Effects Of Corticotropin-releasing Factor Research Articles

The effects of corticotropin-releasing factor on motor learning

Corticotropin-releasing factor (CRF) is mainly secreted from the hypothalamic paraventricular nuclei and plays a crucial role in stress-related responses. Recent studies have reported that CRF is a neuromodulator in the central nervous system. In the cerebellum, CRF is essential for the induction of long-term depression (LTD) at the parallel fiber-Purkinje cell synapses. Given that LTD is thought to be one of the fundamental mechanisms of motor learning, CRF may affect motor learning. However, the role of CRF in motor learning in vivo remains unclear. In this study, we aimed to examine the role of CRF in motor learning. This was achieved through a series of behavioral experiments involving the in vivo administration of CRF and its antagonists. Rats injected with CRF directly into the cerebellum exhibited superior performance on the rotarod test, especially during initial training phases, compared to control subjects. Conversely, rats receiving a CRF receptor antagonist demonstrated reduced endurance on the rotating rod compared to controls. Notably, CRF mRNA expression levels in the cerebellum did not show significant variance between the CRF-injected and control groups. These findings imply a critical role of endogenous CRF in cerebellar motor learning and suggest that exogenous CRF can augment this process. (199 words)

Corticotropin Releasing Factor (CRF) Coexpression in GABAergic, Glutamatergic, and GABA/Glutamatergic Subpopulations in the Central Extended Amygdala and Ventral Pallidum of Young Male Primates.

The central extended amygdala (CEA) and ventral pallidum (VP) are involved in diverse motivated behaviors based on rodent models. These structures are conserved, but expanded, in higher primates, including human. Corticotropin releasing factor (CRF), a canonical "stress molecule" associated with the CEA and VP circuitry across species, is dynamically regulated by stress and drugs of abuse and misuse. CRF's effects on circuits critically depend on its colocation with primary "fast" transmitters, making this crucial for understanding circuit effects. We surveyed the distribution and colocalization of CRF-, VGluT2- (vesicular glutamate transporter 2), and VGAT- (vesicular GABA transporter) mRNA in specific subregions of the CEA and VP in young male monkeys. Although CRF-containing neurons were clustered in the lateral central bed nucleus (BSTLcn), the majority were broadly dispersed throughout other CEA subregions, and the VP. CRF/VGAT-only neurons were highest in the BSTLcn, lateral central amygdala nucleus (CeLcn), and medial central amygdala nucleus (CeM) (74%, 73%, and 85%, respectively). In contrast, lower percentages of CRF/VGAT only neurons populated the sublenticular extended amygdala (SLEAc), ventrolateral bed nucleus (BSTLP), and VP (53%, 54%, 17%, respectively), which had higher complements of CRF/VGAT/VGluT2-labeled neurons (33%, 29%, 67%, respectively). Thus, the majority of CRF-neurons at the "poles" (BSTLcn and CeLcn/CeM) of the CEA are inhibitory, while the "extended" BSTLP and SLEAc subregions, and neighboring VP, have a more complex profile with admixtures of "multiplexed" excitatory CRF neurons. CRF's colocalization with its various fast transmitters is likely circuit-specific, and relevant for understanding CRF actions on specific target sites.SIGNIFICANCE STATEMENT The central extended amygdala (CEA) and ventral pallidum (VP) regulate multiple motivated behaviors through differential downstream projections. The stress neuropeptide corticotropin releasing factor (CRF) is enriched in the CEA, and is thought to "set the gain" through modulatory effects on coexpressed primary transmitters. Using protein and transcript assays in monkey, we found that CRF neurons are broadly and diffusely distributed in CEA and VP. CRF mRNA+ neurons colocalize with VGAT (GABA) and VGluT2 (glutamate) mRNAs in different proportions depending on subregion. CRF mRNA was also coexpressed in a subpopulation of VGAT/VGluT2 mRNA ("multiplexed") cells, which were most prominent in the VP and "pallidal"-like parts of the CEA. Heterogeneous CRF and fast transmitter coexpression across CEA/VP subregions implies circuit-specific effects.

