RT Journal Article
SR Electronic
T1 Subunit Composition and Pharmacology of Two Classes of Striatal Presynaptic Nicotinic Acetylcholine Receptors Mediating Dopamine Release in Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1526
OP 1535
DO 10.1124/mol.65.6.1526
VO 65
IS 6
A1 Outi Salminen
A1 Karen L. Murphy
A1 J. Michael McIntosh
A1 John Drago
A1 Michael J. Marks
A1 Allan C. Collins
A1 Sharon R. Grady
YR 2004
UL http://molpharm.aspetjournals.org/content/65/6/1526.abstract
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.