Partial agonist and neuromodulatory activity of S 24795 for alpha7 nAChR responses of hippocampal interneurons

24795 evoked methyllycaconitine-sensitive inward currents in voltage-clamped hippocampal interneurons with maximum amplitude about 14% that of ACh-evoked responses. Experiments with rat alpha 7 receptors expressed in Xenopus oocytes confirmed that S 24795 is a partial agonist of alpha 7 nAChR with an EC50 of 34 +/- 11 mu M and I-max of approximately 10% relative to ACh. When 60 mu M ACh was co-applied to alpha 7-expressing oocytes along with increasing concentrations of S 24795, there was a progressive decrease in response compared to the responses to 60 mu M ACh alone (IC50 45 9 pM). The positive allosteric modulator 5-hydroxyindole potentiated ACh- and S 24795-evoked responses of OC7 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 a7 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 (EC50S approximate to 30 mu M). (c) 2007 Elsevier Ltd. All rights reserved.