Central Administration Of Corticotropin-releasing Factor Research Articles

Comparisons of stress-related neuronal activation induced by restraint in adult male rat offspring with prenatal exposure to buprenorphine, methadone, or morphine.

Prenatal opioid exposure may impede the development of adaptive responses to environmental stimuli by altering the stress-sensitive brain circuitry located at the paraventricular nucleus of the hypothalamus (PVH) and locus coeruleus (LC). Corticotropin-releasing factor (CRF) released from neurons in the PVH has emerged as a key molecule to initiate and integrate the stress response. Methadone (Meth) and buprenorphine (Bu) are two major types of synthetic opioid agonists for first-line medication-assisted treatment of opioid (e.g., morphine, Mor) use disorder in pregnant women. No studies have compared the detrimental effects of prenatal exposure to Meth versus Bu on the stress response of their offspring upon reaching adulthood. In this study, we aimed to compare stress-related neuronal activation in the PVH and LC induced by restraint (RST) stress in adult male rat offspring with prenatal exposure to the vehicle (Veh), Bu, Meth, or Mor. CFos-immunoreactive cells were used as an indicator for neuronal activation. We found that RST induced less neuronal activation in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. RST-induced neuronal activation was completely prevented by central administration of a CRF receptor antagonist (α-helical CRF9-41, 10 μg/3 μL) in all exposure groups, suggesting the crucial role of CRF in this stress response. In offspring without RST, central administration of CRF (0.5 μg/3 μL)-induced neuronal activation in the PVH and LC. CRF-induced neuronal activation was lessened in the Meth or Mor exposure groups compared with that in the Bu or Veh groups; no significant difference was detected between the Bu and Veh exposure groups. Moreover, RST- or CRF-induced neuronal activation in the Meth exposure group was comparable with that in the Mor exposure group. Further immunohistochemical analysis revealed that the Meth and Mor exposure groups displayed less CRF neurons in the PVH of offspring with or without RST compared with the Bu or Veh groups. Thus, stress-induced neuronal activation in the PVH and LC was well preserved in adult male rat offspring with prenatal exposure to Bu, but it was substantially lessened in those with prenatal exposure to Meth or Mor. Lowered neuronal activation found in the Meth or Mor exposure groups may be, at least in part, due to the reduction in the density of CRF neurons in the PVH.

Astrocytes in the PVN are involved in corticotropin-releasing factor-induced sympathetic activation in rats

Corticotropin-releasing factor (CRF) plays a key role in stress responses in the brain. CRF activates not only the hypothalamic-pituitary-adrenal axis but also the sympathetic nervous system. We previously reported that both central administration of CRF and exposure to acute restraint stress (RS) increase plasma catecholamine levels and activate presympathetic neurons in the paraventricular hypothalamic nucleus (PVN). However, it is unclear whether glial cells in brain regions including the PVN are involved in CRF- or stress-induced sympathetic activation. In this study, we examined roles of astrocytes in the CRF-induced elevation of plasmas catecholamine levels (noradrenaline and adrenaline) using fluorocitrate which blocks glial metabolic function. Intracerebroventricular pretreatment of fluorocitrate suppressed the CRF-induced elevation of plasma levels of noradrenaline and adrenaline. On the other hand, microinjection of fluorocitrate into the PVN suppressed the CRF-induced elevation of adrenaline, but not of noradrenaline. Furthermore, we tried to examine effects of inhibition of astrocytes on RS-induced sympathetic activation. Our results suggest that astrocytic function in the brain is important for the CRF-induced sympathetic activation and the effects might be brain region-dependent.

