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Received for publication October 5, 2006.
Revised January 31, 2007.
Accepted for publication March 6, 2007.
-CONOTOXIN MII-SENSITIVE SUBTYPES OF NICOTINIC ACETYLCHOLINE RECEPTORS ISOLATED BY BREEDING OF NULL MUTANT MICE
Subtypes of nicotinic acetylcholine receptors (nAChR) containing 
6 subunits comprise 25-30% 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 6
2*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 to wildtype (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 wildtype 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.
Key words:
Dopamine, Nicotinic cholinergic
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