Neuroactive steroids attenuate oxytocin stress responses in late pregnancy

In late pregnant rats neuroendocrine stress responses, expressed as increased oxytocin secretion and activation of the hypothalamo–pituitary–adrenal axis, are attenuated. These adaptations preserve the oxytocin store for parturition and prevent pre-term birth, and protect the fetuses from adverse programming by exposure to excess glucocorticoid. Mechanisms of adaptations for oxytocin neurones are reviewed, using challenge with systemic interleukin-1β, simulating activation of immune signaling by infection, as a stressor of special relevance in pregnancy. In virgin rats, systemic interleukin-1β stimulates the firing of oxytocin neurones, and hence oxytocin secretion, but interleukin-1β has no effects in late pregnant rats. This lack of response is reversed by naloxone treatment just before interleukin-1β administration, indicating endogenous opioid suppression of oxytocin responses in late pregnancy. This opioid presynaptically inhibits noradrenergic terminals impinging on oxytocin neurones. Finasteride pretreatment, inhibiting progesterone conversion to allopregnanolone, a positive GABAA receptor allosteric modifier, also restores an oxytocin response to interleukin-1β. This finasteride effect is reversed by allopregnanolone treatment. In virgin rats allopregnanolone attenuates the oxytocin response to interleukin-1β, which is exaggerated by naloxone. The effects of naloxone and finasteride in late pregnant rats in restoring an oxytocin response to interleukin-1β are not additive. Accordingly, allopregnanolone may both enhance GABA inhibition of oxytocin neurone responses to interleukin-1β, and induce opioid suppression of noradrenaline release onto oxytocin neurones.