Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of ?5 subunit-containing ?-aminobutyric acid type A receptors: implications for treating cognitive deficits

BackgroundMultiple cognitive and psychiatric disorders are associated with an increased tonic inhibitory conductance that is generated by ?5 subunit-containing ?-aminobutyric acid type A (?5 GABAA) receptors. Negative allosteric modulators inhibit GABAA receptors (?5-NAMs) being developed as treatments for these disorders. The effects of ?5-NAMs have been studied on recombinant expressed in non-neuronal cells; however, no study has compared drug the native neurones, which was goal this study.MethodsThe five (basmisanil, Ono-160, L-655,708, ?5IA, MRK-016) current evoked a low concentration GABA were using whole-cell recordings cultured mouse hippocampal neurones. Drug saturating miniature postsynaptic currents (mIPSCs) also examined.ResultsThe caused concentration-dependent decrease current. potencies varied 50% inhibition (IC50) basmisanil (127 nM) significantly higher than those other compounds (0.4–0.8 nM). In contrast, maximal efficacies drugs similar (35.5–51.3% inhibition). did not modify or mIPSCs.ConclusionsBasmisanil markedly less potent ?5-NAMs, unexpected result based studies Studying receptor-selective neurones could inform selection future clinical trials.