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The Journal of Neuroscience, October 7, 2009, 29(40):12428-12439; doi:10.1523/JNEUROSCI.2939-09.2009

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Neurobiology of Disease
Chronic Nicotine Selectively Enhances {alpha}4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway

Cheng Xiao,1 Raad Nashmi,2 Sheri McKinney,1 Haijiang Cai,1 J. Michael McIntosh,3,4 and Henry A. Lester1

1Division of Biology, California Institute of Technology, Pasadena, California 91125, 2Department of Biology, University of Victoria, Victoria, British Columbia V8W3N5, Canada, and 3Departments of Psychiatry and 4Biology, University of Utah, Salt Lake City, Utah 84112

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

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional {alpha}4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and {alpha}4 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 {alpha}4* nAChRs were not found on the neuronal somata; however, nicotine acts via {alpha}4β2* 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 {alpha}4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of {alpha}4β2* 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.

Received June 20, 2009; revised Aug. 22, 2009; accepted Aug. 29, 2009.

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






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