PT  - JOURNAL ARTICLE
AU  - Outi Salminen
AU  - Karen L. Murphy
AU  - J. Michael McIntosh
AU  - John Drago
AU  - Michael J. Marks
AU  - Allan C. Collins
AU  - Sharon R. Grady
TI  - Subunit Composition and Pharmacology of Two Classes of Striatal Presynaptic Nicotinic Acetylcholine Receptors Mediating Dopamine Release in Mice
AID  - 10.1124/mol.65.6.1526
DP  - 2004 Jun 01
TA  - Molecular Pharmacology
PG  - 1526--1535
VI  - 65
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/65/6/1526.short
4100  - http://molpharm.aspetjournals.org/content/65/6/1526.full
SO  - Mol Pharmacol2004 Jun 01; 65
AB  - 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 α-conotoxin MII (α-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 α-CtxMII occurs within minutes; recovery is slow. The IC50 is 1 to 3 nM. α-CtxMII-sensitive and -resistant components have significant differences in pharmacology. The five agonists tested were more potent at activating the α-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 α-CtxMII-sensitive sites. Methyllycaconitine was 9-fold more potent at inhibiting the α-CtxMII-sensitive sites, whereas dihydro-β-erythroidine was a 7-fold more potent inhibitor of the α-CtxMII-resistant response. Both the transient and persistent phases of nicotine-stimulated dopamine release were partially inhibited by α-CtxMII with equal potency. The subunit composition of functional nAChRs, was assessed in mice with null mutations for individual nAChR subunits. The β2 subunit is an absolute requirement for both classes. In contrast, deletion of β4 or α7 subunits had no effect. The α-CtxMII-sensitive response requires β3 and is partially dependent upon α4 subunits, probably α6β3β2 and α4α6β3β2, whereas the α-CtxMII-resistant release requires α4 and is partially dependent upon α5 subunits, probably α4β2 and α4α5β2.