Hypothalamic mechanism of corticotropin-releasing factor’s anorexigenic effect in Japanese quail (Coturnix japonica)

Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with anorexigenic effects across various species, with particularly potent reductions in food intake in rodents and chickens (Gallus gallus domesticus), a species for which the most is known. The purpose of the current study was to determine the hypothalamic mechanism of CRF-induced anorexigenic effects in 7 day-old Japanese quail (Coturnix japonica), a less-intensely-selected gallinaceous relative to the chicken that can provide more evolutionary perspective. After intracerebroventricular (ICV) injection of 2, 22, or 222 pmol of CRF, a dose-dependent decrease in food intake was observed that lasted for 3 and 24 h for the 22 and 222 pmol doses, respectively. The 2 pmol dose had no effect on food or water intake. The numbers of c-Fos immunoreactive cells were increased in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) at 1 h post-injection in quail injected with 22 pmol of CRF. The hypothalamic mRNA abundance of proopiomelanocortin, melanocortin receptor subtype 4, CRF, and CRF receptor sub-type 2 was increased at 1 h in quail treated with 22 pmol of CRF. Behavior analyses demonstrated that CRF injection reduced feeding pecks and jumps and increased the time spent standing. In conclusion, results demonstrate that the anorexigenic effects of CRF in Japanese quail are likely influenced by the interaction between CRF and melanocortin systems and that injection of CRF results in species-specific behavioral changes.

Hypothalamic mechanisms associated with corticotropin-releasing factor-induced anorexia in chicks

Central administration of corticotropin-releasing factor (CRF), a 41-amino acid peptide, is associated with potent anorexigenic effects in rodents and chickens. However, the mechanism underlying this effect remains unclear. Hence, the objective of the current study was to elucidate the hypothalamic mechanisms that mediate CRF-induced anorexia in 4 day-old Cobb-500 chicks. After intracerebroventricular (ICV) injection of 0.02 nmol of CRF, CRF-injected chicks ate less than vehicle chicks while no effect on water intake was observed at 30 min post-injection. In subsequent experiments, the hypothalamus samples were processed at 60 min post-injection. The CRF-injected chicks had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), dorsomedial nucleus (DMN), ventromedial hypothalamus (VMH), and paraventricular nucleus (PVN) of the hypothalamus than vehicle-treated chicks. CRF injection was associated with decreased whole hypothalamic mRNA abundance of neuropeptide Y receptor sub-type 1 (NPYR1). In the ARC, CRF-injected chicks expressed more CRF and CRF receptor sub-type 2 (CRFR2) mRNA but less agouti-related peptide (AgRP), NPY, and NPYR1 mRNA than vehicle-injected chicks. CRF-treated chicks expressed greater amounts of CRFR2 and mesotocin mRNA than vehicle chicks in the PVN and VMH, respectively. In the DMN, CRF injection was associated with reduced NPYR1 mRNA. In conclusion, the results provide insights into understanding CRF-induced hypothalamic actions and suggest that the anorexigenic effect of CRF involves increased CRFR2-mediated signaling in the ARC and PVN that overrides the effects of NPY and other orexigenic factors.

Sex differences in circuits activated by corticotropin releasing factor in rats

Women are more likely than men to suffer from psychiatric disorders characterized by corticotropin releasing factor (CRF) hypersecretion, suggesting sex differences in CRF sensitivity. In rodents, sex differences in the sensitivity of specific brain regions to CRF have been identified. However, regions do not work in isolation, but rather form circuits to coordinate distinct responses to stressful events. Here we examined whether CRF activates different circuits in male and female rats. Following central administration of CRF or artificial cerebrospinal fluid (aCSF), neuronal activation in stress-related areas was assessed using cFOS. Functional connectivity was gauged by correlating the number of cFOS-positive cells between regions and then identifying differences within each sex in correlations for aCSF-treated and CRF-treated groups. This analysis revealed that CRF altered different circuits in males and females. As an example, CRF altered correlations involving the dorsal raphe in males and the bed nucleus of the stria terminalis in females, suggesting sex differences in stress-activated circuits controlling mood and anxiety. Next, plasma estradiol and progesterone levels were correlated with cFOS counts in females. Negative correlations between estradiol and neuronal activation in the regions within the extended amygdala were found in CRF-treated, but not aCSF-treated females. This result suggests that estrogens and CRF together modulate the fear and anxiety responses mediated by these regions. Collectively, these studies reveal sex differences in the way brain regions work together in response to CRF. These differences could drive different stress coping strategies in males and females, perhaps contributing to sex biases in psychopathology.