Roles of corticotropin-releasing factor signaling in the lateral habenula in anxiety-like and alcohol drinking behaviors in male rats

Corticotropin-releasing factor (CRF) signaling in the mesocorticolimbic system is known to modulate anxiety-like behavior and alcohol consumption, behaviors that also have been associated with the hyper-glutamatergic state of the lateral habenula (LHb) neurons in rats. However, the role of CRF signaling in the LHb on the glutamate transmission, anxiety-like behaviors and alcohol consumption is unknown. Here, we used male rats that had been consuming alcohol for three months to address this gap in the literature. First, using electrophysiological techniques, we evaluated CRF's effects on the glutamate transmission in LHb neurons in brain slices. CRF facilitated glutamate transmission. The facilitation was greater in neurons of alcohol-withdrawing rats than in those of naïve rats. The facilitation was mimicked by the activation of CRF receptor 1 (CRF1R) but attenuated by the activation of CRF receptor 2 (CRF2R). This facilitation was mediated by upregulating CRF1R-protein kinase A signaling. Conversely, protein kinase C blockade attenuated CRF's facilitation in neurons of naïve rats but promoted it in neurons of alcohol-withdrawing rats. Next, using site-direct pharmacology, we evaluated the role of CRF signaling in the LHb on anxiety-like behaviors and alcohol consumption. Intra-LHb inhibition of CRF1R or activation of CRF2R ameliorated the anxiety-like behaviors in alcohol-withdrawing rats and reduced their alcohol intake when drinking was resumed. These observations provide the first direct behavioral pharmacological and cellular evidence that CRF signaling in the LHb modulates glutamate transmission, anxiety-like behaviors and alcohol consumption, and that adaptation occurs in CRF signaling in the LHb after chronic alcohol consumption.

Участие гормонов гипоталамо-гипофизарно-адренокортикальной системы крыс в гастропротекции при сенситизации и десенситизации капсаицин-чувствительных афферентных нейронов

The aim of this work was to study: a) the contribution of glucocorticoids to gastroprotection induced by sensitization of capsaicin-sensitive afferent neurons (CSN), b) gastroprotective effect of corticotropin-releasing factor (CRF) in rats with desensitization of CSN and possible corticosterone participation in this effect. The study was performed in male Sprague Dawley rats weighing 260-300 g. The immobilization at 10° C (3 h) or indomethacin (35 mg/kg) were used as ulcerogenic stimuli. Sensitization of CSN was induced by administration of capsaicin at the doses of 1 and 10 mg/kg, 1h before the onset of ulcerogenic stimulus. Desensitization was performed by administration of capsaicin in a total dose of 100 mg/kg (20+30+50) in 3 subsequent days, 2 weeks before the start of the experiment. CRF was injected at the dose of 2.5 mg/kg, i. p., 30 minutes before indomethacin in rats with CSN desensitization. To estimate the involvement of corticosterone in the gastroprotective effects, metyrapone (inhibitor of glucocorticoid synthesis) at the dose of 30 mg/kg was used. Capsaicin, administered at doses of 1 and 10 mg/kg, caused a gastroprotective effect in both ulcerogenic models. The metyrapone administration 30 minutes before capsaicin eliminated its gastroprotective effect for the 1 mg/kg dose, but not 10 mg/kg dose. The CRF administration caused a gastroprotective effect in both control rats, and rats with CSN desensitization. The results obtained in experiments with metyrapone indicate that CRF gastroprotective effect observed in rats with desensitization of CSN are at least partially mediated by corticosterone.

Imepitoin Shows Benzodiazepine-Like Effects in Models of Anxiety.

Imepitoin is a low affinity partial agonist for the benzodiazepine binding site of γ-aminobutyric acid (GABAA) receptors, and is currently used as an antiepileptic in dogs. Here we tested imepitoin for anxiolytic properties. In an in vitro model, imepitoin was capable of preventing the effect of corticotrophin releasing factor (CRF) on locus coeruleus neurons without suppressing the basal activity of these cells, an activity which is suggestive for an anti-stress effect of imepitoin. In addition, we applied a battery of standard rodent preclinical tests for anxiety behavior including elevated plus mazes in mice and rats, light-dark-box in mice and rats, social interaction test in rats, or the Vogel conflict test in rats. In all models, the observed profile of imepitoin appeared similar to benzodiazepines and typical for anxiolytic drugs. We also observed anxiolytic activity in dogs in a provoked open field sound-induced fear model, where reactions to noises were elicited by a sound recording of thunderstorms. Imepitoin caused an increase in locomotion measured in distance traveled and an ameliorating effect on cortisol levels in response to thunderstorm noises. For comparison, dexmedetomidine caused a decrease in locomotion and had no effect on cortisol. In all animal models the doses needed for an anxiolytic effect were not associated with sedation. In rodents, there was at least a factor of 10 between anxiolytic doses and doses with mild signs of sedation. In summary, imepitoin showed similar anxiolytic activities as benzodiazepines but without producing the known adverse reactions of benzodiazepines such as sedation.

