bluuebunny/crossref_metadata_2025_split huggingface dataset:
Growth Hormone-Releasing Activity of Thymulin on Pituitary Somatotropes Is Age Dependent
Authors: Brown OscarA. , Sosa YolandaE. , Dardenne Mireille , Pléau Jean-Marie , Goya RodolfoG. 
Published: April 2003

Thymulin is a Zn-bound nonapeptide produced by the thymic epithelial cells (TEC) whose secretion is modulated by growth hormone (GH), among others. We assessed the ability of thymulin to influence the release of GH from dispersed anterior pituitary (AP) cells from young, middle-aged and senescent Sprague-Dawley female rats. Perifused and incubated AP cells were used in different sets of experiments and GH release was measured by RIA. Perifusion of young and senescent AP cells with thymulin doses, ranging from 10<sup>–8</sup> to 10<sup>–5</sup> M, gave a logarithmic dose-response pattern of GH. Supernatants from TEC lines also showed GH secretagogue activity. The GH release was always lower in the senescent cells. AP cells incubated with 10<sup>–8</sup>–10<sup>–3</sup> M thymulin showed a time- and dose-dependent response, the latter being bell-shaped with a maximum at 10<sup>–7</sup> M thymulin. Preincubation of thymulin with an antithymulin serum completely quenched the secretagogue activity of the hormone. Coincubation of thymulin with GHRH revealed a semiadditive release of GH in young and middle-aged AP cells and an additive effect in senescent cells. In middle-aged AP cells, the synthetic GH secretagogue GHRP-6 showed a synergistic effect with thymulin on GH release. The calcium chelator EGTA, but not the calcium ionophore A23187, blocked the GH-releasing activity of thymulin in AP cells. The cAMP enhancers, caffeine, NaF and forskolin significantly increased the thymulin-stimulated release of GH while trifluoperazine, a protein kinase C inhibitor, had no effect. The inositol phosphate enhancer LiCl potentiated the action of thymulin on GH release. The data suggest that the GH-releasing activity of thymulin is receptor-mediated and involves calcium, cAMP and inositol phosphates. In addition, senescence appears to impair somatotrope responsiveness to thymulin.
Leukemia Inhibitory Factor as an Intrapituitary Mediator of ACTH Secretion
Authors: Schwartz Jeffrey , Ray DavidW. , Perez FrankM. 
Published: April 2003

In the normal anterior pituitary, intercellular interactions are important for the expression of hormones including adrenocorticotropin (ACTH). Leukemia inhibitory factor (LIF) is secreted by anterior pituitary cells and stimulates both basal and corticotropin-releasing hormone (CRH)-stimulated ACTH secretion in AtT<sub>20</sub> cells. To determine the effects of LIF on normal pituitary cells, we measured the effects of LIF and an immunoneutralizing antiserum against LIF on ACTH secretion by cultured sheep anterior pituitary cells. In intact populations of anterior pituitary cells, LIF (10 nM) stimulated ACTH secretion (from 0.30 ± 0.06 to 0.77 ± 0.01 ng/well per 3 h) and antiserum to LIF (by itself) had no effect (0.29 ± 0.05 ng/well per 3 h). In marked contrast, following pharmacological elimination of CRH-target cells, a condition known to disinhibit ACTH secretion, basal ACTH secretion was elevated (0.74 ± 0.13 ng/well per 3 h); LIF produced no further stimulation (0.73 ± 0.22 ng/well per 3 h) but immunoneutralization of LIF significantly reduced secretion to 0.50 ± 0.10 ng/well per 3 h. Medium, conditioned by exposure to CRH-target-depleted cultures of anterior pituitary cells, increased net ACTH secretion (from 0.29 ± 0.03 to 6.54 ± 0.71 ng/well per 3 h), when added as a challenge to naive, cultured anterior pituitary cells. Inclusion of antiserum to LIF significantly attenuated (5.29 ± 0.62 ng/well per 3 h) this response. The presence in and secretion of LIF by normal individual pituitary cells was detected using immunocytochemical methods. Seven to 8% of all cells stained positively for LIF, with 66 ± 11% of those secreting detectable amounts of LIF under unstimulated conditions. LIF colocalized with TSH and LH in pituitary cells. Taken together, these data suggest that LIF can stimulate ACTH secretion by normal anterior pituitary cells, and potentially plays a role as an intrapituitary stimulator of ACTH secretion under certain conditions.
Fos Expression in the Female Rat Brain during the Proestrous Prolactin Surge and following Mating
Authors: Yang Shu-Ping , Lee Youngsoo , Voogt JamesL. 
Published: April 2003

