Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice.

Published

Journal Article

Pharmacological evaluation of nicotine-stimulated dopamine release from striatum has yielded data consistent with activation of a single population of nicotinic acetylcholine receptors (nAChR). However, discovery that alpha-conotoxin MII (alpha-CtxMII) partially inhibits the response indicates that two classes of presynaptic nAChRs mediate dopamine release. We have investigated the pharmacology and subunit composition of these two classes of nAChR. Inhibition of nicotine-stimulated dopamine release from mouse striatal synaptosomes by alpha-CtxMII occurs within minutes; recovery is slow. The IC50 is 1 to 3 nM. alpha-CtxMII-sensitive and -resistant components have significant differences in pharmacology. The five agonists tested were more potent at activating the alpha-CtxMII-sensitive nAChRs; indeed, this receptor is the highest affinity functional nAChR found, so far, in mouse brain. In addition, cytisine was more efficacious at the alpha-CtxMII-sensitive sites. Methyllycaconitine was 9-fold more potent at inhibiting the alpha-CtxMII-sensitive sites, whereas dihydro-beta-erythroidine was a 7-fold more potent inhibitor of the alpha-CtxMII-resistant response. Both the transient and persistent phases of nicotine-stimulated dopamine release were partially inhibited by alpha-CtxMII with equal potency. The subunit composition of functional nAChRs, was assessed in mice with null mutations for individual nAChR subunits. The beta2 subunit is an absolute requirement for both classes. In contrast, deletion of beta4 or alpha7 subunits had no effect. The alpha-CtxMII-sensitive response requires beta3 and is partially dependent upon alpha4 subunits, probably alpha6beta3beta2 and alpha4alpha6beta3beta2, whereas the alpha-CtxMII-resistant release requires alpha4 and is partially dependent upon alpha5 subunits, probably alpha4beta2 and alpha4alpha5beta2.

Full Text

Duke Authors

Cited Authors

  • Salminen, O; Murphy, KL; McIntosh, JM; Drago, J; Marks, MJ; Collins, AC; Grady, SR

Published Date

  • June 2004

Published In

Volume / Issue

  • 65 / 6

Start / End Page

  • 1526 - 1535

PubMed ID

  • 15155845

Pubmed Central ID

  • 15155845

Electronic International Standard Serial Number (EISSN)

  • 1521-0111

International Standard Serial Number (ISSN)

  • 0026-895X

Digital Object Identifier (DOI)

  • 10.1124/mol.65.6.1526

Language

  • eng