The mechanism underlying the central glucagon-induced hyperglycemia and anorexia in chicks

We investigated the mechanism underlying central glucagon-induced hyperglycemia and anorexia in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of glucagon in chicks induced hyperglycemia and anorexia from 30min after administration. However, the plasma insulin level did not increase until 90min after glucagon administration, suggesting that glucose-stimulated insulin secretion from pancreatic beta cells may be suppressed by central glucagon. The plasma corticosterone concentration significantly increased from 30min to 120min after administration, suggesting that central glucagon activates the hypothalamic pituitary adrenal (HPA) axis in chicks. However, central administration of corticotropin-releasing factor (CRF), which activates the HPA axis in chicken hypothalamus, significantly reduced not only food intake but also plasma glucose concentration, suggesting that CRF and the activation of the HPA axis are related to the glucagon-induced anorexia but not hyperglycemia in chicks. Phentolamine, an α-adrenergic receptor antagonist, significantly attenuated the glucagon-induced hyperglycemia, suggesting that glucagon induced hyperglycemia at least partly via α-adrenergic neural pathway. Co-administration of phentolamine and α-helical CRF, a CRF receptor antagonist, significantly attenuated glucagon-induced hyperglycemia and anorexia. It is therefore likely that central administration of glucagon suppresses food intake at least partly via CRF-induced anorexigenic pathway in chicks.

Behavioral and physiological responses to central administration of corticotropin-releasing factor in the bluebanded goby (Lythrypnus dalli)

Central manipulation of neuromodulators is critical to establishing causal links between brain function and behavioral output. The absence of a rigorous method of evaluating intracerebroventricular (icv) injection efficacy in small model organisms is one reason why peripheral administration of neuroactive substances is more common. We use the bluebanded goby (Lythrypnus dalli), a small, highly social fish, to 1) validate our method of icv injection by testing the hypothesis that corticotropin-releasing factor (CRF) elevates ventilation rate (VR) and 2) propose a novel bioassay using basal physiology and behavior during recovery from anesthesia/icv administration to assess injection efficacy, neuromodulator activity, and procedural confounds. Central CRF administration significantly increased ventilation rate, demonstrating successful delivery of CRF to the brain. There were no significant differences in cortisol among treatments. The injection procedure did, however, decouple the temporal relationship between the initiation of ventilation and time to regain equilibrium present in control fish. Importantly, neither icv vehicle nor CRF injection affected the initiation of ventilation, disrupted the stereotyped recovery pattern following anesthesia, or initiated an endocrine stress response. Taken together, we suggest that 1) icv injection can be effectively used to manipulate central levels of CRF in L. dalli and 2) physiological and behavioral recovery from anesthesia may be used to evaluate injection/technique efficacy. We will use these data in future studies as a measure of effective CRF delivery, to allow for appropriate recovery from icv injection, and to better evaluate independent effects of CRF on social and/or sexual behavior.

Stress-induced decreases in local cerebral glucose utilization in specific regions of the mouse brain

BackgroundRestraint stress in rodents has been reported to activate the hypothalamic-pituitary-adrenocortical (HPA) axis and to increase c-fos expression in regions that express components of the corticotropin-releasing factor (CRF) system. We have previously reported that acute central administration of CRF increased a measure of relative local cerebral glucose utilization (LCGU), a measure of neuronal activity in specific brain regions, and activated the HPA axis in mice. It was hypothesized that the involvement of the CRF system in the stress response would lead to similar changes in relative LCGU after restraint stress. In the present studies the effect of restraint stress on relative LCGU and on the HPA axis in C57BL/6N mice were examined.FindingsRestraint stress activated the HPA axis in a restraint-duration dependent manner, but in contrast to the reported effects of CRF, significantly decreased relative LCGU in frontal cortical, thalamic, hippocampal and temporal dissected regions. These findings support evidence that stressors enforcing limited physical activity reduce relative LCGU, in contrast to high activity stressors such as swim stress.ConclusionsIn conclusion, the present studies do not support the hypothesis that stress-induced changes in relative LCGU are largely mediated by the CRF system. Further studies will help to delineate the role of the CRF system in the early phases of the relative LCGU response to stress and investigate the role of other neurotransmitter systems in this response.