A prolactin (PRL) surge occurs in the female rat during proestrus in response to elevated estradiol levels. The elevated release of ovarian steroids on the day of proestrus is also associated with sexual receptivity. Mating triggers twice-daily PRL surges that supplant the proestrous PRL surge and are responsible for maintaining luteal function during the first half of pregnancy. In order to understand the neuronal mechanisms controlling the proestrous- and mating-induced PRL surges, we examined patterns of Fos expression by immunocytochemistry in specific brain regions as a measure of neuronal activity. Intact female rats were sacrificed at 09.00, 15.00, and 18.00 h on the day of proestrus and the day of diestrus. Brain tissues were also collected at 21.00 h on the day of proestrus from rats receiving intromissions or mounts from males or taken directly from their homecage. On the day of proestrus, the number of neurons expressing Fos in the medial preoptic area (mPOA), medial amygdaloid nucleus (mAMYG), and ventromedial nucleus of the hypothalamus (VMH) was few and was associated with low plasma PRL levels at 09.00 h; however, the number of Fos-positive cells in these brain regions significantly increased at 15.00 and 18.00 h when the proestrous PRL surge occurred. Mating during the evening of proestrus resulted in a dramatic increase in the number of Fos-positive cells in the mPOA, mAMYG, and VMH as well as in the arcuate nucleus (ARC). Nonmated animals in diestrus showed low and unchanged PRL levels and Fos expression in all the brain areas throughout the day. These results suggest that the mPOA, mAMYG, VMH and ARC may be important brain sites for the integration of stimuli associated with proestrous- and mating-induced PRL surges.
PACAP Gene Expression in Neurons of the Rat Hypothalamo-Pituitary-Adrenocortical Axis Is Induced by Endotoxin and Interleukin-1β
Authors: Hannibal Jens , Jessop David S. , Fahrenkrug Jan , Harbuz Michael S. , Larsen Philip J. 
Published: April 2003

Inflammatory stress due to infection by various micro-organisms is known to activate the hypothalamo-pituitary-adrenocortical (HPA) axis through inflammatory mediators. Recently, pituitary-adenylate-cyclase-activating polypeptide (PACAP) was shown to be located in corticotropin-releasing factor containing neurons of the medial parvocellular part of the hypothalamic paraventricular nucleus (mpPVN). In the present study, we demonstrate that PACAP gene expression is induced in neurons of the mpPVN after intraperitoneal administration of bacterial lipopolysaccharide (LPS) which was accompanied by a marked increase in PACAP immunoreactivity in the external zone of the median eminence. As determined by quantitative in situ hybridization, PACAP gene expression was rapidly induced after 4 h and was elevated for 48 h, declining to normal levels after 72 h. A significant increase in PACAP mRNA was also observed following intraperitoneal injection of interleukin-1β. PACAP gene expression was not induced by LPS in vagotomized animals, suggesting that the increase in PACAP mRNA following immune activation by LPS is mediated via the vagus nerve. The findings suggest that PACAP may function as a hypothalamo-pituitary-releasing factor during acute inflammation.
Effect of Exogenous Nitric Oxide and Inhibitors of Nitric Oxide Synthase on the Hypothalamic Pituitary Adrenal Axis Responses to Neural Stimuli
Authors: Weidenfeld Joseph , Feldman Shaul , DeKeyser Freda G. , Ovadia Haim 
Published: April 2003

It has been shown that the hypothalamic-pituitary-adrenal (HPA) axis responses to immune-derived stimuli in particular can be modulated by nitric oxide (NO). In the present study we examined the effect of endogenous and exogenous NO on the HPA axis responses to neural stimuli which are not related to immune functions. Intracerebroventricular injection of NOR-3, a donor of NO, had no effect on basal HPA axis activity but significantly attenuated the secretion of median eminence (ME) CRH-41 as well as the serum ACTH and corticosterone (CS) in response to acute photic stimulation in a dose-dependent manner. Intracerebroventricular administration of N-ω-nitro-<i>L</i>-arginine methyl ester (<i>L</i>-NAME), a general NOS inhibitor, significantly enhanced ACTH and CS responses to this stress but did not change the basal levels of these hormones. On the other hand, i.c.v. injection of aminoguanidine, an inhibitor of inducible NO synthase (NOS) but not of neuronal NOS, did not affect the HPA axis responses to photic stimulation. These results suggest that: (1) NO is involved in modulation of the HPA axis responses to neural stimuli which are not dependent on immune factors, (2) the effect of NO is mediated by inhibition of hypothalamic ME CRH-41 secretion, and (3) this effect is probably mediated by neuronal NOS and not by inducible NOS.
Central LPS-Induced <i>c-fos</i> Expression in the PVN and the A1/A2 Brainstem Noradrenergic Cell Groups Is Altered by Adrenalectomy
Authors: Condé Gillian L. , Renshaw Derek , Zubelewicz Barbara , Lightman Stafford L. , Harbuz Michael S. 
Published: April 2003

