Orexin-A is synthesized in the posterolateral hypothalamus and immunoreactive fibres project to many central nervous system structures, including the paraventricular nucleus, which is rich in corticotropin releasing factor (CRF) neurones and neuropeptide Y (NPY) innervation. We investigated the central effects of orexin-A on the hypothalamic-pituitary-adrenal (HPA) axis by measuring plasma concentrations of corticosterone and adrenocorticotropic hormone (ACTH) in vivo. We explored the potential neuropeptide pathways involved by investigating the effects of orexin-A on CRF, NPY, arginine vasopressin (AVP) and noradrenaline release from hypothalamic explants in vitro. Intracerebroventricular (i.c.v.) injection of orexin-A (3 nmol) in male rats stimulated increases in plasma concentrations of corticosterone between 10 and 40 min after injection, and of plasma ACTH at 20 and 90 min after injection. Orexin-A significantly stimulated CRF and NPY release from hypothalamic explants in vitro. Orexin-A did not stimulate CRF release in the presence of the selective NPY Y1 receptor antagonist, BIBP3226. BIBP3226 alone did not alter CRF release from hypothalamic explants. Orexin-A had no effect in vitro on the release of other neuropeptides, AVP and noradrenaline, involved in the central regulation of the HPA axis. These results suggest that orexin-A is involved in activation of the HPA axis, and that these effects could be mediated via the release of NPY.

The distribution of orexin A-immunoreactive neurons and orexin type I receptors in the CNS suggests important roles in regulating the hypothalamo-pituitary gonadal (HPG) axis and sexual behaviors. We examined orexin A interactions in the HPG axis in vivo and in vitro.Orexin A stimulated LH-releasing hormone (LHRH) release in hypothalamic explants harvested from male rats (؉133%) and from females at proestrus (؉233%), with no effect at estrus or metestrus. Orexin A dose dependently inhibited LHRH-stimulated LH release in dispersed pituitaries from proestrous females only. A selective NPY1-receptor antagonist abolished in vitro release of LHRH by orexin A. Hyperestrogenization in female rats reduced orexin A content in hypothalamus (؊28%), midbrain (؊26%), medulla (؊40%), thalamus (؊36%), olfactory tubercles (؊25%), and cortex (؊35%), brain regions that are important in HPG control and sex-cycle specific behaviors. Orexin A content was lower in hypothalamus (؊20%) and higher in midbrain (؉40%), medulla (؉31%), and thalamus (؉33%) at late proestrus vs. other cycle stages. Orexin A release after administration of 56 mM KCl was significantly greater in hypothalamic explants harvested on the morning of proestrus than at estrus or metestrus, and orexin A release was stimulated by estradiol (E2) in explants from males. These results reveal important interactions for orexin A in the HPG axis. (Endocrinology 142: -5302, 2001)O REXIN A, ALSO known as hypocretin-1, is a 33-amino acid peptide synthesized almost exclusively in the posterolateral hypothalamus (1). Orexin A immunoreactive fibers project to a number of CNS sites involved in hypothalamopituitary gonadal (HPG) axis control. Within the hypothalamus, orexin A immunoreactive fibers project to the septal preoptic and arcuate nucleus median eminence region (2, 3). These areas are directly involved in the control of the HPG axis via LH-releasing hormone (LHRH) neuronal projections to the median eminence (4). Orexin A immunoreactive neurons also project to the medulla and midbrain dorsal raphe and the pontine locus coeruleus (2, 3). These areas are involved in the control of the HPG through noradrenergic, adrenergic, and serotoninergic projections to the preoptic hypothalamus and via the paraventricular hypothalamus (4, 5). Orexin A immunoreactive neurons and LHRH neurons project to areas that are important in the control of sexual behavior, including the amygdala, olfactory bulbs, and central gray matter (4). Furthermore, the orexin receptor (type 1) is expressed in the medial preoptic area and at high levels in the monoaminergic locus coeruleus and dorsal/median raphe (6). The distribution of orexin A immunoreactive neurons and orexin type I receptors suggest potentially important roles in the regulation of the HPG axis and sexual behaviors.Previous studies have shown that injection of orexin A into the lateral cerebral ventricle stimulates plasma LH in ovariectomized (OVEX) steroid-replaced rats (7). By contrast, orexin A inhibits plasma LH when injected into the later...

The mother's brain is prepared by the hormones of pregnancy to show the strong maternal feelings that ensure the newborn is cared for. These hormones induce a cascade of changes in the brain, reducing stress reactions, evoking maternal behaviour and preparing the neuroendocrine circuits that drive the birth process and ensure that the suckling infant gets milk. The nerve cells that make oxytocin are involved in all of these aspects of motherhood, and details are emerging of how their performance is adapted by pregnancy.

The adipocyte derived hormone leptin has been implicated as an important nutritional signal to the reproductive system, but the role of other adipocyte related cytokines is not clear. Tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 are present in adipose tissue and released into the circulation where plasma levels correlate positively with body mass index and body fat mass. These cytokines could play a role in signalling nutritional status to the hypothalamic-pituitary-gonadal axis. We investigated the effects of TNF-alpha and IL-6 on basal and luteinizing hormone releasing hormone (LHRH) stimulated luteineizing hormone (LH) release from cultured anterior pituitary cells, harvested from either proestrus female or male Wistar rats. We examined the effects of TNF-alpha and IL-6 on LHRH release from hypothalamic explants harvested from proestrus female and male rats in vitro. IL-6 significantly suppressed LHRH stimulated LH release from male dispersed pituitaries throughout the dose range, but did not influence basal LH release. IL-6 had no effect on basal or LHRH stimulated LH release in dispersed pituitaries from proestrus females. By contrast, TNF-alpha significantly suppressed LHRH stimulated LH release in dispersed pituitaries from proestrus female rats in a dose responsive manner, but did not influence basal LH release. TNF-alpha had no effect on basal or LHRH stimulated LH release in dispersed pituitaries from male rats. TNF-alpha and IL-6 had no effect on LHRH release from male hypothalamic explants in vitro. TNF-alpha and IL-6 had no effect on LHRH release from proestrus female hypothalamic explants in vitro. TNF-alpha and IL-6 have differential effects in dispersed pituitaries harvested from males and proestrus female rats. TNF-alpha and IL-6 may be important in mediating some of the nutritional effects on the reproductive axis by acting at the level of the anterior pituitary rather than the hypothalamus.

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