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Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Drenan, Ryan M. and Grady, Sharon R. and Steele, Andrew D. and McKinney, Sheri and Patzlaff, Natalie E. and McIntosh, J. Michael and Marks, Michael J. and Miwa, Julie M. and Lester, Henry A. (2010) Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors. Journal of Neuroscience, 30 (29). pp. 9877-9889. ISSN 0270-6474. PMCID PMC3390922. https://resolver.caltech.edu/CaltechAUTHORS:20100811-085614377

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Abstract

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.2056-10.2010 DOIArticle
http://www.jneurosci.org/cgi/content/abstract/30/29/9877PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390922/PubMed CentralArticle
ORCID:
AuthorORCID
Drenan, Ryan M.0000-0002-8141-8577
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2010 the authors. Received April 14, 2010; revised June 14, 2010; accepted June 16, 2010. This work was supported by grants from the National Institutes of Health (NIH) (DA17279 and AG033954 to H.A.L.; DA19375 to H.A.L. and M.J.M.; DA12242, DA015663, and DA03194 to M.J.M.; 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.). A.D.S. is funded by the Broad Fellow Program in Brain Circuitry at Caltech and an Ellison Medical Foundation New Scholar in Aging award. R.M.D. was supported by postdoctoral fellowships from TRDRP (15FT-0030) and NIH (DA021492 and NS007251). We thank members of the Lester laboratory for helpful discussion. Thanks to P. Deshpande, M. Liu, C. Xiao, E. Mackey, G. Akopian, S. Benazouz, L. Sandoval, C. Baddick, and C. Wageman. We thank Oliver King and Cynthia Hsu for writing Matlab programs for home cage behavior data analysis.
Funders:
Funding AgencyGrant Number
NIHDA17279
NIHAG033954
NIHDA19375
NIHDA12242
NIHDA015663
NIHDA03194
NIHMH53631
NIHGM48677
Moore FoundationUNSPECIFIED
Croll Research FoundationUNSPECIFIED
California Tobacco Related Disease Research Program (TRDRP)12RT-0245
California Tobacco Related Disease Research Program (TRDRP)15FT-0030
CaltechUNSPECIFIED
Ellison Medical FoundationUNSPECIFIED
NIHDA021492
NIHNS007251
Issue or Number:29
PubMed Central ID:PMC3390922
Record Number:CaltechAUTHORS:20100811-085614377
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100811-085614377
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:19388
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:13 Aug 2010 17:59
Last Modified:09 Mar 2020 13:18

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