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The Journal of Neuroscience, August 1, 2007, 27(31):8202-8218; doi:10.1523/JNEUROSCI.2199-07.2007

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Behavioral/Systems/Cognitive
Chronic Nicotine Cell Specifically Upregulates Functional 4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path

Raad Nashmi,¹ Cheng Xiao,¹ Purnima Deshpande,¹ Sheri McKinney,¹ Sharon R. Grady,² Paul Whiteaker,² Qi Huang,¹ Tristan McClure-Begley,² Jon M. Lindstrom,³ Cesar Labarca,¹ Allan C. Collins,² Michael J. Marks,² and Henry A. Lester¹

¹Division of Biology, California Institute of Technology, Pasadena, California 91125, ²Institute of Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, and ³Department of Neuroscience, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Henry A. Lester, 156-29 Caltech, Pasadena, CA 91125. Email: lester{at}caltech.edu

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 4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased 4 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 4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional 4* 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 4* 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 4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional 4* 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.

Key words: nicotine addiction; GFP; knock-in mouse; nicotinic receptor; GABAergic; dopaminergic

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Received Dec. 14, 2006; revised June 12, 2007; accepted June 14, 2007.

Correspondence should be addressed to Henry A. Lester, 156-29 Caltech, Pasadena, CA 91125. Email: lester{at}caltech.edu

This article has been cited by other articles:

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