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Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (O.S., K.L.M., M.J.M., A.C.C., S.R.G.); Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.); and Howard Florey Institute, University of Melbourne, Parkville, Melbourne, Australia (J.D.)
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 
-conotoxin MII (-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 -CtxMII occurs within minutes; recovery is slow. The IC50 is 1 to 3 nM. -CtxMII-sensitive and -resistant components have significant differences in pharmacology. The five agonists tested were more potent at activating the -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 -CtxMII-sensitive sites. Methyllycaconitine was 9-fold more potent at inhibiting the -CtxMII-sensitive sites, whereas dihydro-
-erythroidine was a 7-fold more potent inhibitor of the -CtxMII-resistant response. Both the transient and persistent phases of nicotine-stimulated dopamine release were partially inhibited by -CtxMII with equal potency. The subunit composition of functional nAChRs, was assessed in mice with null mutations for individual nAChR subunits. The 2 subunit is an absolute requirement for both classes. In contrast, deletion of 4 or 7 subunits had no effect. The -CtxMII-sensitive response requires 3 and is partially dependent upon 4 subunits, probably 632 and 4632, whereas the -CtxMII-resistant release requires 4 and is partially dependent upon 5 subunits, probably 42 and 452.
Address correspondence to: Sharon R. Grady, Institute for Behavioral Genetics, University of Colorado, 447UCB, Boulder, CO 80309. E-mail: sharon.grady{at}colorado.edu
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