Cyclooxygenase and nitric oxide synthase in the presympathetic neurons in the paraventricular hypothalamic nucleus are involved in restraint stress-induced sympathetic activation in rats

Stress is one of the important factors to activate the sympathetic nervous system. We recently reported that central administration of corticotropin-releasing factor (CRF), known as a stress-related neuropeptide, increases the expression of both cyclooxygenase (COX) and nitric oxide synthase (NOS) in presympathetic neurons in the paraventricular hypothalamic nucleus (PVN). In the present study, therefore, we investigated whether brain COX and NOS can also mediate restraint stress (RS)-induced sympathetic activation by assessing the plasma catecholamine levels and neuronal activation of presympathetic neurons in the PVN. In addition, we examined effects of RS on the expression of both COX and NOS isozymes in the presympathetic PVN neurons. Intraperitoneal administration of an inhibitor for COX-1, COX-2 or inducible NOS (iNOS), but not for neuronal NOS (nNOS), reduced RS-induced elevation of plasma catecholamine levels and Fos expression in the presympathetic PVN neurons. Moreover, RS increased the expression of COX-1, COX-2 and iNOS in the presympathetic PVN neurons, whereas nNOS expression did not change. These results suggest that COX-1, COX-2 and iNOS in the presympathetic PVN neurons mediate acute RS-induced sympathetic activation.

Brainstem reticulospinal neurons are targets for corticotropin-releasing factor-Induced locomotion in roughskin newts

Stress-induced release or central administration of corticotropin-releasing factor (CRF) enhances locomotion in a wide range of vertebrates, including the roughskin newt, Taricha granulosa. Although CRF's stimulatory actions on locomotor behavior are well established, the target neurons through which CRF exerts this effect remain unknown. To identify these target neurons, we utilized a fluorescent conjugate of CRF (CRF-TAMRA 1) to track this peptide's internalization into reticulospinal and other neurons in the medullary reticular formation (MRF), a region critically involved in regulating locomotion. Epifluorescent and confocal microscopy revealed that CRF-TAMRA 1 was internalized by diverse MRF neurons, including reticulospinal neurons retrogradely labeled with Cascade Blue dextran. In addition, we immunohistochemically identified a distinct subset of serotonin-containing neurons, located throughout the medullary raphé, that also internalized the fluorescent CRF-TAMRA 1 conjugate. Chronic single-unit recordings obtained from microwire electrodes in behaving newts revealed that intracerebroventricular (icv) administration of CRF-TAMRA 1 increased medullary neuronal firing and that appearance of this firing was associated with, and strongly predictive of, episodes of CRF-induced locomotion. Furthermore, icv administered CRF-TAMRA 1 produced behavioral and neurophysiological effects identical to equimolar doses of unlabeled CRF. Collectively, these findings provide the first evidence that CRF directly targets reticulospinal and serotonergic neurons in the MRF and indicate that CRF may enhance locomotion via direct effects on the hindbrain, including the reticulospinal system.

Interaction between the effects of corticotropin-releasing factor and prepulse parameters on prepulse inhibition in two inbred rat strains and the F1 generation of a cross between them

