Corticotropin-releasing Factor Secretion Research Articles

Corticotropin-releasing factor is involved in acute stress-induced analgesia and antipruritus.

Under the condition of stress, the hypothalamic-pituitary-adrenal axis (HPA axis) is activated and causes the secretion of corticotropin-releasing factor (CRF). Previous studies have demonstrated that CRF is involved in the regulation of pain and itch. Thus, it remains worthy to explore whether the desensitization of pain and itch under high-intensity acute stress (such as high fear and tension) is related to the sharp increase of CRF. Forced swimming was used to simulate acute stress. ELISA and pharmacological methods were conducted to observe the effects of forced swimming on acute pain or itch and the relationship between blood CRF content and itch or pain behavior. Intracerebroventricular (ICV) administration of CRF was conducted to examine the effects of CRF on acute pain or itch. Intrathecal administration of CRF receptor agonist or antagonist was conducted to examine the receptor mechanisms of the regulatory role of CRF in pain and itch. ELISA experiment showed that the serum CRF in mice reached its peak within 5-10 min after acute stress (forced swimming). Behavioral data showed that the scratching behavior induced by itch agents decreased after acute swimming, while the mechanical pain threshold increased significantly. The inhibitory effect of acute stress on pain and itch is mediated by CRF receptor2 (CRFR2). Then, ICV injection of CRF was used to simulate the massive release of CRF under acute stress, and we observed that the scratching behavior induced by histamine or chloroquine was significantly inhibited after ICV injection of CRF. The above effects of CRF are mainly mediated by CRFR2. These results suggest that 5-10min after acute stress, a large amount of CRF is released into the blood from the hypothalamus, which significantly inhibits acute pain and itch by acting on CRFR2. ICV injection of CRF can replicate the antipruritus effects of acute stress. The present study investigated the mechanism of acute stress-induced analgesia and antipruritus and provided theoretical support for the treatment of pain and itch.

Трудности и ошибки диагностики вторичного гипокортицизма у больных старческого возраста

Adrenal insufficiency is a relatively rare condition, especially among individuals older than 65 years. Therefore, the specific manifestations of primary and secondary adrenal insufficiency are understudied in elderly patients. The article elucidates new data on the senile physiological hyperplasia of the zona fasiculata of the adrenal cortex: human aging is tightly linked to an increasing secretion of glucocorticoids. A clinical case of secondary adrenal insufficiency due to empty sella syndrome (ESS) and hydrocephalus in a senile patient is described. The patient’s medical history included two key elements aggravating the adrenal insufficiency: adrenalectomy and chemotherapy with platinum derivatives which could have impact on the adrenal glands. The specific symptoms experienced by the patient and the clinical course of the disease correlated with the residual secretion of adrenocorticotropic hormone (ACTH), cerebral disorders (ESS) and the compensatory secretion of corticotropin releasing factor. The clinical presentation of adrenal insufficiency was vague and atypical. In addition, it was found that the patient had hyposecretion of anabolic androgenic steroids. In turn, it caused a muscle hypotrophy and facilitated the recurrence of pelvic organ prolapse after the earlier performed pelvic floor reconstructive surgery. In such clinical cases the treatment should be aimed at improving the state of the hypothalamic-pituitary system and increasing the production of endogenous corticotropin releasing factor, ACTH, and cortisol. Androgen replacement therapy in androgen-deficient elderly patients has not been developed. KEYWORDS: secondary adrenal insufficiency, adrenocorticotropic hormone; empty sella syndrome, glucocorticoids. FOR CITATION: Tereshchenko I.V. Difficulties and diagnostic errors in old patients with secondary adrenal insufficiency. Russian Medical Inquiry. 2022;6(9):534–537 (in Russ.). DOI: 10.32364/2587-6821-2022-6-9-534-537.

