The GABAA Agonist THIP Increases Non-REM Sleep and Enhances Non-REM Sleep-Specific Delta Activity in the Rat During the Dark Period

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Abstract
Peripheral administration of the selective γ-aminobutyric acid (GABAA) receptor agonists muscimol and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) to rats has recently been found to increase nonrapid eye movement sleep (non-REMS) duration and to enhance delta activity (0.5–4.0 Hz) within non-REMS during the light period, i.e. the circadian rest phase. In this vehicle-controlled study, we investigated the sleep response to two doses of THIP (2 and 4 mg/kg) administered intraperitoneally to eight rats at the beginning of the dark period. Electroencephalogram and electromyogram recordings were made continuously during the first 6-hours postinjection. The 4-mg/kg THIP dose significantly increased the time in non-REMS, lengthened the non-REMS episodes, and elevated delta activity within non-REMS. Quantitatively similar, but smaller effects were induced by 2 mg/kg THIP. Neither dose of THIP affected the time in REMS. These effects are very similar to those evoked by THIP and muscimol during the light period. This indicates that GABAA agonists dose-dependently promote non-REMS, by increasing non-REMS maintenance, and increase the intensity of non-REMS, and that these effects are independent of the light-dark and circadian cycle.

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