Levels of prepulse inhibition (PPI) depend on the interval between the startling and prepulse stimuli. Brown Norway rats show less PPI of the acoustic startle response than Wistar–Kyoto (WKY) rats when the interval between the prepulse and startling stimulus is 100 ms. Central administration of corticotropin-releasing factor (CRF) decreases PPI at this inter-stimulus interval. Here, the effect of CRF on PPI over a range of inter-stimulus intervals was examined in WKY and BN rats, and in the F1 generation of a cross between them. Rats received an intracerebroventricular infusion of either saline or CRF 30 min prior to testing PPI. Test trials included startle stimulus alone trials, and trials on which a prepulse stimulus of either 6, 12, or 15 dB above background preceded the startling stimulus by either 20, 75, 100, 500 or 2000 ms. CRF decreased PPI in WKY rats at all inter-stimulus intervals and all prepulse intensities, while the effect of CRF on PPI in BN rats only occurred at intermediate intervals. BN and WKY rats showed different levels of PPI only at the intermediate intervals. Baseline PPI in the F1 rats resembled the WKY phenotype. The CRF-induced change in PPI in the F1 generation has some qualities of the effects in each of the progenitor strains. These results suggest that both the effect of rats strain and of CRF on PPI depend on the inter-stimulus interval, and that there is an interaction between prepulse stimulus intensity and the inter-stimulus interval.

Regulation of relaxin 3 gene expression via cAMP‐PKA in a neuroblastoma cell line

Relaxin 3 is expressed in neurons of the brain stem that inneravate wide areas of the forebrain. Relaxin 3 mRNA levels in these neurons are increased in response to restraint stress, and by central administration of corticotropin-releasing factor (CRF). In the present study, we observed that relaxin 3 was expressed in a mouse neuroblastoma cell line, Neuro2a, and investigated the intracellular signaling that activated relaxin 3 gene transcription in vitro. By means of a clone stably transfected with a relaxin 3 promoter-EGFP gene, we observed that dibutyryl cyclic AMP and forskolin increased the relaxin 3 promoter activity. These increases were inhibited by pretreatment with PKA inhibitors, H89 and KT5720. Moreover, the promoter activity was enhanced by CRF treatment after expression of CRF-R1 receptor on the cells. Taken together, these results indicate that relaxin 3 transcription is activated via the cAMP-PKA pathway in the downstream of CRF-R1.

Central administration of corticotropin-releasing factor induces tissue specific oxidative damage in chicks

Corticotropin-releasing factor (CRF) modulates the activity of the hypothalamic–pituitary–adrenal (HPA) axis, and has a key role in mediating neuroendocrine effects which occur in response to stressful stimuli. We have recently shown that intracerebroventricular (ICV) injection of CRF in neonatal chicks increased homeothermy that was associated with enhanced gene transcripts of mitochondrial fatty acid (FA) transport and oxidation enzymes in a tissue specific manner. These observations prompted an investigation into the potential role of CRF in a state of oxidative damage in different tissues. We therefore, investigated whether CRF-induced changes in metabolism are accompanied by oxidative damage in the plasma, brain and other tissues. Neonatal chicks ( Gallus gallus) with or without ICV-CRF (42 pmol) were kept at thermoneutral temperature (30 °C). After 3 h, malondialdehyde (MDA) was measured in the plasma, brain, heart, liver and skeletal muscle (gastrocnemius). ICV-CRF significantly decreased the weight gain and feed consumption of chicks. Plasma, heart and liver revealed significantly higher MDA levels in chicks with ICV-CRF as compared to that of control chicks, but this pattern was not observed in the brain and muscle. Gene transcripts of enzymes involved in mitochondrial FA transport and oxidation, and 3-hydroxyacyl CoA dehydrogenase and citrate synthase enzyme activities in the brain were not changed by ICV-CRF. In conclusion, central administration of CRF in neonatal chicks induces tissue specific oxidative damage: higher MDA levels were observed in the heart and liver while no such change occurred in the brain and muscle.

Homeothermy in neonatal chicks exposed to low environmental temperature with or without intracerebroventricular administration of corticotropin-releasing factor

To determine the mechanism of sensitivity to low-temperature exposure (20 °C for 3 h) and corticotropin-releasing factor (CRF) induced increased homeothermy, we investigated gene transcripts of putative thermogenic proteins and mitochondrial fatty acid (FA)-oxidation enzymes in neonatal chicks. The hypothalamic–pituitary–adrenal (HPA) axis in low-temperature-exposed neonatal chicks was activated by central administration of CRF. Neonatal chicks showed hypothermia on exposure to low-temperature, with no enhancement of HPA axis and gene transcripts of avian adenine nucleotide translocator, avian uncoupling protein, avian peroxisome-proliferator-activated receptor-γ co-activator-1α, and mitochondrial FA transport and oxidation enzymes in vital organs. However, central administration of CRF activated the HPA axis under low environmental temperature and induced increased homeothermy that was associated with the enhancement of gene transcripts and activities of mitochondrial FA-oxidation enzymes in the liver and heart.

