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Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway

Xiao, Cheng and Nashmi, Raad and McKinney, Sheri and Cai, Haijiang and McIntosh, J. Michael and Lester, Henry A. (2009) Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway. Journal of Neuroscience, 29 (40). pp. 12428-12439. ISSN 0270-6474. PMCID PMC2787412. doi:10.1523/JNEUROSCI.2939-09.2009. https://resolver.caltech.edu/CaltechAUTHORS:20091102-100009481

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Abstract

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional α4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and α4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-β-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3–1000 µM ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional α4* nAChRs were not found on the neuronal somata; however, nicotine acts via α4β2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these α4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of α4β2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.2939-09.2009 DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787412//PubMed CentralArticle
ORCID:
AuthorORCID
Xiao, Cheng0000-0001-9649-7450
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2009 Society for Neuroscience. Received June 20, 2009; revised Aug. 22, 2009; accepted Aug. 29, 2009. This work was supported by grants from the U.S. National Institutes of Health (DA17279, AG033954, MH53631), from Targacept Inc., and from Louis and Janet Fletcher. We also acknowledge support from the Natural Sciences and Engineering Research Council Canada (R.N.), the NARSAD Young Investigator Program (R.N.), and the California Tobacco-Related Disease Research Program (16FT-0066 to C.X.). We thank J. Drago for 4 knock-out mice, P. Deshpande and C. D. Son for much assistance, and R. Srinivasan and B. N. Cohen for comments.
Funders:
Funding AgencyGrant Number
NIHDA17279
NIHAG033954
NIHMH53631
Natural Sciences and Engineering Research Council of Canada (NSERC)UNSPECIFIED
National Alliance for Research on Schizophrenia & DepressionUNSPECIFIED
California Tobacco-Related Disease Research Program16FT-0066
Issue or Number:40
PubMed Central ID:PMC2787412
DOI:10.1523/JNEUROSCI.2939-09.2009
Record Number:CaltechAUTHORS:20091102-100009481
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20091102-100009481
Official Citation:Cheng Xiao, Raad Nashmi, Sheri McKinney, Haijiang Cai, J. Michael McIntosh, and Henry A. Lester Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway J. Neurosci. 29: 12428-12439; doi:10.1523/JNEUROSCI.2939-09.2009
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16535
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:03 Nov 2009 22:39
Last Modified:08 Nov 2021 23:27

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