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ABSTRACT: Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17β-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.
Endocrinology 08/2012; 153(10):4894-904. · 4.46 Impact Factor
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ABSTRACT: Stress exerts profound inhibitory effects on reproductive function by suppressing the pulsatile release of gonadotrophin-releasing hormone (GnRH) and therefore luteinising hormone (LH). This effect is mediated in part via the corticotrophin-releasing factor (CRF) system, although another potential mechanism is via GABAergic signalling within the medial preoptic area (mPOA) because this has known inhibitory influences on the GnRH pulse generator and shows increased activity during stress. In the present study, we investigated the role of the preoptic endogenous GABAergic system in stress-induced suppression of the GnRH pulse generator. Ovariectomised oestradiol-replaced rats were implanted with bilateral and unilateral cannulae targeting toward the mPOA and lateral cerebral ventricle, respectively; blood samples (25 μl) were taken via chronically implanted cardiac catheters every 5 min for 6 h for the measurement of LH pulses. Intra-mPOA administration of the specific GABA(A) receptor antagonist, bicuculline (0.2 pmol each side, three times at 20-min intervals) markedly attenuated the inhibitory effect of lipopolysaccharide (LPS; 25 μg/kg i.v.) but not restraint (1 h) stress on pulsatile LH secretion. By contrast, restraint but not LPS stress-induced suppression of LH pulse frequency was reversed by application of the selective GABA(B) receptor antagonist, CGP-35348, into the mPOA (1.5 nmol each side, three times at 20-min intervals). However, intra-mPOA application of either bicuculline or CGP-35348 attenuated the inhibitory effect of CRF (1 nmol i.c.v.) on the pulsatile LH secretion. These data indicate a pivotal and differential role of endogenous GABAergic signalling in the mPOA with respect to mediating psychological and immunological stress-induced suppression of the GnRH pulse generator.
Journal of Neuroendocrinology 12/2011; 24(3):477-88. · 3.14 Impact Factor
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ABSTRACT: The bed nucleus of the stria terminalis (BNST) occupies a central position in the neural circuitry regulating the hypothalamic-pituitary-adrenocortical axis response to stress. The potential role of the BNST in stress-induced suppression of the gondotrophin-releasing hormone (GnRH) pulse generator, the central regulator of the reproductive system, was assessed by examining the effects of micro-infusion of corticotrophin-releasing factor (CRF) or its antagonist into the BNST on pulsatile luteinising hormone (LH) secretion or stress-induced inhibition of LH pulses, respectively. Ovariectomised oestrogen-treated rats were implanted chronically with bilateral cannulae in the dorsolateral BNST and i.v. catheters. CRF (25, 50 or 100 pmol in 200 nl of artificial cerebrospinal fluid) administered bilaterally into the BNST resulted in a dose-dependent decrease in LH pulse frequency, and induced Fos expression in glutamic acid decarboxylase immunostained neurones in the medial preoptic area. These results suggest that the activation of hypothalamic GABAergic neurones in response to intra-BNST administration of CRF may be involved in the suppression of LH pulses. Furthermore, administration of CRF antagonist (280 pmol astressin-B, three times at 20-min intervals) into the BNST effectively blocked the suppression of pulsatile LH secretion in response to restraint (1 h) but not hypoglycaemic (0.25 U insulin/kg, i.v.) stress. These data suggest that CRF innervation of the dorsolateral BNST plays a key, but differential, role in stress-induced suppression of the GnRH pulse generator.
Journal of Neuroendocrinology 12/2010; 23(1):3 - 11. · 3.14 Impact Factor
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ABSTRACT: The bed nucleus of the stria terminalis (BNST) occupies a central position in the neural circuitry regulating the hypothalamic-pituitary-adrenocortical axis response to stress. The potential role of the BNST in stress-induced suppression of the gondotrophin-releasing hormone (GnRH) pulse generator, the central regulator of the reproductive system, was assessed by examining the effects of micro-infusion of corticotrophin-releasing factor (CRF) or its antagonist into the BNST on pulsatile luteinising hormone (LH) secretion or stress-induced inhibition of LH pulses, respectively. Ovariectomised oestrogen-treated rats were implanted chronically with bilateral cannulae in the dorsolateral BNST and i.v. catheters. CRF (25, 50 or 100 pmol in 200 nl of artificial cerebrospinal fluid) administered bilaterally into the BNST resulted in a dose-dependent decrease in LH pulse frequency, and induced Fos expression in glutamic acid decarboxylase immunostained neurones in the medial preoptic area. These results suggest that the activation of hypothalamic GABAergic neurones in response to intra-BNST administration of CRF may be involved in the suppression of LH pulses. Furthermore, administration of CRF antagonist (280 pmol astressin-B, three times at 20-min intervals) into the BNST effectively blocked the suppression of pulsatile LH secretion in response to restraint (1 h) but not hypoglycaemic (0.25 U insulin/kg, i.v.) stress. These data suggest that CRF innervation of the dorsolateral BNST plays a key, but differential, role in stress-induced suppression of the GnRH pulse generator.
