Central oxytocin receptors (OTR) may be involved in adaptations of the brain oxytocin (OT) system during gestation, which are critical for systemic release of OT during parturition and lactation. We used quantitative autoradiography to determine changes in OTR binding in numerous brain sites during the course of gestation in the rat. Furthermore, to evaluate the importance of ovarian steroids in mediating pregnancy-related changes in OTR binding, we measured binding in ovariectomized animals treated with progesterone and/or estrogen, and in pregnant animals treated with exogenous progesterone during late gestation. We found that OTR binding was significantly increased in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) by midgestation (day 15) compared with control. In addition, there was a further significant increase in OTR binding in these nuclei by late gestation (day 20). The bed nucleus of the stria terminalis (BNST) and the medial preoptic area (MPOA) also showed significant gestation-associated increases in OTR binding, which were similar during mid- and late pregnancy. Treatment with exogenous progesterone throughout pregnancy did not alter the increase in OTR binding characteristic of late gestation in any of these brain sites. Finally, estrogen treatment in ovariectomized animals resulted in increased OTR binding in the SON, BNST, and MPOA, but not the PVN. These data demonstrate that OTR binding in the hypothalamus is increased during mid- and late-gestation, compared with ovariectomized control animals, which may be mediated by increased estradiol.

Background: Phytoestrogens derived from soy foods (or isoflavones) have received prevalent usage due to their 'health benefits' of decreasing: a) age-related diseases, b) hormone-dependent cancers and c) postmenopausal symptoms. However, little is known about the influence of dietary phytoestrogens on regulatory behaviors, such as food and water intake, metabolic hormones and neuroendocrine parameters. This study examined important hormonal and metabolic health issues by testing the hypotheses that dietary soy-derived isoflavones influence: 1) body weight and adipose deposition, 2) food and water intake, 3) metabolic hormones (i.e., leptin, insulin, T3 and glucose levels), 4) brain neuropeptide Y (NPY) levels, 5) heat production [in brown adipose tissue (BAT) quantifying uncoupling protein (UCP-1) mRNA levels] and 6) core body temperature.

The expression of neuropeptide Y (NPY) and its co-messenger, agouti-related peptide (AgRP), in arcuate neurons of the hypothalamus is increased during lactation in rats. Our research has been addressing the questions of the physiological actions of these peptides during lactation and the physiological signals associated with lactation that result in increased expression of their genes. Our studies indicate that NPY and AgRP exert pleiotropic actions during lactation that help integrate neuroendocrine regulation of energy balance with controls over anterior and posterior pituitary hormone secretion. Further, reciprocal signaling to the NPY/AgRP system by leptin and ghrelin is responsible for the changes in expression of these hypothalamic peptides in lactating animals, and thus, may contribute to regulation of food intake and the various neuroendocrine adaptations of lactation.

The neurohypophysial hormone oxytocin (OT), synthesized in magnocellular paraventricular (PVN) and supraoptic (SON) nuclei, is well known for its effects in lactation. Our previous studies showed that central OT receptor (OTR) binding is increased during gestation and that blockade of central OTRs, specifically during mid-late gestation, causes a delay in OT release during suckling and reduces weight gain in pups, suggesting decreased milk delivery. In the present study, we tested whether central OTR blockade during late gestation disrupts the gestation-related plasticity in intrinsic membrane properties. Whole cell current-clamp recordings were performed in OT neurons from pregnant rats (19 -22 days in gestation) that were infused with an OTR antagonist (OTA) or artificial cerebrospinal fluid (aCSF) and from virgin rats infused with aCSF into the third ventricle via an osmotic minipump beginning on days 12-14 of gestation. The amplitudes of both Ca 2ϩ -dependent afterhyperpolarizations (AHPs), an apamin-sensitive medium AHP (mAHP) and an apamin-insensitive slow AHP (sAHP), were significantly increased during late gestation in control pregnant animals. However, the amplitude of the sAHP from pregnant rats treated with the OTA was significantly smaller than that of pregnant control rats and similar to that of virgins. These results indicate that the diminished efficiency in lactation due to OTR blockade may be partly a result of an altered sAHP that would shape OT bursting. These findings suggest that central actions of OT during late gestation are necessary for programming the plasticity of at least some of the intrinsic membrane properties in OT neurons during lactation.vasopressin; electrophysiology; hypothalamus; lactation; hyperpolarizing afterpotentials THE NEUROHYPOPHYSIAL HORMONES oxytocin (OT) and vasopressin (VP) are synthesized in the magnocellular cells (MNCs) located in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. These hormones are released into the systemic circulation from the neurohypophysis in response to physiological demands, such as milk ejection and parturition for OT (14, 30) and osmotic and cardiovascular challenge for VP (31). The release of OT is determined by the rate and pattern of neuronal activity of SON and PVN neurons (31). During lactation, OT neurons display a short (2-4 s), highfrequency (up to 80 Hz) burst of action potentials shortly before each milk ejection. This bursting activity is synchronized among all OT neurons (4) and results in a bolus release of OT into the bloodstream. This pulsatile OT release into the general circulation is believed to maximize the biological effects of OT (6) and is requisite for milk ejection (17,33,36).The firing patterns of MNCs are critically modulated by intrinsic membrane properties, such as the Ca 2ϩ -dependent afterhyperpolarizations (AHPs) and the Ca 2ϩ -dependent depolarizing afterpotentials (DAPs). Both AHPs and DAPs are specifically enhanced during lactation (37-39), indicating that these changes interact with ...

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The expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), both of which are important neuropeptides involved in regulation of energy balance and hormone secretion, is up-regulated in the arcuate nucleus during lactation in rodents. The present study tested whether reductions in circulating insulin and/or leptin that occur in lactation provide the critical signals to these systems. Lactating female rats received 3-day infusions of either bovine insulin or recombinant rat leptin via Alzet Osmotic minipumps implanted subcutaneously in regimens designed to restore serum concentrations of these hormones to the higher non-lactating level. Compared to non-lactating rats in diestrus, lactating rats displayed significantly lower serum concentrations of insulin and leptin, and significantly increased NPY peptide concentrations in the paraventricular nucleus (PVN) and median eminence, and AgRP mRNA in the arcuate nucleus. Infusion of leptin in lactating females significantly increased serum concentrations of leptin and significantly reduced NPY concentrations in the PVN and median eminence, and decreased NPY and AgRP mRNAs in the arcuate nucleus. The same effects were produced by infusion of insulin in lactating rats, which restored both insulin and leptin concentrations in serum. The levels of pro-opiomelanocortin mRNA in the arcuate nucleus were not different in non-lactating and lactating females, and were not altered by leptin or insulin treatment. These findings support the hypothesis that the reduction in circulating leptin during lactation contributes to increased expression of NPY and AgRP in hypothalamic systems involved in the behavioural and neuroendocrine adaptations to lactation.

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