Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, C101

Oral Communications

Hypothalamic mechanisms mediating inhibition of prolactin secretion following stress in early pregnant mice

V. Parker1, A. J. Douglas1

1. The University of Edinburgh, Edinburgh, United Kingdom.


In early pregnancy prolonged stress exposure is associated with suppressed progesterone secretion and consequent disturbance of the pregnancy protective cytokine balance, threatening pregnancy maintenance (1). Circulating prolactin is increased and facilitates progesterone secretion, mediates implantation and is an immune regulator. We hypothesised that stress effects in early pregnant mice would be different from in virgins and would decrease prolactin secretion due to increased tuberoinfundibular dopamine (TIDA) neurone activity (dopamine inhibits prolactin). In addition, as progesterone/prolactin suppress interleukin (IL)6 we expected that stress would elevate IL6 release due to depletion of these hormones. To test the effect of stress on the prolactin system, virgin and day (d)5.5 pregnant c57/Bl6 mice (~20g, n=6-8) were administered lipopolysaccharide (LPS; I.P. 12.5µg) or vehicle and killed 90min later. Plasma was assayed for hormones/IL6 by RIA or ELISA and TIDA activation was analysed by double immunocytochemistry (ICC) for tyrosine hydroxylase (TH, enzyme in dopamine synthesis)/Fos expression. LPS decreased plasma progesterone and prolactin (2 way ANOVA; p<0.001 interaction) and increased IL6 (p<0.01 interaction) and TIDA activation (p<0.05 interaction) in pregnant vs. virgin mice. We then tested whether the different responses were due to altered prolactin negative feedback or to stress-induced pro-inflammatory cytokines. To test if pregnancy or stress alters prolactin negative feedback to TIDA neurones, d5.5 pregnant mice (n=7; previously given LPS or vehicle) were injected with ovine prolactin (1 μg/g body weight; I.P.). Brains were processed by double ICC for pSTAT5 (mediates prolactin signal transduction in TIDA neurones) and TH. Stress alone did not alter pSTAT5/TH labelling, however, after LPS prolactin treatment increased pSTAT5 in TIDA neurones (p<0.001 interaction), suggesting that LPS increases TIDA responsiveness to prolactin. This may mean that LPS increases prolactin feedback in early pregnancy. To test the effect of cytokines on the prolactin system, d5.5 mice (n=5-7) were treated with IL6 (I.P. 200ng), TNF alpha (α; I.P. 3μg) or vehicle. TNFα decreased prolactin (1 way ANOVA; p<0.001) and progesterone secretion (p<0.01) vs. vehicle, but IL6 had no effect. However, both cytokines induced TIDA neurone activation (p<0.01). As only TNFα inhibited prolactin secretion this suggests additional TNFα action in the pituitary. In conclusion, stress-induced suppression of prolactin during early pregnancy is associated with increased activation and signalling in TIDA neurones. The increased responsiveness of TIDA neurones in pregnancy may be due to prolactin or other cytokines (e.g. IL6/TNFα).

Where applicable, experiments conform with Society ethical requirements