Behavioral and epigenetic consequences of oxytocin treatment at birth.

Oxytocin is used in approximately half of all births in the United States during labor induction and/or augmentation. However, the effects of maternal oxytocin administration on offspring development have not been fully characterized. Here, we used the socially monogamous prairie vole to examine the hypothesis that oxytocin exposure at birth can have long-term developmental consequences. Maternally administered oxytocin increased methylation of the oxytocin receptor (Oxtr) in the fetal brain. As adults, oxytocin-exposed voles were more gregarious, with increased alloparental caregiving toward pups and increased close social contact with other adults. Cross-fostering indicated that these effects were the result of direct action on the offspring, rather than indirect effects via postnatal changes in maternal behavior. Male oxytocin-exposed offspring had increased oxytocin receptor density and expression in the brain as adults. These results show that long-term effects of perinatal oxytocin may be mediated by an epigenetic mechanism.

Neuroendocrine and behavioural responses to exposure to an infant in male prairie voles.

Paternal behaviour and pair-bond formation are defining characteristics of social monogamy. However, in comparison to pair-bonding, the endocrine factors associated with the male care of young are not well studied. In the present study, plasma concentrations of oxytocin, vasopressin and corticosterone (CORT) were measured in reproductively naïve male prairie voles as a function of exposure to an infant or control manipulations (i.e. handling or exposure to a wooden dowel). Plasma oxytocin concentrations were transiently elevated within 10 min of pup exposure. Although plasma CORT concentration typically increases after handling, after 10 min of pup exposure, the concentration of plasma CORT was not increased, suggesting an attenuation of CORT release by pup exposure. Group differences in the concentrations of plasma hormones were no longer detected at 20 or 60 min after treatment. These patterns of rapid change in the concentrations of plasma oxytocin and CORT were observed in both juvenile and adult males but not detected after control procedures. Plasma vasopressin, assessed only in adult males, did not vary as a function of pup exposure or other manipulations. In the paraventricular nucleus of the hypothalamus, pup exposure also increased activation (as assessed by the measurement of c-Fos) of neurones that stained for either oxytocin or vasopressin, whereas it decreased c-Fos expression in neurones stained for corticotrophin-releasing hormone. In addition, brief pup exposure (20 min) facilitated subsequent partner preference formation when alloparental males and pup attackers were considered as a group. In the context of other studies, these data support the hypothesis that neuroendocrine changes associated with male alloparental behaviour are related to those implicated in pair-bonding.

Effect of non-peptide corticotropin-releasing factor receptor type 1 antagonist on adrenocorticotropic hormone release and interleukin-1 receptors followed by stress.

Previous studies demonstrated that ether-laparotomy significantly increased iodine-125-labeled interleukin-1alpha ([125I]IL-1alpha) binding in the mouse anterior pituitary at 2 h after the onset of stress. Corticotropin-releasing factor (CRF) receptor antagonist, D-Phe CRF (12-41), abolished ether-laparotomy-induced increase in [125I]IL-1alpha binding in the pituitary, showing that CRF plays a pivotal role in the regulation of IL-1 receptors under stress conditions. In an attempt to define the effect of CRA 1000 (2-(N-(2-methylthio-4-isopropylphenyl)-N-ethylamino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine), a non-peptide CRF receptor type 1 antagonist on the regulation of hypothalamic-pituitary-adrenal (HPA) axis and IL-1 receptors in the mouse, we measured plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, [125I]IL-1alpha binding and the expression of transcripts for type 1 IL-1 receptor (IL-1R1 mRNA) in the pituitary at 2 h after endotoxin lipopolysaccharide (LPS) treatment or ether-laparotomy stress with or without CRA 1000 pretreatment. A single injection of LPS dramatically increased plasma ACTH and corticosterone levels compared with saline injection. In contrast, plasma ACTH levels were significantly attenuated in response to one LPS injection following oral CRA 1000 pretreatment. LPS-induced plasma corticosterone levels tended to be lower after CRA 1000 pretreatment but it did not reach statistical significance. Ether-laparotomy stress significantly increased plasma ACTH and corticosterone levels at 2 h after the onset of stress and CRA 1000 pretreatment did not affect the peak ACTH and corticosterone levels following stress. Ether-laparotomy stress resulted in a robust increase in [125I]IL-1alpha binding and IL-1R1 mRNA levels in the pituitary. CRA 1000 pretreatment significantly decreased ether-laparotomy stress-induced IL-1R1 mRNA levels but did not affect [125I]IL-1alpha binding. Pretreatment with CRA 1000 without stress significantly increased [125I]IL-1alpha binding and IL-1R1 mRNA levels compared with those in vehicle pretreatment. These data demonstrate differential effects of CRA 1000 in HPA axis following endotoxin and ether-laparotomy stress and complex interactions between CRF and IL-1 receptors during stress.