Possible GABAergic modulation in the protective effect of allopregnanolone on sleep deprivation-induced anxiety-like behavior and oxidative damage in mice

Abstract

Sleep is considered critical for maintaining physical and mental health. Sleep deprivation is a type of stress that affects the human population globally. Stress increases plasma levels of neurosteroids in the brain, which have potent effects on the GABAergic system. In the present study, we investigated the possible involvement of GABAergic modulation in the protective effect of allopregnanolone on sleep deprivation-induced anxiety-like behavior and oxidative damage in mice. Pretreatment with allopregnanolone (10 and 20 mg/kg i.p.) significantly improved locomotor activity, weight loss and anxiety-like behavior. Biochemically, allopregnanolone treatment significantly restored reduced glutathione and catalase activity and attenuated elevated lipid peroxidation and nitrite levels when compared with untreated 72-h sleep-deprived animals (P < 0.05). A combination of flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with allopregnanolone (10 mg/kg) antagonized the protective effect of allopregnanolone and caused further impairment in locomotor activity, anxiety-like behavior, weight loss and oxidative damage. However, muscimol (0.05 mg/kg) in combination with allopregnanolone (10 mg/kg) potentiated its behavioral and antioxidant effects. These effects were significant when compared with the effects of either agent alone (P < 0.05). The present study indicates that allopregnanolone induces its protective effect by GABAergic modulation at various recognition sites on the GABA-benzodiazepine receptor complex. It also suggests that allopregnanolone could be used in the management of sleep deprivation-induced anxiety-like behavior and related oxidative damage.