title: Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons.
abstract: S 24795 evoked methyllycaconitine-sensitive inward currents in voltage-clamped hippocampal interneurons with maximum amplitude about 14% that of ACh-evoked responses. Experiments with rat alpha7 receptors expressed in Xenopus oocytes confirmed that S 24795 is a partial agonist of alpha7 nAChR with an EC(50) of 34+/-11 microM and I(max) of approximately 10% relative to ACh. When 60 microM ACh was co-applied to alpha7-expressing oocytes along with increasing concentrations of S 24795, there was a progressive decrease in response compared to the responses to 60 microM ACh alone (IC(50) 45+/-9 microM). The positive allosteric modulator 5-hydroxyindole potentiated ACh- and S 24795-evoked responses of alpha7 receptors in both oocytes and hippocampal interneurons. In hippocampal slice experiments, depending on the ACh concentrations in the application pipette and the ratio of ACh to S 24795, co-application of S 24795 with ACh variously increased, decreased, or had no effect on responses, compared to ACh alone. In order to estimate the effective dilution factor for the pressure application experiments, we tested alpha7 receptors in oocytes with ACh alone and in co-application with S 24795 at the same ratios as in the slice experiments, but at varying dilution factors. The pattern of interaction seen in the slice experiments was most closely matched under the conditions of a 3:100 dilution, suggesting that the pipette solution was diluted approximately 30-fold at the site of action. This dilution factor was consistent with the potency of ACh and S 24795 in the oocyte expression system (EC(50)s approximately 30 microM).
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Lopez-Hernandez
authors.forename: Andon N
authors.initials: AN
authors.lastname: Placzek
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Thinschmidt
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.forename: Caryn
authors.initials: C
authors.lastname: Trocme-Thibierge
authors.forename: Philippe
authors.initials: P
authors.lastname: Morain
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D018679:Cholinergic Agonists / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007395:Interneurons / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D018679:Cholinergic Agonists; D018680:Cholinergic Antagonists; C579165:Chrna7 protein, rat; D007211:Indoles; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C524163:S 24795; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; C026785:5-hydroxyindole; D000109:Acetylcholine; D000157:Aconitine