Effects Of Corticotropin-releasing Factor Research Articles

The effect of corticotropin releasing factor on heart rate, body temperature and behavior in rats

The effect of corticotropin releasing factor on heart rate, body temperature and behavior in rats

Effects of corticotropin-releasing factor (CRF) and opiates on amphibian locomotion

Male rough-skinned newts ( Taricha granulosa) were used as a model for the study of the neuroendocrine regulation of locomotion. Intracerebroventricular (i.c.v.) injections of nanogram quantities of corticotropin-releasing factor (CRF) dose-dependently increased locomotion as measured in a circular open-field test arena. In other studies animals received intraperitoneal (i.p.) injections of saline or naloxone, a synthetic opioid antagonist, followed by i.c.v. injections of saline or CRF. With 1-min intervals between injections, neither i.p. saline nor naloxone injections modified the stimulatory effects of CRF injections on locomotor activity. In contrast, with 20-min intervals between injections, the naloxone-plus-CRF injected newts displayed more locomotor activity than the saline-plus-CRF injected newts, suggesting that the opioid system modulated the behavioral effects of CRF. An i.p. injection of bremazocine, an opiate κ-receptor agonist, suppressed spontaneous locomotion but not CRF-induced locomotion. In contrast, an i.p. injection of morphine, an opiate μ-receptor agonist, did not affect spontaneous locomotion but reduced CRF-induced locomotion, indicating further that the opioid system may modulate the behavioral effects of CRF in this amphibian. The present study provides the first evidence that both CRF and opioids may be involved in the regulation of amphibian locomotor activity.

Central administration of corticotropin releasing factor in the pig: Effects on operant feeding, drinking and plasma cortisol

Four experiments were carried out to investigate the effects of corticotropin releasing factor (CRF) on ingestive behaviour and cortisol secretion in the prepubertal pig. In Experiment 1, 19-hr food-deprived animals were given intracerebroventricular (ICV) injections of 2.5, 10 or 20 μg CRF, or saline vehicle, 5 min after the start of a 30-min operant-feeding session. The total number of food reinforcements obtained in the posttreatment period did not change after 2.5 or 10 μg CRF, although the latter dose reduced intake in the final 5 min of the test; overall food consumption, however, was reduced after 20 μg CRF. In Experiment 2, pigs were treated intravenously with 20 μg CRF, or saline, using the same test situation as in Experiment 1; neither treatment significantly affected operant feeding. In Experiment 3, 19-hr water-deprived pigs were given ICV injections of 20 μg CRF, or saline, 15 min before the start of a 30-min operant-drinking session. Water intake was increased in the 5-min period directly after CRF injection, but there was no overall reduction in drinking. In Experiment 4, blood samples were taken at 15-min intervals for 30 min before and 90 min after ICV injection of 20 μg CRF, or saline, in food and water replete animals. Both treatments appeared to increase plasma cortisol levels, as determined by radioimmunoassay, but the effect was more pronounced after CRF.

Effects of Corticotrophin Releasing Factor, Muscarine and Somatostatin on Rubidium and Potassium Efflux from Mouse AtT‐20 Pituitary Cells

Effects of secretagogues and anti-secretagogues of ACTH secretion on K+ permeability in the clonal pituitary cell line AtT-20 were measured by recording 86Rb or 42K efflux. Efflux was accelerated by the secretagogues K+, corticotrophin, forskolin, isoprenaline, and the Ca-ionophore A23187. Efflux was reduced by the inhibitors somatostatin, muscarine, and oxotremorine, or by removing external Ca. Efflux was also reduced by the K+-channel blocking compound d-tubocurarine but not by tetraethylammonium. Muscarine, oxotremorine, somatostatin, and 0 Ca2+ also reduced intracellular Ca2+ measured by quin-2 fluorescence. It is suggested that most of the resting 86Rb or 42K efflux measured under these conditions occurs via tubocurarine-sensitive Ca2+-dependent K+-channels, and that changes in efflux rate produced by secretagogues or anti-secretagogues are secondary to changes in intracellular Ca2+.

Neuromodulatory effects of corticotropin releasing factor on cerebellar purkinje cells: An in vivo study in the cat

Corticotropin releasing factor, a 41 amino acid peptide, has been localized in climbing fibers and mossy fibers in the cat's cerebellar cortex. In the present study, corticotropin releasing factor was iontophoretically applied to Purkinje cells, isolated extracellularly, to assess the effect of this peptide on the firing rate of the neuron. By itself corticotropin releasing factor had little or no effect on cellular activity. However, this peptide potentiated the excitatory effects of aspartate and glutamate, the putative neurotransmitters of the climbing fiber and mossy fiber-parallel fiber systems, respectively. In addition, corticotropin releasing factor blocked the suppressive effects induced by the iontophoretic application of GABA. Finally, it shortened or eliminated the period of suppression produced by activation of climbing fibers in the cerebellar cortex. These data suggest that corticotropin releasing factor functions as a neuromodulator rather than as a neurotransmitter in cerebellar circuitry.

