Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS42091, NS59910]; the National Institutes of Health National Institute of Mental Health [Grant MH53631]; the National Institutes of Health National Institute of General Medical Sciences [Grant GM48677]; and the California Tobacco-Related Disease Research Program [Grant 17RT-0119].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.067561.
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ABBREVIATIONS:
- nAChR
- nicotinic acetylcholine receptor
- RTI-121
- 3β-(4-iodophenyl)tropane-2β-carboxylic acid
- 6-OHDA
- 6-hydroxydopamine
- α-CtxMII
- α-conotoxinMII
- *
- possible presence of other nicotinic subunits in the receptor complex.
- Received July 19, 2010.
- Accepted August 23, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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