Journal of Neuroendocrinology 11/2010; 23(1):3-11. · 3.14 Impact Factor
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ABSTRACT: Puberty is a developmental process that is dependent upon activation of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. It is well established that the stress neuropeptide, corticotrophin-releasing factor (CRF), has a profound inhibitory action on GnRH pulse generator frequency. Although stress is known to affect the timing of puberty, the role of CRF is unknown. The present study aimed to test the hypothesis that CRF plays a critical role in the timing of puberty. On postnatal day (pnd) 28, female rat pups were chronically implanted with i.c.v. cannulae and received 14 days of administration of either CRF, CRF receptor antagonist (astressin-B) or artificial cerebrospinal fluid via an osmotic mini-pump. A separate group of rats served as nonsurgical controls. As a marker of puberty, rats were monitored for vaginal opening and first vaginal oestrus. Levels of CRF, CRF receptor types 1 and 2 (CRF-R1, CRF-R2) mRNA expression in micropunches of the medial preoptic area (mPOA), hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC) were determined across pubertal development; brain tissue was collected from a naive group of rats on pnd 14, 32, on the day of vaginal opening, and pnd 77 (Adult). Administration of CRF resulted in a delay in the onset of puberty, whereas astressin-B advanced pubertal onset. Additionally, CRF and CRF-R1 mRNA expression was reduced in the mPOA, but not ARC, at puberty. In the PVN, expression of CRF, but not CRF-R1 mRNA, was reduced at the time of puberty. These data support the hypothesis that CRF signalling may play an important role in modulating the timing of puberty in the rat.
Journal of Neuroendocrinology 12/2009; 22(2):102-9. · 3.14 Impact Factor
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ABSTRACT: Immunological challenge experienced in early life can have long-term programming effects on the hypothalamic-pituitary-adrenal axis that permanently influence the stress response. Similarly, neonatal exposure to immunological stress enhances stress-induced suppression of the hypothalamic-pituitary gonadal (HPG) axis in adulthood, but may also affect earlier development, including the timing of puberty. To investigate the timing of the critical window for this programming of the HPG axis, neonatal female rats were injected with lipopolysaccharide (LPS; 50 microg/kg i.p.) or saline on postnatal days 3 + 5, 7 + 9, or 14 + 16 and monitored for vaginal opening and first vaginal oestrus as markers of puberty. We also investigated the effects of neonatal programming on the development of the expression patterns of kisspeptin (Kiss1) and its receptor (Kiss1r) in hypothalamic sites known to contain kisspeptin-expressing neuronal populations critical to reproductive function: the medial preoptic area (mPOA) and the arcuate nucleus in neonatally-stressed animals. We determined that the critical period for a significant delay in puberty as a result of neonatal LPS exposure is before 7 days of age in the female rat, and demonstrated that Kiss1, but not Kiss1r mRNA, expression in the mPOA is down-regulated in pre-pubertal females. These data suggest that the mPOA population of kisspeptin neurones play a pivotal role in controlling the onset of puberty, and that their function can be affected by neonatal stress.
