971.full
SO  - Mol Pharmacol2010 Nov 01; 78
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 because 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.