The A1 and A2 brainstem noradrenergic cell groups project to the hypothalamic paraventricular nucleus (PVN), which is involved in integrating the stress response. Bi-directional communication between the brain and immune system is well established, with both neuroendocrine and immune responses being activated by lipopolysaccharide (LPS). The mechanisms underlying such activation and differences between alternative routes of administration remain unclear. We examined activation of the PVN and A1/A2 cell groups, by assessing <i>c-fos</i> mRNA, or counting Fos-positive neurons in either the PVN or in brainstem A1/A2 cell groups 3 h after intracerebroventricular (i.c.v.) LPS, in control and adrenalectomized (ADX) rats. We also measured corticotropin-releasing hormone (CRH) mRNA in the PVN, and plasma corticosterone (CORT) levels. A group of ADX/CORT-replaced animals received i.c.v. LPS, and CRH mRNA and Fos peptide in the PVN were analysed. ADX increased CRH mRNA in the PVN, as did LPS, but no enhancement of this response was seen in LPS/ADX animals. <i>C-fos</i> mRNA also increased in both the PVN and the A2 cell group following LPS, but this response was potentiated by ADX. Fos peptide-containing cells increased in the PVN and A2 following LPS, and this change was amplified by ADX. Only 11.25% of Fos was found in DBH-positive (putative noradrenergic) neurons, suggesting activation of neurons containing other transmitters. ADX/LPS/CORT animals showed numbers of Fos neurons in the brainstem, and CRH mRNA levels in the PVN which were comparable to intact/LPS animals. Central LPS activates the hypothalamo-pituitary-adrenal axis, a process mediated partly by brainstem noradrenergic neurons, suggesting the involvement of afferent/efferent pathways within the brain. Peripheral administration of LPS involves activation of vagal inputs leading to the nucleus tractus solitarius. We suggest that centrally administered LPS activates the A2 cell group by a mechanism independent of the vagus. In the absence of CORT, despite the lack of a CRH mRNA response, an exaggerated <i>c-fos</i> and peptide response to LPS is observed, which is reversed following CORT pretreatment.
Suppression of Tonic Luteinizing Hormone Secretion and Norepinephrine Release near the GnRH Neurons by Estradiol in Ovariectomized Rats
Authors: Legan Sandra J. , Callahan W. Hunter 
Published: April 2003

One of the major neurotransmitters that controls pulsatile luteinizing hormone (LH) secretion is norepinephrine (NE). NE pulses detected in the median eminence of ovariectomized rhesus monkeys are highly correlated with both GnRH and LH pulses. In contrast, previous reports suggest that this is not the case in rats, thus it remains to be determined whether NE stimulates LH release on a pulse-by-pulse basis in that species. Further, a variety of indirect evidence supports the hypothesis that in rats, estradiol exerts its negative feedback action on LH secretion in part by inhibiting noradrenergic neurotransmission that is stimulatory to LH release, but there is no direct evidence to support this hypothesis. Therefore the following study was designed to test the hypothesis that estradiol suppresses NE release in the vicinity of the GnRH neurons after ovariectomy. In addition, we examined whether episodes of NE release are correlated with LH pulses in ovariectomized rats. Blood samples and microdialysates of the diagonal band of Broca/medial preoptic area (DBB/MPOA) were collected every 5 min from 09:00 to 14:00 h from untreated or estradiol-treated (4–5 days), long-term ovariectomized (1–4 months) rats for determination of plasma LH by RIA and NE release by HPLC. The results indicate that in both untreated and estradiol-treated ovariectomized rats, LH pulses are not correlated with episodes of NE. Thus, NE may play a permissive role in the control of pulsatile LH secretion in rats. Further, estradiol treatment leads to a suppression of both plasma LH levels and NE release in the DBB/MPOA, supporting the hypothesis that a decrease in NE neurotransmission that is stimulatory to LH release mediates the negative feedback action of estradiol on tonic LH secretion.
Chronic Ventromedial Hypothalamic Infusion of Norepinephrine and Serotonin Promotes Insulin Resistance and Glucose Intolerance
Authors: Luo Shuqin , Luo Jing , Cincotta Anthony H. 
Published: April 2003

