It is well known that there is a general reduction in the stress response throughout pregnancy and lactation. However, in several mammals, including rats, the response to the neuroimmune stressor, lipopolysaccharide (LPS) is particularly attenuated at near term. This is manifested as a marked reduction in the febrile response in the day or so around parturition, but which recovers in the post partum period. We have carried out a series of physiological and neurochemical investigations to attempt to identify the mechanisms underlying the reduced neuroimmune response. As a number of pro-inflammatory cytokine are know to mediate LPS fever, we measured circulating cytokines using ELISAs to test the hypothesis that there was an alteration in peripheral cytokines at term. However, levels of pro-inflammatory cytokines (IL-1β, IL-6, IFNγ, and TNFα) in the plasma taken 2h after LPS were similar at gestational day (G) 15, G22 or lactation day (L) 5. In addition to pro-inflammatory cytokines, LPS also causes synthesis and release of a variety of anti-inflammatory molecules, but neither IL-1ra and IL-10, nor the immunosuppressive hormone, corticosterone, were different at the 3 stages of reproduction. Peripheral pyrogens, including cytokines are known to cause fever by initiating the synthesis of prostaglandin E (PGE) that acts on neurons in the anterior hypothalamus /preoptic area to activate thermogenesis and reduce heat loss. To test the hypothesis that PGE synthesis or action was altered at term, we used semi-quantitative Western blots to measure levels of inducible COX-2, the rate limiting enzyme for the synthesis of PGE that is found in endothelial cells of the brain vasculature. We found that COX-2 levels are reduced at G22 compared to G15 or at L5. Pro-inflammatory cytokines activate COX-2 through a number of signaling pathways, so we explored if these were similarly altered. However, the reduced COX-2 expression was not associated with alterations in activation of transcriptional factors NFκB, STAT 3 and STAT5 or of ERK1/2. While lipocalin-prostaglandin D2 synthase, an enzyme that could potentially produce anti-inflammatory cytokines, was generally reduced at late gestation, its further reduction at L5 dissociated the activity of this enzyme from the reduced neuroimmune response at term. Thus we concluded that the reduced fevers at term were most likely associated with a reduction in PGE synthesis in the brain, but the mechanisms responsible for the reduced COX-2 induction remain elusive. There also appear to be changes within the brain itself that will affect febrile responses. For example, febrile responses to intraventricular application of PGE are reduced specifically at near term. This does not appear to be associated with alterations in hypothalamic levels of the prostaglandin receptor EP-3, but does appear to reflect a generalized suppression of sympathetic output at this time; activation of brown adipose tissue (which in rats is a major contributor to the elevation in body temperature), heart rate and blood pressure were all attenuated to a similar extent at term. The brain contains neurotransmitters such as arginine vasopressin (AVP) that act as antipyretics; as their levels are increased in brain during pregnancy we asked if the suppressed sympathetic output was associated with either altered receptors numbers or action of AVP However, neither mRNA nor protein levels of the V1 AVP receptor were altered at term and central application of an AVP antagonist failed to reverse the attenuated PEG responses. We conclude that the reduction in neuroimmune responses seen at term in the pregnant rat can be explained by a reduction in the synthesis of prostaglandins due to reduced COX-2 induction as well as a reduced effectiveness of the thermogenic outputs activated by the hypothalamic PGE. Further studies are required to identify the mechanism for these altered responses. Acknowledgements: Supported by Canadian Institutes of Health Research and by Alberta Heritage Foundation for Medical Research