Central administration of corticotropin-releasing factor induces thermogenesis by changes in mitochondrial bioenergetics in neonatal chicks

Corticotropin-releasing factor (CRF), has multiple biological effects and plays a central regulatory role in the hypothalamic–pituitary–adrenal (HPA) axis regulating energy homeostasis that is required for adaptive responses to maintain and support life. Central administration of CRF increases O 2 consumption, CO 2 and heat production resulting in hyperthermia. To determine the precise mechanism for this condition, here we investigated transcripts of candidate genes for thermogenesis and their up-regulator (avian uncoupling protein (avUCP), avian adenine nucleotide translocator (avANT) and avian peroxisome-proliferator-activated receptor-γ co-activator-1α) and mitochondrial bioenergetics (gene transcripts for mitochondrial fatty acid (FA) transport and oxidation enzymes; carnitine-palmitoyl-transferase (CPT)-I; CPT-II, long-chain acyl CoA dehydrogenase (LCAD), 3-hydroxyacyl CoA dehydrogenase (3HADH) and citrate synthase (CS), and enzyme activities of 3HADH and CS) that might explain the bioenergetic basis of CRF-induced increased thermogenesis. Neonatal chicks ( Gallus gallus) with and without i.c.v. injection of CRF (42 pmol) were kept at thermoneutral temperature (30 °C) for 3 h. Central administration of CRF increased the core temperature and plasma NEFA level of chicks compared with the control. This CRF-induced increased thermogenesis was not accompanied by enhancement of avUCP and/or avANT gene transcripts and was associated with increased FA oxidation in tissue specific manner: increase in gene transcript levels of CPT-I, CPT-II, LCAD, 3HADH and CS, and increase in enzyme activities of 3HADH and CS were observed in liver and heart while no such changes were observed in skeletal muscle. In conclusion, these results suggest that CRF-induced increased thermogenesis in neonatal chicks was not accompanied by enhancement of gene transcripts of mitochondrial putative thermogenic proteins, and was induced by tissue specific increase in mitochondrial FA transport and β-oxidation enzymes.

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

Central administration of corticotropin-releasing factor (CRF) elicits a specific pattern of behavioral responses resembling a stress-like state and is anxiogenic in rodent models of anxiety. Specific behaviors evoked by the administration of CRF were measured. The roles of CRF receptor subtypes and that of serotonergic and noradrenergic systems in mediating these responses were studied. Burying, grooming, and head shakes were quantified in rats following intracerebroventricular administration of CRF and urocortin II and after pretreatment with antagonists. The role of forebrain norepinephrine in the behavioral responses to CRF (0.3 microg) was examined following pretreatment with the neurotoxin DSP-4 and that of serotonin after depletion using systemic administration of para-chlorophenylalanine (p-CPA). CRF at 0.3 and 3.0 microg caused robust increases in burying, grooming, and head shakes, but urocortin II was ineffective. Pretreatment with either antalarmin or propranolol significantly attenuated the CRF-evoked behaviors. Destruction of forebrain norepinephrine pathways blocked spontaneous burying behavior elicited by CRF and conditioned burying directed towards an electrified shock probe. In contrast, depletion of 5-HT selectively attenuated CRF-evoked grooming. Overt behavioral responses produced by CRF, burying, grooming, and head shakes appeared to be mediated through the CRF(1) receptor. Spontaneous burying behavior evoked by CRF or conditioned burying directed towards a shock probe was disrupted by lesion of the dorsal noradrenergic bundle and may represent anxiety-like behavior caused by CRF activation of the locus ceruleus. In contrast, CRF-evoked increases in grooming were dependent on serotonin.