The ventromedial hypothalamus (VMH) is involved in the regulation of peripheral metabolism. We and others have shown that activities, or extracellular metabolites of norepinephrine (NE) and serotonin (5-HT) are elevated in the VMH of both genetically and seasonally insulin-resistant and glucose-intolerant animals. This study examined whether chronic increases in VMH NE and 5-HT concentration of normal animals might lead to insulin-resistant and glucose-intolerant conditions in hamsters. Euinsulinemic, glucose-tolerant hamsters were infused continuously for 5 weeks into the right VMH with either vehicle, NE (5 or 25 nmol/h), 5-HT (2.5 nmol/h), or NE (5 or 25 nmol/h) plus 5-HT (2.5 nmol/h) through osmotic minipumps. Compared to vehicle, NE (25 nmol/h) significantly increased the glucose total area under the curve (TAUC) by 32% during glucose tolerance tests (GTT) conducted after 5 weeks’ infusion. 5-HT alone significantly increased the GTT insulin TAUC (131%) and basal plasma insulin level (116%) but not glucose TAUC. NE (5 nmol/h) plus 5-HT infusion significantly increased insulin TAUC (129%) and basal plasma insulin (120%), whereas NE (25 nmol/h) plus 5-HT infusion significantly increased both the GTT glucose and insulin TAUC (43 and 113%, respectively), as well as basal plasma insulin level (158%), relative to vehicle infusion. Our findings demonstrate for the first time the differential and, more importantly, interactive effects of increased VMH NE and 5-HT in producing hyperinsulinemia, insulin resistance and glucose intolerance.
Neuroendocrine Consequences of Fasting in Adult Male Macaques: Effects of Recombinant Rhesus Macaque Leptin Infusion
Authors: Lado-Abeal Joaquin , Hickox John R. , Cheung Tony L. , Veldhuis Johannes D. , Hardy Daniel M. , Norman Reid L. 
Published: April 2003

Fasting inhibits the gonadotropic axis and stimulates the corticotropic and somatotropic axes. Since leptin is a product of fat cells that has been implicated in the control of both reproduction and metabolism, we hypothesized that the decrease in leptin observed during fasting was responsible for these effects on reproductive and metabolic hormones. Recombinant rhesus leptin (rrhLep) produced in our laboratory was infused (100 µg/h) into fasted adult male rhesus macaques (6–9 kg) beginning at midnight after the first missed meal and continuing until the end of the study. Bioactive luteinizing hormone (LH), testosterone, cortisol and growth hormone (GH) were measured in plasma from samples collected at 15-min intervals for the last 15 h (42–57 h) of the fast. We analyzed pulsatile LH and GH secretion by deconvolution analysis and the orderliness of pulsatile LH and GH release by the approximate entropy (ApEn) statistic. There was no difference in LH pulse frequency between control and fasted groups, but there was a significant decrease in the mean concentration of LH released (7.6 ± 1.4 ng/ml control vs. 2.7 ± 0.65 ng/ml fasted) that was not relieved with rrhLep infusions (2.8 ± 0.83 ng/ml). Model-free Cluster analysis confirmed these inferences and also indicated that the peak height was lower in the fasted (4.6 ± 1.0 ng/ml) and the fasted + rrhLep (2.85 ± 1.0 ng/ml) groups compared to controls (16.3 ± 1.4 ng/ml). Testosterone levels reflected those of LH. Fasting resulted in an increase in GH secretory pulse frequency (5.3 ± 0.95 pulses/15 h control vs. 12.8 ± 1.4 pulses/15 h fasted) and this increase was not affected by rrhLep infusion (12.5 ± 1.4 pulses/15 h). In addition, fasting also increased the ApEn (decreased the orderliness) of pulsatile GH secretion, and this characteristic was not relieved with rrhLep infusions. Cortisol levels in fasted animals were 2- to 3-fold higher than those observed in control studies, and this increase was particularly pronounced at the time when the animals expected their first meal of the day. The increase in circulating cortisol observed in fasted animals was not affected by rrhLep infusion. Glucose levels at the end of the sampling period were 80 mg/dl in controls, 48 mg/dl in fasted animals and 58 mg/dl in the fasted + rrhLep group. Circulating leptin levels averaged 1.2 ± 0.37 ng/ml in control animals, 0.7 ± 0.2 ng/ml in fasted animals and 10.1 ± 5.6 ng/ml in fasted animals infused with rrhLep. These studies suggest that intravenous replacement with homologous leptin does not reverse the acute changes in GH, LH and cortisol secretion observed with fasting in the adult male macaque.
Variations in Plasma Levels of Substance P and Effects of a Specific Substance P Antagonist of the NK<sub>1</sub> Receptor on Preovulatory LH and FSH Surges and Progesterone Secretion in the Cycling Cynomolgus Monkey
Authors: Kerdelhué Bernard , Williams Robert F. , Lenoir Véronique , Fardin Véronique , Kolm Paul , Hodgen Gary D. , Jones Georgeanna Seegar , Scholler Robert , Jones Jr. Howard W. 
Published: April 2003

