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-1beta, simulating activation of immune signaling by infection, as a stressor of special relevance in pregnancy. In virgin rats, systemic interleukin-1beta stimulates the firing of oxytocin neurones, and hence oxytocin secretion, but interleukin-1beta has no effects in late pregnant rats. This lack of response is reversed by naloxone treatment just before interleukin-1beta 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 GABA(A) receptor allosteric modifier, also restores an oxytocin response to interleukin-1beta. This finasteride effect is reversed by allopregnanolone treatment. In virgin rats allopregnanolone attenuates the oxytocin response to interleukin-1beta, which is exaggerated by naloxone. The effects of naloxone and finasteride in late pregnant rats in restoring an oxytocin response to interleukin-1beta are not additive. Accordingly, allopregnanolone may both enhance GABA inhibition of oxytocin neurone responses to interleukin-1beta, and induce opioid suppression of noradrenaline release onto oxytocin neurones.
Russell
J A
JA
Laboratory of Neuroendocrinology, Centre for Integrative Physiology, School of Biomedical Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, UK. j.a.russell@ed.ac.uk
Brunton
P J
PJ
D000818:Animals; D005260:Female; D023421:Models, Animal; D010121:Oxytocin / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology; D013256:Steroids / Q000627:therapeutic use*; D013312:Stress, Physiological / Q000503:physiopathology* / Q000517:prevention & control
D011963:Receptors, GABA-A; D013256:Steroids; D010121:Oxytocin