Fecal pellet output does not always correlate with colonic transit in response to restraint stress and corticotropin-releasing factor in rats

Fecal pellet output has been assessed as a colonic motor activity because of its simplicity. However, it remains unclear whether an acceleration of colonic transit correlates well with an increase in fecal pellet output. We examined the causal relationship between colonic transit and fecal pellet output stimulated by the central application of corticotropin-releasing factor (CRF) and restraint stress. Immediately after intracisternal injection of CRF, (51)Cr was injected via a catheter positioned in the proximal colon. Ninety minutes after (51)Cr injection, the total number of excreted feces was counted, and then the rats were killed. The radioactivity of each colonic segment was evaluated, and the geometric center (GC) of the distribution of (51)Cr was calculated. For the restraint stress study, after administration of (51)Cr into the proximal colon, rats were submitted to wrapping restraint stress for 90 min. Then they were killed, and GC was calculated. Both restraint stress and CRF significantly accelerated colonic transit. There was a positive correlation observed between fecal pellet output and GC of colonic transit in response to restraint stress, but not CRF, when the number of excreted feces was more than three. In contrast, there was no significant correlation observed between the two in stress and CRF when the number of excreted feces was less than two. The acceleration of colonic transit in response to restraint stress and central administration of CRF does not always correlate with an increase in fecal pellet output.

Central administration of neuromedin U suppresses food intake in chicks

The appetite-suppressive action of brain-gut peptides is similar in both chickens and mammals. In mammals, the brain-gut peptide neuromedin U (NMU) suppresses food intake via hypothalamic neuropeptides, corticotropin-releasing factor (CRF), oxytocin, and arginine-vasopressin. In chickens, central administration of CRF, oxytocin, or arginine-vasotocin (AVT, a nonmammalian equivalent of arginine-vasopressin) suppresses food intake. However, the anorexigenic action of NMU in chickens has not yet been identified. In the present study, we analyzed the effects of the central administration of NMU on food intake and hypothalamic mRNA levels of CRF, AVT and mesotocin (a nonmammalian equivalent of oxytocin) in chicks. Intracerebroventricular administration of NMU in chicks significantly suppressed food intake and induced wing-flapping behavior. NMU also significantly upregulated mRNA expression of CRF and AVT, but did not influence mRNA expression of mesotocin in the hypothalamus. These results suggest that NMU functions as an appetite-suppressive peptide via CRF and AVT in the central nervous system in chicks.

Antisocial and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin-releasing factor

Social interaction phenotyping is an unexplored niche in animal modeling of epilepsy despite the sensitivity of affiliative behaviors to emotionality and stress, which are known seizure triggers. Thus, the present studies examined the social phenotype of seizure-susceptible El and nonsusceptible ddY strains both in untreated animals and following preexposure to a handling stressor. The second aim of the present studies was to evaluate the dependence of sociability in El mice on the proconvulsive, stress neuropeptide corticotropin-releasing factor (CRF) using CRF–SAP, a conjugate of CRF and the toxin saporin, which selectively reduced CRF peptide levels in the basolateral amygdala of El mice. El mice exhibited lower social investigation times than ddY counterparts, whereas central administration of CRF–SAP normalized social investigation times relative to ddY controls. Moreover, handling-induced seizures in El mice were reduced by 50% following treatment with CRF–SAP relative to saporin alone-injected El controls. The results of this study suggest that tonically activated CRF systems in the El mouse brain suppress affiliative behavior and facilitate evoked seizures.

Corticotropin‐releasing factor 1 receptor‐mediated mechanisms inhibit colonic hypersensitivity in rats

The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress-mediating hormones, such as corticotropin-releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar-Kyoto (WKY) rats with genetic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the current study we tested the hypothesis that a selective, non-peptide CRF1 receptor antagonist, antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that antalarmin (20 mg kg-1, i.p.) significantly decreased the visceromotor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F-344) rats, and in this model, antalarmin significantly inhibited the CRF-induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F-344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treatment of IBS.