Effect of corticotropin-releasing factor on the electrical and mechanical activities of the guinea-pig ventricular myocardium

1. 1. The effects of the physiological levels of corticotropin-releasing factor (CRF) on isolated guinea-pig ventricular myocardium were studied using a force transducer and standard microelectrode techniques. 2. 2. CRF increased the contractile force of muscles concentration-dependently in normal Tyrode and a high-K + (27 mM) solution. The positive inotropic effect of CRF was associated with a significant enhancement of the slow action potentials of partially depolarized muscles in high-K + solution. CRF potentiated the effect of increasing Ca 2+ concentration of Tyrode solution. 3. 3. The inotropic effect of CRF was reduced in the presence of diltiazem, and suppressed by phentolamine, metoclopramide, and cimetidine, but was not affected by propranolol and cold condition. 4. 4. It is suggested that an increase in the slow inward Ca 2+ current induced by CRF plays an important role in its positive inotropic effect and that its effect differs from that of cardiotonic steroids.

Corticotropin-Releasing Factor and Gonadotropin-Releasing Hormone Pulse Generator Activity in the Rhesus Monkey

The effect of corticotropin-releasing factor (CRF) on the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, the central neuronal system governing pulsatile pituitary luteinizing hormone (LH) secretion, was studied electro-physiologically in 6 ovariectomized rhesus monkeys bearing bilateral arrays of recording electrodes implanted in the mediobasal hypothalamus. 'Volleys' of increased multiunit activity (MUA) were recorded for 6-10 h in animals placed in primate chairs. The circulating concentrations of LH and cortisol were determined by radioimmunoassay in blood samples taken every 10 min for 3-4 h prior to the administration of CRF (200 micrograms, i.v.) and for 3-6 h thereafter. CRF resulted in a significant decrease in the frequency of pulse generator activity in 4 of 6 animals, a significant decrease in the duration of MUA volleys and a rise in circulating cortisol levels in all 6 monkeys. Treatment with metyrapone (30 mg/kg, i.m.), an inhibitor of adrenal steroidogenesis that prevented the CRF-induced rise in serum cortisol levels, did not reverse the inhibitory effects of CRF on the frequency or duration of MUA volleys. The opiate antagonist naloxone (0.8 mg/kg, i.v., 10 min prior to CRF followed by 0.8 mg/kg/h infusion) blocked the effects of CRF on MUA volley frequency in 2 of 3 animals, but failed to block the effect of CRF on MUA volley duration, suggesting that endogenous opioids may mediate the action of CRF on pulse generator frequency but not on duration.

The Vasopressin Receptor System in the Neonatal Pituitary Gland: Evidence for Reduced Binding Capacity and Signal Transmission

The present study was aimed at evaluating the capacity of anterior pituitary cells from neonatal rats to bind arginine vasopressin (AVP) and show AVP-receptor-mediated signal transmission. We found that in cultures of pituitary cells of 10-day-old pups, in contrast to cultures of cells of adults, AVP was unable to trigger sustained adrenocorticotropin (ACTH) secretion and, in addition, was also less potent in synergizing with the effect of corticotropin-releasing factor (CRF) on both ACTH output and cyclic AMP formation. Binding studies revealed the existence of a much lower number of AVP receptor sites in membranes of neonatal pituitary gland than in those of adult tissue (32.3 +/- 9.0 and 137.6 +/- 6.2 fmol/mg protein, respectively), although the binding of agonists and the apparent molecular weight (Mr about 120,000) of the receptors were similar. Activation by phorbol ester PMA of protein kinase C, a messenger involved in AVP action, resulted in a dose-related enhancement of ACTH secretion that was 2-3 times smaller for immature corticotrophs than for mature ones. Importantly, PMA treatment allowed AVP to significantly stimulate ACTH secretion from neonatal cells, while it failed to similarly affect AVP-evoked hormone output from adult tissue. Our results indicate that pituitary corticotrophs of rat pups fail to properly transduce AVP-receptor-mediated signalling and, thereby, suggest an explanation for the postnatal 'stress nonresponsive period'.