Journal of Neuroendocrinology 07/2009; 21(8):683-9. · 3.14 Impact Factor
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ABSTRACT: Identification of kisspeptin (Kiss1) and its G protein-coupled receptor 54 (Kiss1r) as an essential component of the hypothalamic-pituitary-gonadal (HPG) axis controlling gonadotrophin secretion raises the possibility that kisspeptin-Kiss1r signalling may play a critical role in the transduction of stress-induced suppression of reproduction. We examined the effects of: (i) three different stressors, known to suppress pulsatile luteinising hormone (LH) secretion; (ii) corticotrophin-releasing factor (CRF); and (iii) corticosterone on Kiss1 and Kiss1r expression in key hypothalamic sites regulating gonadotrophin secretion: the medial preoptic area (mPOA) and arcuate nucleus (ARC). Ovariectomised oestrogen-replaced rats were implanted with i.v., subcutaneous or i.c.v. cannulae. Blood samples were collected at 5-min intervals for 5-6 h for detection of LH. Quantitative reverse transcriptase-polymerase chain reaction was used to determine Kiss1 and Kiss1r mRNA levels in brain punches of the mPOA and ARC collected 6 h after restraint, insulin-induced hypoglycaemia or lipopolysaccharide stress, or after i.c.v. administration of CRF, or acute or chronic subcutaneous administration of corticosterone. We observed down-regulation of at least one component of the kisspeptin-Kiss1r signalling system by each of the stress paradigms within the mPOA and ARC. CRF decreased Kiss1 and Kiss1r expression in both the mPOA and ARC. Both acute and chronic stress levels of corticosterone resulted in a concomitant decrease in Kiss1 and an increase in kiss1r mRNA expression in the mPOA and ARC. This differential regulation of Kiss1 and Kiss1r might account for the lack of effect corticosterone has on pulsatile LH secretion. Considering the pivotal role for kisspeptin-Kiss1r signalling in the control of the HPG axis, these results suggest that the reduced Kiss1-Kiss1r expression may be a contributing factor in stress-related suppression of LH secretion.
Journal of Neuroendocrinology 02/2009; 21(1):20-9. · 3.14 Impact Factor
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ABSTRACT: Calcitonin gene-related peptide (CGRP) is involved in a variety of stress responses and plays a pivotal role in stress-induced suppression of the GnRH pulse generator in the rat. Intracerebroventricular administration of CGRP suppresses luteinizing hormone (LH) pulses and increases Fos expression within the medial preoptic area (mPOA) and paraventricular nucleus (PVN). The aims of the present study were to investigate whether the mPOA or PVN are sites of action for CGRP-induced suppression of LH pulses and whether lipopolysaccharide (LPS), restraint or insulin-induced hypoglycaemia, stressors known to suppress LH pulses, affect mRNA expression for CGRP and its receptor subunits (calcitonin receptor-like receptor (CL) and RAMP-1) in the mPOA and PVN. Micro-infusion of CGRP (50, 250 or 500 pmol) into the mPOA, but not the PVN, dose-dependently suppressed LH pulse frequency. LPS, restraint and hypoglycaemia suppressed RAMP-1 mRNA, but not CL or CGRP mRNA expression in the mPOA. In the PVN, all three stressors suppressed CL mRNA expression, but only LPS or restraint suppressed RAMP-1 mRNA, and CGRP mRNA was unaffected. These results provide evidence that, unlike the PVN, the mPOA might play an important role in the inhibitory effect of CGRP on pulsatile LH secretion. Additionally, CGRP receptor function may be involved in this brain region in stress-induced suppression of the GnRH pulse generator.
Stress (Amsterdam, Netherlands) 01/2009; 12(3):259-67. · 3.21 Impact Factor
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ABSTRACT: Corticotrophin-releasing hormone (CRH) plays a pivotal role in the suppression of the gonadotrophin-releasing hormone (GRH) pulse generator in response to stress and intracerebroventricular (i.c.v.) administration of calcitonin gene-related peptide (CGRP). We have previously shown both CRH receptor subtypes, CRH-R1 and CRH-R2, are involved in the stress-induced suppression of LH pulses. The aims of the present study were to examine the role of CRH-R1 and CRH-R2 in CGRP-induced suppression of LH pulses, and to investigate the effects of CGRP on CRH expression in the paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA), which have prominent CRH neurone populations that receive dense CGRP innervations. The suppression of LH pulses by CGRP (1.5 microg i.c.v.) was completely prevented by intravenous administration of the CRH-R1 antagonist SSR125543Q (7.5 mg/rat i.v., 30 min before CGRP), but was not affected by the CRH-R2 antagonist, astressin(2)-B (100 microg i.c.v., 10 min before CGRP). CGRP increased the CRH mRNA expression in PVN and CeA. These results provide evidence of a role for CRH-R1 in mediating the suppressive effects of CGRP on pulsatile LH secretion in the female rat, and additionally raise the possibility of an involvement of PVN and CeA CRH neuronal populations in this suppression.