ANTIDEPRESSANT ACTIVITY OF THYMOQUINONE POSSIBLY THROUGH INVOLVEMENT OF CORTICOTROPIN RELEASING FACTOR

Objective: Present study aimed to evaluate the antidepressant-like activity of thymoquinone (TQ) in unstressed and stressed condition and to explore the possible underlying mechanism for this activity.Methods: TQ (5, 10, and 20 mg/kg) and fluoxetine per se were administered to the unstressed and stressed mice; immobility periods were observed using forced swim test (FST) and tail suspension test (TST). Effect of corticotropin-releasing factor (CRF)-1 antagonist on antidepressant-like activity was also evaluated. The mechanism of action was also explored by measuring plasma corticosterone levels.Results: TQ (20 mg/kg) and fluoxetine per se significantly decreased immobility periods in stressed mice indicating significant antidepressant-like activity under stress. There was no significant effect on locomotor activity of the mice on treatment with TQ and fluoxetine per se. It significantly decreased plasma corticosterone level. Antalarmin (a CRF-1 receptor antagonist) significantly attenuated TQ induced the antidepressant-like effect in both FST and TST.Conclusion: TQ significantly produced antidepressant-like activity in mice possi‑bly through inhibiting CRF activity and decreasing plasma corticosterone levels.

CRF modulates glutamate transmission in the central amygdala of naïve and ethanol-dependent rats

Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) is hypothesized to drive the development of alcohol dependence, as it regulates ethanol intake and several anxiogenic behaviors linked to withdrawal. Excitatory glutamatergic neurotransmission contributes to alcohol reinforcement, tolerance and dependence. Therefore, in this study we used in vitro slice electrophysiology to investigate the effects of CRF and its receptor subtype (CRF1 and CRF2) antagonists on both evoked and spontaneous action potential-independent glutamatergic transmission in the CeA of naive and ethanol-dependent Sprague-Dawley rats. We found that CRF (25–200 nM) concentration-dependently diminished evoked compound excitatory postsynaptic potentials (EPSPs), but increased miniature excitatory postsynaptic current (mEPSC) frequencies similarly in CeA neurons of both naïve and ethanol-dependent rats, indicating reduced evoked glutamatergic responses and enhanced vesicular glutamate release, respectively. This CRF-induced vesicular glutamate release was prevented by the CRF1/2 antagonist (Astressin B) and the CRF1 antagonist (R121919), but not by the CRF2 antagonist (Astressin 2B). Similarly, CRF's effects on evoked glutamatergic responses were completely blocked by CRF1 antagonism, but only slightly decreased in the presence of the CRF2 antagonist. Moreover, CRF1 antagonism reveals a tonic facilitation of vesicular glutamate, whereas the CRF2 antagonism revealed a tonic inhibition of vesicular glutamate release. Collectively our data show that CRF primarily acts at presynaptic CRF1 to produce opposite effects on CeA evoked and spontaneous glutamate release and that the CRF system modulates CeA glutamatergic synapses throughout the development of alcohol dependence.

CRF1 but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine

RationaleGiven the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment. ObjectivesWe evaluated the anxiolytic effects of corticotropin releasing factor (CRF)1 receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI). MethodsIn guinea pig pups, the CRF1 receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC. ResultsCRF1 but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF1 receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice. ConclusionsCurrent results indicate robust anxiolytic properties of CRF1 receptor antagonists in guinea pigs and mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF1 receptor antagonists with SSRIs following chronic drug administration.

PT632. Alteration of the effects of corticotropin-releasing factor on synaptic transmission in the dorsolateral bed nucleus of the stria terminalis of chronic pain model rats

PT632. Alteration of the effects of corticotropin-releasing factor on synaptic transmission in the dorsolateral bed nucleus of the stria terminalis of chronic pain model rats

Effects of Corticotropin-Releasing Factor (CRF) on Somatic Pain Sensitivity in Conscious Rats: Involvement of Types 1 and 2 CRF Receptors

Corticotropin-releasing factor (CRF) is involved in the regulation of pain sensitivity and can cause an analgesic effect in animals and humans. The aim of the study was to investigate the involvement of CRF1 and CRF2 receptors in CRF-induced analgesic effect (after intraperitoneal injection) on somatic pain sensitivity in conscious rats. Somatic pain sensitivity was tested by tail flick latency (tail flick test). The involvement of CRF1 and CRF2 receptors was studied by their selective antagonists NBI 27914 and astressin 2B, respectively. Systemic administration of CRF caused an increase in tail flick latency (analgesic effect). Pretreatment with NBI 27914 or astressin 2B eliminated CRF-induced analgesic effect. Besides, NBI 27914, but not astressin 2B, increased basal tail flick latency. The data obtained indicate that the analgesic effect can be mediated by both CRF1 and CRF2 receptors. CRF-1 receptor, in contrast to the CRF2 receptors, may be involved in the regulation of the basal level of pain sensitivity.

