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In vivo activation of midbrain dopamine neurons via sensitized, high-affinity α6*nicotinic acetylcholine receptors

Drenan, Ryan M. and Grady, Sharon R. and Whiteaker, Paul and McClure-Begley, Tristan and McKinney, Sheri and Miwa, Julie M. and Bupp, Sujata and Heintz, Nathaniel and McIntosh, J. Michael and Bencherif, Merouane and Marks, Michael J. and Lester, Henry A. (2008) In vivo activation of midbrain dopamine neurons via sensitized, high-affinity α6*nicotinic acetylcholine receptors. Neuron, 60 (1). pp. 123-136. ISSN 0896-6273. PMCID PMC2632732. doi:10.1016/j.neuron.2008.09.009.

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α6-containing (α6*) nicotinic ACh receptors (nAChRs) are selectively expressed in dopamine (DA) neurons and participate in cholinergic transmission. We generated and studied mice with gain-of-function α6* nAChRs, which isolate and amplify cholinergic control of DA transmission. In contrast to gene knockouts or pharmacological blockers, which show necessity, we show that activating α6* nAChRs and DA neurons is sufficient to cause locomotor hyperactivity. α6(L9'S) mice are hyperactive in their home cage and fail to habituate to a novel environment. Selective activation of α6* nAChRs with low doses of nicotine, by stimulating DA but not GABA neurons, exaggerates these phenotypes and produces a hyperdopaminergic state in vivo. Experiments with additional nicotinic drugs show that altering agonist efficacy at α6* provides fine tuning of DA release and locomotor responses. α6*-specific agonists or antagonists may, by targeting endogenous cholinergic mechanisms in midbrain or striatum, provide a method for manipulating DA transmission in neural disorders.

Item Type:Article
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URLURL TypeDescription CentralArticle
Drenan, Ryan M.0000-0002-8141-8577
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2008 Elsevier B.V. Accepted 4 September 2008. Published: October 8, 2008. Available online 8 October 2008. We thank members of the Lester lab for helpful discussions. Special thanks to B. Drenan. Thanks to C. Wageman, E. Myers, C. Xiao, A. Tapper, R. Nashmi, C. Fonck, J. Schwarz, J. Jankowsky, M. Liu, P. Deshpande, S. Benazouz, and C. Zhou. This work was supported by H.H.M.I. (N.H., J.M. Miwa, S.B.) and grants from NIH (DA09121, DA17279, and NS11756 to H.A.L.; DA19375 to H.A.L. and M.J.M.; DA03194 to M.J.M.; DA12242 to M.J.M. and P.W.; MH53631 and GM48677 to J.M. McIntosh), the Moore Foundation, the Croll Research Foundation (to J.M. Miwa) and the California Tobacco Related Disease Research Program (TRDRP; 12RT-0245 to H.A.L.). R.M.D. was supported by postdoctoral fellowships from TRDRP (15FT-0030) and NIH (DA021492 and NS007251).
Funding AgencyGrant Number
Gordon and Betty Moore FoundationUNSPECIFIED
Croll Research FoundationUNSPECIFIED
California Tobacco-Related Disease Research Program12RT-0245
California Tobacco-Related Disease Research Program15FT-0030
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:1
PubMed Central ID:PMC2632732
Record Number:CaltechAUTHORS:DREn08
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Official Citation:Ryan M. Drenan, Sharon R. Grady, Paul Whiteaker, Tristan McClure-Begley, Sheri McKinney, Julie M. Miwa, Sujata Bupp, Nathaniel Heintz, J. Michael McIntosh, Merouane Bencherif, Michael J. Marks, Henry A. Lester, In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6∗ Nicotinic Acetylcholine Receptors, Neuron, Volume 60, Issue 1, 9 October 2008, Pages 123-136, ISSN 0896-6273, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13498
Deposited By: Tony Diaz
Deposited On:07 Aug 2009 22:07
Last Modified:08 Nov 2021 22:38

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