Effects of corticotropin-releasing factor (CRF), tuftsin and dermorphin on behavior of squirrel monkeys maintained by different events

The effects of intracerebroventricular (ICV) administration of ovine CRF (0.1–30.0 μg/kg), dermorphin (0.3–30.0 μg/kg) and tuftsin (10–3000 μg/kg) were examined in squirrel monkeys trained to respond under a multiple 3-min fixed-interval schedule of food presentation and either shock presentation or stimulus-shock termination. Initial administration of the 41-amino acid polypeptide CRF increased food-maintained responding by 150–200% in 2 of 3 subjects. However, no other doses tested affected response rates, a result that may have been due to the rapid development of tolerance. The tetrapeptide tuftsin selectively increased responding maintained by food presentation at doses that decreased shock-maintained responding. The heptapeptide dermorphin selectively increased food-maintained responding when responding in the other component of the multiple schedule was maintained by shock presentation. When responding was maintained by a multiple food, stimulus-shock termination schedule, dermorphin decreased response rates in both components. Dermorphin's rate increases were blocked by the opiate antagonist naloxone, indicating that dermorphin's actions were mediated through the opiate receptor. These results indicate that the behavioral effects of tuftsin, dermorphin, and perhaps CRF, depend on the manner in which responding is controlled by its consequences. While the actions of tuftsin and dermorphin are believed to be mediated through the opiate system, the behavioral effects observed in primates appear different from the effects of morphine under similar schedule conditions.

Effects of corticotropin releasing factor, desipramine and haloperidol on a DRL schedule of reinforcement

Rats were trained on a schedule of differential-reinforcement-of-low-rate (DRL) which has been proposed to be differentially sensitive to antidepressant drugs. Desipramine and haloperidol decreased response rate and increased reinforcement rate. CRF decreased response rate and failed to change reinforcement rate. Amphetamine produced the opposite pattern of increased response rate and decreased reinforcement rate. These results question the specificity of the DRL task as a screen for antidepressants and suggest that drugs that moderately lower response rate may produce a behavioral profile on this task similar to that of tricyclic antidepressants.

Effects of corticotropin releasing factor on genetically obese (fatty) rats

Corticotropin releasing factor (CRF) has been administered into the third ventricle of lean and genetically obese Zucker fatty rats in both acute and chronic experiments. Following a single injection of CRF (5 μg or approximately 1 nmole) there was an acute reduction of food intake in both the lean and obese animals, but the effect was greater in the obese. This effect persisted for the first three hours but was no longer detectable in either lean or genetically obese animals at 6 hours. Binding of GDP to mitochondria from interscapular brown adipose tissue in 21-hour deprived animals was lower in the fatty rats than in the lean controls. The injection of CRF significantly increased GDP binding in both the lean and fatty rats. During chronic infusion of CRF into the third ventricle of fatty rats, there was a significant decrease in food intake in the obese rats and fall of body weight in both groups. The basal levels of GDP binding were significantly lower in the saline-infused fatty rats than in the saline-infused lean controls. The chronic infusion of CRF increased GDP binding in the fatty rats but not in the lean animals. The CRF-treated values for GDP binding in fatty rats however, remained significantly below the baseline values in the control animals. Chronic CRF infusion also significantly lowered glucose levels in the fatty rat. These studies are consistent with the hypothesis that CRF may be involved in the decreased food intake and increased sympathetic activity observed in genetically obese fatty rats following adrenalectomy.

Dissociated effects of corticotropin-releasing factor on acid secretion and blood flow.

Peripherally administered corticotropin-releasing factor (CRF) inhibits gastric acid secretion in the rat via unknown mechanisms. Because intravenous CRF can produce marked systemic hypotension, the hypothesis that its antisecretory effect is due to a reduction in gastric mucosal blood flow (MBF) was tested. Corpus MBF was measured by hydrogen gas clearance in fasted, urethan-anesthetized rats. CRF (15 nmol.kg-1.h-1 iv) had no significant effect on MBF but significantly decreased systemic blood pressure (BP) by 21.8 +/- 3.4%. This dose of CRF significantly decreased acid secretion stimulated by 40 micrograms.kg-1.h-1 pentagastrin iv but did not decrease MBF despite a 30.3 +/- 2.3% decrease in BP. To avoid the confounding effect of systemic hypotension on MBF, close gastric intra-arterial infusions were performed. CRF (1.7 nmol/h ia) had no effect on BP and did not increase MBF. CRF (3.4 nmol/h ia) slightly decreased BP without modifying MBF. In contrast, histamine (200 micrograms/h ia) significantly increased MBF by 58 +/- 11%. We conclude that 1) the peripheral antisecretory effect of CRF is not related to a decrease in MBF, 2) the maintenance of MBF during CRF-induced hypotension is not due to a direct vasodilator effect of CRF on the gastric microvasculature.