Corticotropin-releasing factor augments LPS-induced immune/inflammatory responses in JAWSII cells.

The effect of corticotropin-releasing factor (CRF) on gastrointestinal tract inflammation via modulation of the immune system cells such as dendritic cells (DCs) is not known. We investigated the expression of CRF and its receptors CRFR1 and CRFR2 in a colonic DC model (JAWSII cells) in a pro-inflammatory and anti-inflammatory milieu. The mRNA expression of CRF and protein expression of CRFR1 and CRFR2 was assessed, and lipopolysaccharide (LPS) was used to induce the maturation of JAWSII cells. JAWSII cells were divided into four groups: control, CRF, LPS, and LPS + CRF. The levels of secreted cytokines IL-6, IL-4, TNF-α, and MIP-1α were determined, both in JAWSII cells and in the culture supernatant, by qRT-PCR and ELISA. The expression of CRFR1 and CRFR2 in JAWSII cells was accompanied by a low CRF expression. Compared with control group, CRF group did not affect the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and MIP-1α, but LPS treatment significantly increased the expression of these cytokines, indicating maturation of JAWSII cells. CRF further augmented the production of IL-6, TNF-α, and MIP-1α in mature JAWSII cells, with no increase in TNF-α mRNA expression. However, the expression of anti-inflammatory factor IL-4 did not change after LPS treatment. CRF treatment decreased the expression of IL-4 in both mature and immature JAWSII cells. JAWSII cells produce low level of CRF and express CRFR1 and CRFR2 surface receptors. CRF promotes immune/inflammatory responses in mature JAWSII cells when induced by LPS treatment.

Corticotropin-releasing Factor Changes the Phenotype and Function of Dendritic Cells in Mouse Mesenteric Lymph Nodes.

Background/AimsDendritic cells (DCs) are a significant contributor to the pathology of numerous chronic inflammatory autoimmune disorders; however, the effects of Corticotropin-releasing factor (CRF) on intestinal DCs are poorly understood. In this study, we investigated the role of CRF in alterations of intestinal dendritic cell phenotype and function.MethodsMouse mesenteric lymph node dendritic cells (MLNDCs) were obtained using magnetic bead sorting. Surface expression of CRF receptor type 1 (CRF-R1) and CRF-R2 was determined by double-labeling immunofluorescence and quantitative polymerase chain reaction (qPCR) and MLNDCs were subsequently exposed to CRF in the presence or absence of CRF-R1 and CRF-R2 antagonists. Expression of surface molecules (MHC-I and MHC-II) and co-stimulatory molecules (CD80 and CD86) was determined by flow cytometric and western blot analyses, and the T cell stimulatory capacity of MLNDCs was evaluated by mixed lymphocyte reaction.ResultsImmunofluorescent staining and quatitative polymerase chain reaction indicated that both the CRF receptors (CRF-R1 and CRF-2) are expressed on the surface of MLNDCs. Exposure to CRF increased the expression of MHC-II on MLNDCs as well as their capacity to stimulate T cell proliferation. MLNDCs treated with CRF-R1 antagonist exhibited a phenotype characterized by a less activated state and reduced surface expression of MHC-II, and consequently showed reduced capacity to stimulate T cells. In contrast, treatment of MLNDCs with CRF-R2 antagonist yielded an opposite result.ConclusionsCRF can alter the phenotype and function of intestinal DCs through direct action on CRF-R1 and CRF-R2, and activation of the CRF-R1 and CRF-R2 pathways yields opposing outcomes.

Effects of corticotropin releasing factor (CRF) on sleep and temperature following predictable controllable and uncontrollable stress in mice.

