title: Characterization of [(125) I]epibatidine binding and nicotinic agonist-mediated (86) Rb(+) efflux in interpeduncular nucleus and inferior colliculus of beta2 null mutant mice.
abstract: The beta2 nicotinic acetylcholine receptor subunit null mutation eliminated most high affinity [(3) H]epibatidine binding in mouse brain, but significant binding remained in accessory olfactory nucleus, medial habenula, inferior colliculus and interpeduncular nucleus. Residual [(125) I]epibatidine binding sites in the inferior colliculus and interpeduncular nucleus were subsequently characterized. Inhibition of [(125) I]epibatidine binding by 12 agonists and six antagonists was very similar in these regions. Most acetylcholine-stimulated (86) Rb(+) efflux is eliminated in thalamus and superior colliculus of beta2 null mutants, but significant activity remained in inferior colliculus and interpeduncular nucleus. This residual activity was subsequently characterized. The 12 nicotinic agonists tested elicited concentration-dependent (86) Rb(+) efflux. Epibatidine was the most potent agonist. Cytisine was also potent and efficacious. EC(50) values for quaternary agonists were relatively high. Cytisine-stimulated (86) Rb(+) efflux was inhibited by six classical nicotinic antagonists. Mecamylamine and D-tubocurarine were most potent, while decamethonium was the least potent. Agonists and antagonists exhibited similar potency in both brain regions. Alpha-bungarotoxin (100 nm) did not significantly inhibit cytisine-stimulated (86) Rb(+) efflux, while the alpha3beta4 selective antagonist, alphaConotoxinAuIB, inhibited a significant fraction of the response in both brain regions. Thus, beta2 null mutant mice express residual nicotinic activity with properties resembling those of alpha3beta4*-nAChR.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Paul
authors.initials: P
authors.lastname: Whiteaker
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Allan C
authors.initials: AC
authors.lastname: Collins
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007245:Inferior Colliculi / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics*; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics; D012414:Rubidium Radioisotopes / Q000493:pharmacokinetics*; D014316:Tritium; D000093843:Quinolizidine Alkaloids
chemical_list: D000109:Acetylcholine; D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007457:Iodine Radioisotopes; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D014316:Tritium; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine