Endotoxin increases sleep and brain allopregnanolone concentrations in newborn lambs

Infection has been identified as a risk factor for sudden infant death syndrome (SIDS). Synthesis of allopregnanolone, a neuroactive steroid with potent sedative properties, is increased in response to stress. In this study, we investigated the effect of endotoxin (lipopolysaccharide, LPS) on brain and plasma allopregnanolone concentrations and behavior in newborn lambs. LPS was given intravenously (0.7 micro g/kg) at 12 and 15 d of age (n = 7), and resulted in a biphasic febrile response (p < 0.001), hypoglycemia, lactic acidemia (p < 0.05), a reduction in the incidence of wakefulness, and increased nonrapid eye movement sleep and drowsiness (p < 0.05) compared with saline-treated lambs (n = 5). Plasma allopregnanolone and cortisol were significantly (p < 0.05) increased after LPS treatment. These responses to LPS lasted 6-8 h, and were similar at 12 and 15 d of age. Each lamb was then given LPS at 20 d of age and killed 3 h posttreatment to obtain samples of the brain. Allopregnanolone concentrations were increased (p < 0.05) in all brain areas except the cerebellum and diencephalon. We suggest that LPS-induced increase of allopregnanolone in the brain may contribute to somnolence in the newborn, and may be responsible for the reduced arousal thought to contribute to the risk of SIDS in human infants.