Effect of Corticotropin-Releasing Factor on the Release and Synthesis of Prolactin

Corticotropin-releasing factor (CRF) has been characterized on the basis of its intrinsic activity to release corticotropin from cultured rat anterior pituitary cells. Injected in intact rats, CRF increases adrenocorticotropic hormone (ACTH) release. Endogenous CRF-like immunoreactivity was detected in the cytoplasm and nucleus of corticotrophs. Using an antirat CRF serum, a similar location of CRF-like immunoreactivity was observed in lactotrophs: cytoplasmic matrix, secretory granules, nucleus and, to a lesser degree, the plasma membrane level were stained. One injection of CRF increased the plasma ACTH concentration 4-fold after 15 min, while plasma prolactin (PRL) increased 2.7-fold 5 min after injection. In vitro, incubation of female pituitary cells with rat CRF (10(-10)-10(-8) M) had no significant effect on PRL secretion. In contrast, after 4 days of in vitro pretreatment with 17 beta-estradiol (10(-9) M), rat CRF stimulated PRL secretion by 42%. In situ hybridization of whole pituitary slices showed that rat CRF injection significantly increased the labeling of corticotrophs using an ACTH-cDNA probe, but had no significant effect on the labeling of lactotrophs using a PRL riboprobe. These results indicate that CRF is a factor which can modulate PRL release but not the synthesis of PRL.

Neuropeptide Cells and Fibers in the Hypothalamus and Pituitary of the Fetal Sheep: Comparison of Oxytocin and Arginine Vasopressin

Both oxytocin (OXY) and arginine vasopressin (AVP) enhance the effects of corticotropin-releasing factor on ACTH release by the pituitary. One of these, AVP, plays a role in the control of fluid balance and responses to hypoxemic stress in the fetal sheep. To determine the possibility that OXY also participates in fetal neuroendocrine events, OXY-containing neuronal structures must first be demonstrated within the fetal endocrine hypothalamus. OXY-immunoreactive elements were examined in fetal sheep hypothalami late in gestation and compared to AVP-containing structures using immunocytochemical procedures. Six fetal sheep ranging from 126 to 144 days gestational age were delivered via cesarian section from timed pregnant Rambouillet-Columbia ewes and killed by an overdose of anesthesia. The fetal head was perfused via bilateral carotid catheters and processed for immunocytochemical localization of OXY or AVP using the avidin-biotin complex procedure. At all fetal ages examined, OXY- and AVP-containing neurons were found within the paraventricular nuclei (PVN), supraoptic nuclei (SON) and accessory magnocellular hypothalamic nuclei. OXY-containing neurons were found principally in the SON and PVN. They were generally less numerous and less intensely stained than the AVP neurons. In the SON, they concentrated along the dorsal borders of the nucleus above the AVP neurons. In PVN, clusters of OXY cells were located along the dorsal and lateral borders of the nucleus surrounding the AVP neurons; in the periventricular division, they were intermingled with the AVP neurons. Small numbers of OXY axons were located in the external zone of the median eminence; whereas most OXY axons extended into the hypothalamo-neurohypophyseal tract and posterior lobe of the pituitary. A few of the OXY axons in the pituitary stalk were diverted to the pars intermedia. Likewise, some of the OXY fibers from the external zone of the median eminence entered the pars tuberalis but were rarely found in the distal lobe of the pituitary. In contrast, AVP axons richly innervated the external zone of the median eminence, and neural lobe. Like OXY, AVP axons from the median eminence and the pituitary stalk sent projections to the adenohypophysis. AVP fibers in the pars distalis frequently contacted corticotropes and were more numerous than OXY fibers in this region. These data provide anatomical evidence that OXY and AVP may directly regulate the fetal adenohypophysis. Of these two neuropeptides, AVP predominates anatomically.

Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats.

Corticotropin-releasing factor (CRF) has been administered into the third ventricle of rats in acute and chronic experiments. Following a single 5-micrograms injection of CRF, there was an acute reduction in food intake at 30 and 60 min that was no longer significant at 3 h. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue (IBAT) of 21-h deprived rats was significantly increased 30 min after the acute infusion of 5 micrograms of CRF. Serum corticosterone was elevated in both groups but was significantly higher in the group treated with CRF. Serum glucose was unchanged. During a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle, the treated animals showed a slight, but significant, decrease in food intake but a progressive decline in body weight of 53 g over 7 days. Mitochondrial GDP binding was increased in the ad libitum-fed rats chronically treated with CRF. Serum corticosterone levels, although significantly higher than controls, were lower than following acute administration of CRF. These data show that CRF can acutely reduce food intake and increase sympathetic activity and that chronically it reduces body weight and may increase sympathetic activity without any consistent decrease in food intake.

