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Molecular Pharmacology

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Research ArticleArticle

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

Xiomara A. Perez, Tanuja Bordia, J. Michael McIntosh and Maryka Quik
Molecular Pharmacology November 2010, 78 (5) 971-980; DOI: https://doi.org/10.1124/mol.110.067561
Xiomara A. Perez
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Tanuja Bordia
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J. Michael McIntosh
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Maryka Quik
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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.

  • 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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Molecular Pharmacology: 78 (5)
Molecular Pharmacology
Vol. 78, Issue 5
1 Nov 2010
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Research ArticleArticle

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

Xiomara A. Perez, Tanuja Bordia, J. Michael McIntosh and Maryka Quik
Molecular Pharmacology November 1, 2010, 78 (5) 971-980; DOI: https://doi.org/10.1124/mol.110.067561

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Research ArticleArticle

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

Xiomara A. Perez, Tanuja Bordia, J. Michael McIntosh and Maryka Quik
Molecular Pharmacology November 1, 2010, 78 (5) 971-980; DOI: https://doi.org/10.1124/mol.110.067561
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