Stress (Amsterdam, Netherlands) 02/2008; 11(4):312-9. · 3.21 Impact Factor
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ABSTRACT: Early life exposure to immunological challenge has programming effects on the adult hypothalamo-pituitary-adrenocortical axis stress responsivity, and stress is known to suppress GnRH pulse generator activity, especially LH pulses. We investigated the effects of neonatal exposure to endotoxin on stress-induced suppression of pulsatile LH secretion and the involvement of corticotropin-releasing factor (CRF) receptor mechanisms in adult rats. Pups at 3 and 5 d of age were administered lipopolysaccharide (LPS, 50 microg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17beta-estradiol capsules and i.v. cannulas. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 microg/kg, iv). CRF and CRF-R1 and CRF-R2 receptor mRNA was determined by RT-PCR in medial preoptic area (mPOA) micropunches collected at 3 h after LPS administration. There was no difference in basal LH pulse frequency between neonatal LPS- and neonatal saline-treated controls. However, neonatal endotoxin-treated rats exhibited a significantly greater LPS stress-induced suppression of LH pulse frequency. Basal mPOA CRF-R1 expression was unchanged in neonatal LPS- and neonatal saline-treated rats. However, CRF-R1 expression was significantly increased in response to LPS stress in neonatal LPS-treated animals but not in neonatal saline-treated controls. CRF and CRF-R2 expression was unchanged in all treatment groups. These data demonstrate that exposure to bacterial endotoxin in early neonatal life programs long-term sensitization of the GnRH pulse generator to the inhibitory influence of stress in adulthood, an effect that might involve up-regulation of CRF-R1 expression in the mPOA.
Endocrinology 01/2008; 148(12):5984-90. · 4.46 Impact Factor
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ABSTRACT: Corticotrophin-releasing factor (CRF) plays a pivotal role in stress-induced suppression of the gonadotrophin-releasing hormone pulse generator. We have previously shown that type 2 CRF receptors (CRF(2)) mediate restraint stress-induced suppression of luteinising hormone (LH) pulses in the rat. The present study aimed: (i) to determine whether type 1 CRF receptors (CRF(1)) are also involved in this response to restraint and (ii) to investigate the differential involvement of CRF(1) and CRF(2) in the suppression of LH pulses in response to the metabolic perturbation of insulin-induced hypoglycemia and the innate immunological challenge of lipopolysaccharide (LPS). Ovariectomised rats with oestrogen replacement were implanted with intracerebroventricular (i.c.v.) and intravenous (i.v.) cannulae. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. After 2 h of controlled blood sampling, rats were either exposed to restraint (1 h) or injected intravenously with insulin (0.25 IU/kg) or LPS (5 microg/kg). All three stressors suppressed LH pulses. The CRF(1) antagonist SSR125543Q (11.5 micromol/rat i.v., 30 min before stressor) blocked the inhibitory response to restraint, but not hypoglycaemia or LPS stress. In addition to its effect on restraint, the CRF(2) antagonist astressin(2)-B (28 nmol/rat i.c.v., 10 min before insulin or LPS) blocked hypoglycaemia or LPS stress-induced suppression of LH pulses. These results suggest that hypoglycaemia and LPS stress-induced LH suppression involves activation of CRF(2) while restraint stress-induced inhibition of LH pulses involves both CRF(1) and CRF(2).
Journal of Neuroendocrinology 09/2006; 18(8):602-10. · 3.14 Impact Factor
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ABSTRACT: Recent evidence has shown calcitonin gene-related peptide (CGRP) to be a key mediator of stress-induced suppression of the gonadotrophin-releasing hormone (GnRH) pulse generator, although little is known about the neural pathways involved. In the present study, we investigated the potential direct action of CGRP on GnRH neurones using GT1-7 cells, an established GnRH cell line. First, we detected expression of the CGRP receptor subunits, calcitonin receptor-like receptor and receptor activity-modifying protein-1 in the GT1-7 cells by reverse transcriptase-polymerase chain reaction. Second, we have shown that CGRP inhibits GnRH mRNA expression in the GT1-7 cells, which was effectively reversed by the CGRP receptor antagonist, CGRP8-37. These results suggest that CGRP down regulates expression of GnRH mRNA, via CGRP receptors in the GT1-7 cell, thus implying that a potential direct action of CGRP may mediate a suppressive effect on the GnRH neural network.
