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Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Nashmi, Raad and Xiao, Cheng and Deshpande, Purnima and McKinney, Sheri and Grady, Sharon R. and Whiteaker, Paul and Huang, Qi and McClure-Begley, Tristan and Lindstrom, Jon M. and Labarca, Cesar and Collins, Allan C. and Marks, Michael J. and Lester, Henry A. (2007) Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path. Journal of Neuroscience, 27 (31). pp. 8202-8218. ISSN 0270-6474. PMCID PMC6673074. doi:10.1523/jneurosci.2199-07.2007. https://resolver.caltech.edu/CaltechAUTHORS:20190905-080227761

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Abstract

Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to nicotine itself, and to endogenous acetylcholine, are altered by continued exposure to the drug. To address this problem, we developed mice whose α4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased α4 fluorescence in several regions; among these, midbrain and hippocampus were assessed functionally. Although the midbrain dopaminergic system dominates reward pathways, chronic nicotine does not change α4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional α4* receptors localize to the GABAergic neurons of the VTA and substantia nigra pars reticulata. In consequence, GABAergic neurons from chronically nicotine-treated mice have a higher basal firing rate and respond more strongly to nicotine; because of the resulting increased inhibition, dopaminergic neurons have lower basal firing and decreased response to nicotine. In hippocampus, chronic exposure to nicotine also increases α4* fluorescence on glutamatergic axons of the medial perforant path. In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli enhances induction of long-term potentiation in the medial perforant path, showing that the upregulated α4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional α4* receptors therefore provides a possible explanation for two effects of chronic nicotine: sensitization of synaptic transmission in forebrain and tolerance of dopaminergic neuron firing in midbrain.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/jneurosci.2199-07.2007DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673074PubMed CentralArticle
ORCID:
AuthorORCID
Xiao, Cheng0000-0001-9649-7450
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2007 Society for Neuroscience. Received Dec. 14, 2006; revised June 12, 2007; accepted June 14, 2007. This work was supported by National Institutes of Health Grants DA-3194, DA-15663, DA-19655 (at Boulder); DA-09121, DA-17279, NS-11756 (at Caltech); DA-19375 (at both Boulder and Caltech); and NS-11323 (at the University of Pennsylvania); by the California Tobacco-Related Disease Research Project (Grant 12RT-0245); by Philip Morris USA/International at Caltech; by the Elizabeth Ross Foundation and National Alliance for Research on Schizophrenia and Depression (postdoctoral fellowships to R.N.); and by the W. M. Keck and Plum Foundations. We thank J. Drago for α4 knock-out mice. We thank V. Vargas, J. Wang, J. Silva, and S. Pease for excellent mouse husbandry; D. A. Dougherty, E. M. Schuman, J. L. Jankowsky, and J. Schwartz for comments on this manuscript; and B. N. Cohen, R. M. Drenan, C. Fonck, J. Miwa, R. Pantoja, and A. Tapper for discussions.
Funders:
Funding AgencyGrant Number
NIHDA-3194
NIHDA-15663
NIHDA-19655
NIHDA-09121
NIHDA-17279
NIHNS-11756
NIHDA-19375
NIHNS-11323
California Tobacco-Related Disease Research Project12RT-0245
Philip Morris USAUNSPECIFIED
Elizabeth Ross FoundationUNSPECIFIED
National Alliance for Research on Schizophrenia and DepressionUNSPECIFIED
W. M. Keck FoundationUNSPECIFIED
Plum FoundationUNSPECIFIED
Subject Keywords:nicotine addiction; GFP; knock-in mouse; nicotinic receptor; GABAergic; dopaminergic
Issue or Number:31
PubMed Central ID:PMC6673074
DOI:10.1523/jneurosci.2199-07.2007
Record Number:CaltechAUTHORS:20190905-080227761
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190905-080227761
Official Citation:Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path. Raad Nashmi, Cheng Xiao, Purnima Deshpande, Sheri McKinney, Sharon R. Grady, Paul Whiteaker, Qi Huang, Tristan McClure-Begley, Jon M. Lindstrom, Cesar Labarca, Allan C. Collins, Michael J. Marks, Henry A. Lester. Journal of Neuroscience 1 August 2007, 27 (31) 8202-8218; DOI: 10.1523/JNEUROSCI.2199-07.2007
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:98422
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:05 Sep 2019 19:40
Last Modified:16 Nov 2021 17:39

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