CaltechAUTHORS
Published October 9, 2008 | Version Accepted Version + Supplemental Material
Journal Article Open

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

Creators

Abstract

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.

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).

Attached Files

Accepted Version - nihms75830.pdf

Supplemental Material - DREn08_supp.pdf

Files

DREn08_supp.pdf

Files (6.6 MB)

Name Size Download all
md5:97d0768b2f25738cd41dd2c641665d1f
1.2 MB Preview Download
md5:5cf9f8a786eb97cd006fde124eb582d2
5.4 MB Preview Download

Additional details

Identifiers

PMCID
PMC2632732
Eprint ID
13498
Resolver ID
CaltechAUTHORS:DREn08

Funding

NIH
DA09121
NIH
DA17279
NIH
NS11756
NIH
DA19375
NIH
DA03194
NIH
DA12242
NIH
MH53631
NIH
GM48677
NIH
DA021492
NIH
NS007251
Gordon and Betty Moore Foundation
Croll Research Foundation
California Tobacco-Related Disease Research Program
12RT-0245
California Tobacco-Related Disease Research Program
15FT-0030
Howard Hughes Medical Institute (HHMI)

Dates

Created
2009-08-07
Created from EPrint's datestamp field
Updated
2021-11-08
Created from EPrint's last_modified field