Journal of Neuroendocrinology 10/2005; 17(9):541-4. · 3.14 Impact Factor
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ABSTRACT: Calcitonin gene-related peptide (CGRP) is involved in a variety of stress responses in the rat. Central administration of CGRP activates the hypothalamo-pituitary-adrenal axis resulting in increased corticosterone secretion. We have previously shown that central CGRP suppresses the gonadotrophin-releasing hormone (GnRH) pulse generator, specifically LH pulses. Endogenous opioid peptides (EOPs) have been shown to play an important role in stress-induced suppression of the reproductive axis. The aim of the present study was to test the hypothesis that EOPs mediate CGRP-induced suppression of pulsatile LH secretion. Ovariectomized rats were implanted with intracerebroventricular (i.c.v.) and i.v. cannulae. Intravenous administration of the opioid antagonist naloxone (250 microg) completely blocked the suppression of LH pulses induced by 1.5 microg i.c.v. CGRP and significantly attenuated the suppression of pulsatile LH secretion induced by 5 microg i.c.v. CGRP. Furthermore, intravenous administration of naloxone was found to immediately restore normal LH pulse frequency in animals treated 90 min earlier with 1.5 microg i.c.v. CGRP. Co-administration (i.c.v.) of CGRP (1.5 microg) with the mu and kappa opioid receptor-specific antagonists naloxone (10 microg) and norbinaltorphimine (5 microg), respectively, blocked the CGRP-induced suppression of LH pulses, whilst i.c.v. co-administration of CGRP (1.5 microg) with the delta opioid receptor-specific antagonist naltrindole (5 microg) did not. These data provide evidence that EOPs play a pivotal role in mediating the inhibitory effects of CGRP on pulsatile LH secretion in the rat. They also suggest that the mu and kappa, but not the delta, opioid receptors may be responsible for mediating the effects of CGRP on LH pulses.
The Journal of Physiology 09/2005; 566(Pt 3):921-8. · 4.72 Impact Factor
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ABSTRACT: Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis and can suppress pulsatile luteinizing hormone (LH) secretion, resulting in reproductive dysfunction. The histocompatible inbred Fischer and Lewis rat strains exhibit marked phenotypic differences in the activity of the HPA axis, the former being more reactive. Using Fischer, Lewis and Wistar rats, we assessed effects of repeated restraint stress on pulsatile LH secretion. Adult rats were ovariectomized and fitted with cardiac catheters. Blood samples were collected at 5-min intervals for 3-5 h for detection of LH. Less frequent samples were collected for corticosterone measurement. After 2 h, rats were restrained for 60 min. The same regimen was repeated four times at 6-day intervals. The mean peak corticosterone levels achieved during the first restraint in Fischer rats were significantly higher than those in Lewis and Wistar rats. By the time of the fourth episode of restraint, there had been some adaptation of the corticosterone response in the Fischer, but not in the Lewis or Wistar rats. LH pulses were interrupted during the 1st restraint in all experimental groups, although only Fischer rats showed suppression of LH pulses during the subsequent 2-h postrestraint period. During the fourth restraint, LH pulse frequency was still reduced in Wistar, but not in Fischer and Lewis rats, both of which showed a complete habituation. These results suggest that differential control mechanisms underlie the response of the HPA and HPG axes to repeated restraint stress.
Journal of Neuroendocrinology 08/2004; 16(7):620-7. · 3.14 Impact Factor
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ABSTRACT: Corticotropin-releasing hormone (CRH) is implicated in the suppression of pulsatile luteinizing hormone (LH) secretion by a variety of stressful stimuli; 17beta-oestradiol (E2) has been shown to modulate this inhibitory response. The present study in ovariectomized (OVX) rats was designed to investigate the effect of E2 and progesterone (P4) on hypoglycaemic stress-induced changes in pulsatile LH secretion and on the associated changes in both central and peripheral components of the hypothalamic-pituitary-adrenal axis. E2 enhanced the hypoglycaemic stress-induced suppression of LH pulses; P4 in addition to E2 further potentiated the inhibitory response. The rise in plasma corticosterone following insulin-induced hypoglycaemia (IIH) was highest in the E2 + P4 group. Nevertheless, when such levels were achieved by administration of corticosterone, the occurrence of LH pulses was completely unaffected, irrespective of ovarian steroid milieu. E2 and E2 + P4 up-regulated basal CRH mRNA expression in the paraventricular nucleus (PVN) as measured by in situ hybridization; this signal was also increased in the medial preoptic nucleus (MPN) following E2. IIH resulted in a rise in CRH mRNA in the PVN, but not in the MPN; this rise may reflect a more significant role for the PVN in the present context. Changes in neuropeptide mRNA expression may signal changes in neuronal activity; nevertheless, the profound differences in LH pulse suppression in OVX, E2 and E2 + P4 rats following IIH were not reflected in the concurrent changes in CRH mRNA in the PVN. The results suggest that while corticosterone has no acute effect on LH pulses in the rat, the up-regulation by ovarian steroids of basal CRH mRNA in the PVN and/or MPN may contribute to the central regulation of these pulses in response to stress.
Journal of Neuroendocrinology 06/2003; 15(5):468-76. · 3.14 Impact Factor
