Journal
MOLECULAR PHARMACOLOGY
Volume 71, Issue 6, Pages 1563-1571Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.106.031492
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Funding
- NIDA NIH HHS [R01 DA012242, DA12242, DA015663, DA03194] Funding Source: Medline
- NIMH NIH HHS [R01 MH053631-12, R01 MH053631-11S1, MH53631, R01 MH053631] Funding Source: Medline
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Subtypes of nicotinic acetylcholine receptors (nAChR) containing alpha 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 alpha-conotoxin MII (alpha-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 alpha 6 subclass of nAChRs. Selected-null mutant mice were bred to generate isolated subtypes of alpha 6 beta 2* nAChRs expressed in vivo for assessing pharmacology of alpha 6 beta 2* nAChRs. Binding to striatal membranes and function in synaptosomes from (alpha 4-/-)(beta 3 +/+) and (alpha 4-/-)(beta 3-/-) mice were measured and compared with wild-type (alpha 4-/-)(beta 3 +/+) mice. Gene deletions (alpha 4 and beta 3) decreased binding of 125I-alpha-CtxMII without affecting affinity for alpha-CtxMII or inhibition of alpha-CtxMII binding by epibatidine or nicotine. Deletion of the alpha 4 subunit substantially increased EC50 values for both nicotine-and cytisine-stimulated alpha-CtxMII-sensitive dopamine release from striatal synaptosomes. A further increase in EC50 values was seen upon the additional deletion of the beta 3 subunit. The data indicate that one alpha-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 alpha 6* subtypes, and these nAChR subtypes exhibited differential activation by nicotine and cytisine.
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