EEG-β/γ spectral power elevation in rat: a translatable biomarker elicited by GABAAα2/3-positive allosteric modulators at nonsedating anxiolytic doses

Benzodiazepine drugs, through interaction with GABAAα1, GABAAα2,3, and GABAAα5 subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABAAα2,3-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABAAα2,3-mediated vs. GABAAα1 or GABAAα5 currents in voltage clamped oocytes transfected with those GABAA subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [3H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the β- and and γ-bands. Finally, the dose range that increas...