These studies investigated the role of substance P (SP) in the regulation of the hypothalamic-pituitary-ovarian axis in cynomolgus monkeys with normal menstrual cycles. Plasma concentrations of SP were determined in blood samples taken every morning in normally menstruating cynomolgus monkeys throughout the menstrual cycle. There was a significant decreasing linear trend of SP during the follicular phase (cycle day –13 to day 0) and a significant inverse relationship between SP plasma values and plasma 17β-estradiol (E<sub>2</sub>) values from day –13 to day 0 of the adjusted cycle. Correspondingly, SP area under the curve was significantly greater during the follicular phase than the luteal phase. In a second experiment, plasma concentrations of E<sub>2</sub>, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone and length of cycles were measured after five daily intragastric administrations (10 mg/kg) of an NK<sub>1</sub> receptor (SP receptor) antagonist (RPR 100893; 10 mg/kg) initiated after serum E<sub>2</sub> concentrations had exceeded 125 pg/ml. There was a statistically significant reduction in the amplitude (41% of control) and the area under the curve (37% of control) of the preovulatory LH surge. In addition, there was a reduction of the duration of the LH surge (3 ± 0.1 days in controls vs. 2.1 ± 0.2 days in treated animals). The present results show for the first time that there are significant variations in plasma levels of SP, with a strong negative correlation with serum levels of E<sub>2</sub> during the follicular phase of the cynomolgus monkey, and that endogenous SP has a potentiating role in the interactive hypothalamo-anterior-pituitary mechanisms which lead to the preovulatory LH and FSH surges during the menstrual cycle in the monkey.
Salt Appetite in Salt-Replete Rats: Involvement of Mesolimbic Structures in Deoxycorticosterone-Induced Salt Craving Behavior
Authors: Lucas Louis R. , Pompei Pierluigi , McEwen Bruce S. 
Published: April 2003

Chronic administration of the mineralocorticoid deoxycorticosterone acetate (DOCA) induces a steady and robust increase in salt appetite and plasma Na<sup>+</sup> over the course of treatment. Interestingly, salt appetite behavior persists in rats even with elevated plasma Na<sup>+</sup> levels. Since there is evidence that the pathways normally associated with salt and water homeostasis are relatively unaffected in the DOCA-treated rat, we hypothesized that other regulatory systems may be hyperactive giving rise to this dysfunctional condition. The mesolimbic dopaminergic system has long been associated with orienting and reward-seeking behaviors such as those observed in reproduction, drug abuse, and appetite. Furthermore, we have previously shown that chronic DOCA administration results in an increase in mRNA levels of the endogenous opiate enkephalin in male rats given 24-hour access to tap water and 2% NaCl (two-bottle choice). Thus, in the present study, we tested the hypothesis that the mesolimbic dopaminergic system is dysfunctionally sensitized to the presence of a salt stimulus in DOCA-treated animals. Four groups of rats were injected with DOCA (5 mg/rat/day, 11 days) and one with vehicle (all were given access to water but access to salt was regulated). Two DOCA groups were given 2 h of 2% NaCl access/day and on the last day, one group was not given access (2hX). One of the two remaining DOCA groups was given 24-hour access to salt (24h) and the other no access at all (24hX). Consistent with our hypothesis, in the shell of the nucleus accumbens (AcbSh) we found relatively higher enkephalin- and tachykinin-mRNA abundance in the 2h vs. 2hX and dynorphin-mRNA in the 24h vs. 24hX groups. In addition, there were decreases in dopamine transporter binding in the AcbSh and decreases in tyrosine hydroxylase immunoreactivity throughout the striatum in the 24h vs. 24hX group. Furthermore, rats denied access to salt (2hX and 24hX) had higher cholecystokinin-mRNA levels in the ventral tegmental area compared to the 2h and 24h groups, respectively. These results suggest that basal ganglia structures associated with reward and goal-seeking behavior may be activated to elicit salt craving behavior in the DOCA-induced salt-appetitive rat.