Corticotropin releasing factor (CRF) is a major mediator of central nervous system responses to stressors, including alterations in wakefulness and sleep. However, its role in mediating stress-induced alterations in sleep has not been fully delineated. In this study, we assessed the role of CRF and the non-specific CRF antagonist, astressin (AST), in regulating changes in sleep produced by signaled, escapable shock (SES) and signaled inescapable shock (SIS), two stressors that can increase or decrease sleep, respectively. Male BALB/cJ mice were surgically implanted with transmitters (DataSciences ETA10-F20) for recording EEG, activity and core body temperature by telemetry and a cannula for intracerebroventricular (ICV) microinjections. After baseline (Base) sleep recording, mice were presented tones (90 dB, 2 kHz) that started 5.0 s prior to and co-terminated with footshock (0.5 mA; 5.0 s maximum duration). SES mice (n = 9) always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. Yoked SIS mice (n = 9) were treated identically, but could not alter shock duration. Training with SES or SIS was conducted over 2 days to stabilize responses. Afterwards, the mice received saline, CRF [0.4 μg (0.42 mM) or AST (1.0 μg (1.4 mM)] prior to SES or SIS. Sleep was analyzed over 20 h post-stress recordings. After administration of saline, REM was significantly greater in SES mice than in SIS mice whereas after CRF or AST, REM was similar in both groups. Total 20 h NREM did not vary across condition or group. However, after administration of saline and CRF, NREM episode duration was significantly decreased, and NREM episode number significantly increased, in SIS mice compared to SES animals. SES and SIS mice showed similar stress induced hyperthermia (SIH) across all conditions. These data demonstrate that CRF can mediate stress-induced changes in sleep independently of SIH, an index of hypothalamic-pituitary-adrenal axis activation.

Age-related alterations in the acute central effects of corticotropin-releasing factor (CRF) on energy balance

Age-related alterations in the acute central effects of corticotropin-releasing factor (CRF) on energy balance

Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity.

Overeating beyond individuals' homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood. The present study examined whether a pharmacological stressor, yohimbine, enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor (CRF) receptor blockade by a CRF1-selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed. Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20min prior to yohimbine challenge. The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration. Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity.

Lack of Fpr2/Fpr3 receptors alters the structure and function of pituitary corticotrophs

Lack of Fpr2/Fpr3 receptors alters the structure and function of pituitary corticotrophs

The Analgesic Effect of Corticotropin-Releasing Factor Given into the Periaqueductal Gray Matter of the Midbrain

Corticotropin-releasing factor (CRF) is involved in regulating stress-induced analgesia. One of the key structures of the brain's antinociceptive system is the periaqueductal gray matter of the midbrain (PAGM). The aim of the present work was to study the effects of CRF given into the PAGM on pain sensitivity in conscious rats and the contribution of opioid mechanisms to mediating these effects. Somatic pain sensitivity was tested in terms of the latent period of the tail flick reaction in rats in response to thermal stimulation of the tail. The contribution of opioid mechanisms was studied by blockade of opioid receptors with the antagonist naltrexone, given both systemically and centrally into the PAGM. Administration of CRF (0.7 μg/rat into the PAGM induced an analgesic effect. Both systemic and central administration of naltrexone led to elimination of the analgesic effect of CRF, more quickly after central administration. The data obtained here provide evidence that one of the central mechanisms of the analgesic action of CRF on somatic pain sensitivity may be mediated by PAGM neurons with the involvement of opioid mechanisms.

Age-related disparate shifts in the central anorexic and hypermetabolic effects of corticotropin releasing factor (Crf)

Age-related disparate shifts in the central anorexic and hypermetabolic effects of corticotropin releasing factor (Crf)

Effect of corticotropin-releasing factor on expression of tight junction proteins in intestinal epithelial cells

Effect of corticotropin-releasing factor on expression of tight junction proteins in intestinal epithelial cells

Effects of corticotropin-releasing factor on intermediolateral cell column neurons of newborn rats

Corticotropin-releasing factor (CRF) is a neuropeptide that mediates neuroendocrine, autonomic, and behavioral processes associated with the stress response. CRF-containing fibers and receptors are found in various regions of the central nervous system including the spinal cord. Here, we report excitatory effects of CRF on sympathetic preganglionic neurons in the intermediolateral cell column (IML) of in vitro spinal cord preparations from newborn rats. We also examine the receptor subtypes that are involved in the CRF effects. Application of CRF significantly depolarized the IML neurons and increased the frequency of excitatory postsynaptic potentials (EPSPs) in the IML neurons. These effects were blocked by the CRF receptor 1 antagonist, antalarmin. Menthol, a transient receptor potential channel M8 agonist, depressed EPSPs enhanced by CRF. Our findings suggested that CRF depolarized the IML neurons via direct postsynaptic action and CRF-affected interneurons located in the spinal cord send EPSPs to IML neurons. These excitatory effects of CRF may be caused through CRF1 receptors but not CRF2 receptors.