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Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior

Cohen, B. N. and Mackey, E. D. W. and Grady, S. R. and Mckinney, S. and Patzlaff, N. E. and Wageman, C. R. and Mcintosh, J. M. and Marks, M. J. and Lester, H. A. and Drenan, R. M. (2012) Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior. Neuroscience, 200 . pp. 31-41. ISSN 0306-4522. PMCID PMC3249511. doi:10.1016/j.neuroscience.2011.10.047.

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Firing rates of dopamine (DA) neurons in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) control DA release in target structures such as striatum and prefrontal cortex. DA neuron firing in the soma and release probability at axon terminals are tightly regulated by cholinergic transmission and nicotinic acetylcholine receptors (nAChRs). To understand the role of α6* nAChRs in DA transmission, we studied several strains of mice expressing differing levels of mutant, hypersensitive (leucine 9′ to serine [L9′S]) α6 subunits. α6 L9′S mice harboring six or more copies of the hypersensitive α6 gene exhibited spontaneous home-cage hyperactivity and novelty-induced locomotor activity, whereas mice with an equal number of WT and L9′S α6 genes had locomotor activity resembling that of control mice. α6-dependent, nicotine-stimulated locomotor activation was also more robust in high-copy α6 L9′S mice versus low-copy mice. In wheel-running experiments, results were also bi-modal; high-copy α6 L9′S animals exhibited blunted total wheel rotations during each day of a 9-day experiment, but low-copy α6 L9′S mice ran normally on the wheel. Reduced wheel running in hyperactive strains of α6 L9′S mice was attributable to a reduction in both overall running time and velocity. ACh and nicotine-stimulated DA release from striatal synaptosomes in α6 L9′S mice was well-correlated with behavioral phenotypes, supporting the hypothesis that augmented DA release mediates the altered behavior of α6 L9′S mice. This study highlights the precise control that the nicotinic cholinergic system exerts on DA transmission and provides further insights into the mechanisms and consequences of enhanced DA release.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Lester, H. A.0000-0002-5470-5255
Drenan, R. M.0000-0002-8141-8577
Additional Information:© 2011 IBRO. Published by Elsevier Ltd. Accepted 24 October 2011. Available online 04 November 2011. We thank members of the Lester laboratory for helpful discussion. This work was supported by National Institutes of Health (NIH) grants (DA17279, DA12242, DA015663, DA03194, MH53631, GM48677, and DA030396). R.M.D. was supported by a fellowship from the California Tobacco Related Disease Research Program (15FT-0030), an NIH National Research Service Award (DA021492), and an NIH Pathway to Independence Award (DA030396).
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program15FT-0030
NIH Predoctoral FellowshipDA021492
Subject Keywords:dopamine; cholinergic; nicotinic; acetylcholine; transgenic; mouse
PubMed Central ID:PMC3249511
Record Number:CaltechAUTHORS:20120214-082915834
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Official Citation:B.N. Cohen, E.D.W. Mackey, S.R. Grady, S. Mckinney, N.E. Patzlaff, C.R. Wageman, J.M. Mcintosh, M.J. Marks, H.A. Lester, R.M. Drenan, Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior, Neuroscience, Volume 200, 3 January 2012, Pages 31-41, ISSN 0306-4522, 10.1016/j.neuroscience.2011.10.047.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:29268
Deposited By: Tony Diaz
Deposited On:29 Feb 2012 20:01
Last Modified:09 Nov 2021 17:05

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