Oxidized glutathione regulates physiological sleep in unrestrained rats

Oxidized glutathione (GSSG) is an active component of sleep-promoting substance (SPS) which was originally extracted from the brainstems of 24-h sleep-deprived rats. We analyzed somnogenic and thermoregulatory activities of five doses of GSSG in unrestrained rats. A nocturnal 10-h intracerebroventricular infusion of GSSG significantly enhanced slow wave sleep (SWS) at the dosage range from 20 to 50 nmol and paradoxical sleep (PS) at 25 nmol at the expense of wakefulness during the 12-h dark period. The dose-response relations exhibited a bell shape for both SWS and PS. The administration of 25 nmol/10 h GSSG induced the maximal increase in the total time of nocturnal sleep (35% above the baseline for SWS and 86% for PS). The enhancement of sleep was mainly due to an increase in the duration of SWS episodes and in the number of PS episodes. GSSG at 25 nmol/10 h elicited significant fluctuations in brain temperature (Tbrain), biphasic hypothermal and hyperthermal reactions during the infusion period, followed by a hyperthermal state during the subsequent light period of the recovery day and then a hypothermal state during the dark period. On the basis of recent literature on the inhibitory action of GSSG on the excitatory synaptic membrane of rat brain, we speculate that the sleep-enhancing activity of GSSG was caused by its physiological modulation on the glutamatergic neurotransmission in the brain.