The mitogenic effects of corticotrophin-releasing factor on the anterior pituitary gland of the rat.

The immunohistochemically defined corticotroph population in the anterior pituitary gland of the adult male Sprague-Dawley rat has been quantified at 2 and 6 weeks after bilateral adrenalectomy using the stereological measurement, volume density (Vv). An approximately twofold increase in corticotroph Vv was demonstrated at 2 weeks in adrenalectomized rats compared with that in sham-operated controls and this was maintained at 6 weeks. Daily i.p. injections of ovine corticotrophin-releasing factor (CRF-41) induced a significant dose-related increase in corticotroph Vv when administered at doses of 25 and 50 micrograms/kg body weight, but this was less than the increase following adrenalectomy. Assessment of changes in mitotic activity of the total anterior lobe of adult Sprague-Dawley rats and of the corticotroph population was also made after daily i.p. injections of 50 micrograms CRF-41/kg for 2 and 7 days. There was no increase in overall mitotic index at either time. However, the numbers of mitotic corticotrophs were significantly increased in CRF-injected animals compared with those in saline-injected rats. These results indicate a role for CRF-41 in the regulation of corticotroph growth.

Effects of CRF and ANG II on ACTH and vasopressin release in conscious dogs.

The aim of the present study was to examine the effects of corticotropin-releasing factor (CRF) in conscious dogs and to determine whether the stimulation of adrenocorticotropic hormone (ACTH) release by angiotensin II (ANG II) results from potentiation of the action of CRF. In addition, the possible role of CRF in the stimulation of vasopressin released by ANG II was investigated. The following experiments were performed: 1) intravenous saline infusion; 2) ANG II (10 ng.kg-1.min-1) alone; 3) vasopressin (1 ng.kg-1.min-1) alone; 4) CRF (0.001, 0.01, or 0.1 microgram/kg iv) bolus; 5) vasopressin (1 ng.kg-1.min-1) and CRF (0.1 microgram/kg) together; 6) CRF (0.001, 0.01, or 0.1 microgram/kg) and ANG II (10 ng.kg-1.min-1) together; 7) ANG II (10 ng.kg-1.min-1) followed 15 min later with CRF (0.001, 0.01, or 0.1 microgram/kg). Each dose of CRF was tested on a different day. Infusion of ANG II alone stimulated the release of ACTH, cortisol, and vasopressin. Administration of CRF produced dose-dependent increases in plasma ACTH and cortisol concentrations, and the highest dose of CRF increased plasma vasopressin concentration. CRF given together with ANG II did not potentiate the stimulation of ACTH release by CRF. Vasopressin at the dose tested did not stimulate ACTH release but potentiated the ACTH response to CRF. ANG II stimulated vasopressin release but did not potentiate the AVP response to CRF. These results show that, in conscious dogs, ANG II and CRF each increase plasma ACTH concentration and that the ACTH response to CRF is potentiated by vasopressin but not by ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Cortisol levels in saliva: effects of corticotropin releasing factor and different stressors in normal men

Cortisol levels in saliva: effects of corticotropin releasing factor and different stressors in normal men

Effect of corticotropin releasing factor on immunoreactive parathyroid hormone in the cerebrospinal fluid of sheep

Effect of corticotropin releasing factor on immunoreactive parathyroid hormone in the cerebrospinal fluid of sheep

Regulation of vasopressin and oxytocin release in vitro.

Numerous studies have demonstrated a role for vasopressin (VP) and oxytocin (OT) in the regulation of adrenocorticotropin (ACTH) release. Both VP and OT release potentiate the effect of corticotropin releasing factor (CRF) on ACTH release (1), and they are present in portal plasma at the concentration required for this action (2). VP and CRF are co-localized in parvicellular neurons in the paraventricular nucleus which project to the median eminence (3–6), and both of these hormones are released from the isolated median eminence following depolarization (7). Thus, this appears to be one source of VP for regulation of ACTH release. OT is also present in some CRF neurons (8), but it has not been established whether these neurons project to the median eminence. Thus, it is not clear which neurons release OT into the portal circulation, but there are OT fibers in the external zone of the median eminence (9) suggesting a specific projection for control of the anterior pituitary.