Pharmaco-EEG analysis of ligands varying in selectivity for α1 subunit-containing GABAA receptors during the active phase in rats.

Abstract

Benzodiazepines are known to evoke changes in cortical electrophysiological activity that can be correlated with action at distinct γ-aminobutyric acid type A (GABAA) receptorsubtypes. We used electroencephalography (EEG) paired with electromyography (EMG) to evaluate the role of α1 subunit-containing GABAA receptors (α1GABAARs) in benzodiazepine-induced sedation and changes in EEG band frequencies during the active phase of the light/dark cycle. Male Sprague-Dawley rats (N = 4/drug) were surgically instrumented with EEG/EMG electrodes. The rats were injected i.p. with zolpidem, an α1GABAAR-preferring compound, or L-838,417, which has selective efficacy for α2/3/5 subunit-containing GABAARs (i.e., α1GABAAR-sparing compound), in comparison with the non-selective benzodiazepine, triazolam. All ligands evaluated induced changes in sleep-wake states during the active phase consistent with an increase in slow-wave sleep (SWS). The degree of SWS increase appeared to be related to the magnitude of delta power band changes induced by the ligands, with the strongest effects engendered by the α1GABAAR-preferring drug zolpidem and the weakest effects by the α1GABAAR-sparing compound, L-838,417. Consistent with other research, a selective increase in beta band power was observed with L-838,417, which may be associated with α2GABAAR-mediated anxiolysis. Overall, these findings support the establishment of pharmaco-EEG "signatures" for identifying subtype-selective GABAA modulators in vivo.