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Pharmacology of -Conotoxin MII-Sensitive Subtypes of Nicotinic Acetylcholine Receptors Isolated by Breeding of Null Mutant Mice

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado (O.S., J.A.D., E.L., M.C., A.C.C., M.J.M., S.R.G.); and Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

Subtypes of nicotinic acetylcholine receptors (nAChR) containing 6 subunits comprise 25 to 30% of the presynaptic nAChRs expressed in striatal dopaminergic terminals in rodents and 70% in monkeys. This class of receptors, potentially important in nicotine addiction, binds -conotoxin MII (-CtxMII) with high affinity and is heterogeneous, consisting of several subtypes in mice, possibly an important consideration for the design of compounds that selectively activate or antagonize the 6 subclass of nAChRs. Selected-null mutant mice were bred to generate isolated subtypes of 62* nAChRs expressed in vivo for assessing pharmacology of 62* nAChRs. Binding to striatal membranes and function in synaptosomes from (4–/–)(3+/+) and (4–/–)(3–/–) mice were measured and compared with wild-type (4+/+)(3+/+) mice. Gene deletions (4 and 3) decreased binding of ¹²⁵I--CtxMII without affecting affinity for -CtxMII or inhibition of -CtxMII binding by epibatidine or nicotine. Deletion of the 4 subunit substantially increased EC₅₀ values for both nicotine- and cytisine-stimulated -CtxMII-sensitive dopamine release from striatal synaptosomes. A further increase in EC₅₀ values was seen upon the additional deletion of the 3 subunit. The data indicate that one -CtxMII-sensitive nAChR subtype, prevalent on wild-type dopaminergic terminals, has the lowest EC₅₀ for a nicotine-mediated function so far measured in mice. In conclusion, the gene deletion strategy enabled isolation of 6* subtypes, and these nAChR subtypes exhibited differential activation by nicotine and cytisine.

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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