The effect of magnesium sulfate on the placental corticotropin-releasing factor (CRF) and CRF binding protein mRNA expression in perfused human placental cotyledon

Objectives: Stress stimuli and inflammation influence the secretion of the placental corticotropin-releasing factor CRF (CRF) that has a significant role in controlling the timing of birth. The CRF-binding protein (CRF-BP) binds CRF with high affinity and inhibits its activity. Magnesium sulfate (MgSO4) has been known to ameliorate maternal, fetal and gestational tissue-associated inflammatory response. We aimed to study the effect of MgSO4 on the CRF and CRF-BP mRNA expression levels in perfused human cotyledon.Methods: Placentas from elective caesarean section were obtained and selected cotyledons were cannulated and dually perfused ex-vivo within 30 min. MgSO4 (7 mg/dl) was added to the maternal reservoir. Each perfusion experiment was conducted for 180 min. At the end of the experiment, RNA was extracted from the perfused cotyledon, and RT-PCR was performed to quantify the expression of CRF and CRF-BP. Human HPRT gene served as a reference gene.Results: Perfusion with MgSO4 (n = 3) induced a significantly lower CRF and higher CRF-BP mRNA expression compared to placentas perfused only with medium (n = 3).Conclusion: In the human placenta, MgSO4 possibly exerts its action through different modulation on the CRF and CRF-BP expression.

Crowding stress inhibits serotonin 1A receptor-mediated increases in corticotropin-releasing factor mRNA expression and adrenocorticotropin hormone secretion in the Gulf toadfish

Stimulation of the serotonin 1A (5-HT1A) receptor subtype by 5-HT has been shown to result in an elevation in plasma corticosteroid levels in both mammals and several species of teleost fish, including the Gulf toadfish (Opsanus beta); however, in the case of teleost fish, it is not clearly known at which level of the hypothalamic-pituitary-interrenal axis the 5-HT1A receptor is stimulated. Additionally, previous investigations have revealed that chronic elevations of plasma cortisol mediate changes in brain 5-HT1Areceptor mRNA and protein levels via the glucocorticoid receptor (GR); thus, we hypothesized that the function of centrally activated 5-HT1A receptors is reduced or abolished as a result of chronically elevated plasma cortisol levels and that this response is GR mediated. Our results are the first to demonstrate that intravenous injection of the 5-HT1A receptor agonist, 8-OH-DPAT, stimulates a significant increase in corticotropin-releasing factor (CRF) precursor mRNA expression in the hypothalamic region and the release of adrenocorticotropic hormone (ACTH) from the pituitary of teleost fish compared to saline-injected controls. We also provide evidence that cortisol, acting via GRs, attenuates the 5-HT1A receptor-mediated secretion of both CRF and ACTH.

Nonylphenol effects on the HPA axis of the bioindicator vertebrate, Podarcis sicula lizard

Nonylphenol (NP) is an endocrine disruptor widely distributed in the environment. It accumulates in the lipids of living organisms and enters the human food chain. The main source of human exposure is expected to be food, drinking water and foodstuff contaminated through leaching from packaging or pesticide formulation applications. NP acts as an estrogenic compound and it is able to mimic the action of estradiol 17β (E2) by binding to the estrogen receptor (ER). The aim of the present study was to investigate the NP effects on the hypothalamic–pituitary–adrenal gland (HPA) axis of the bioindicator Podarcis sicula lizard. A time-dependent stimulation of the HPA axis and variations of both catecholamine plasma levels were showed. Moreover, NP effects on adrenal gland morphology were evaluated by light and transmission electron microscopy. Clear morphological signs of adrenal gland stimulation such as an increase of steroidogenic cord diameter and vascularization, a strong escalation of adrenaline cell number and a decrease of noradrenaline cells were observed. The notably elevated levels of adrenal hormones suggested a permanent turning on of hypothalamic corticotropin releasing factor (CRF) secretion together with a lack of the negative feedback of HPA axis, perturbing systemic responses of the organism. Our data may help to predict the biological alterations induced by NP and to extend its impact upon adrenal function.

Do interactions between stress and immune responses lead to symptom exacerbations in irritable bowel syndrome?

Irritable bowel syndrome (IBS) is a common, debilitating gastrointestinal (GI) disorder, with a worldwide prevalence of between 10% and 20%. This functional gut disorder is characterized by episodic exacerbations of a cluster of symptoms including abdominal pain, bloating and altered bowel habit, including diarrhea and/or constipation. Risk factors for the development of IBS include a family history of the disorder, childhood trauma and prior gastrointestinal infection. It is generally accepted that brain-gut axis dysfunction is fundamental to the development of IBS; however the underlying pathophysiological mechanisms remain elusive. Additional considerations in comprehending the chronic relapsing pattern that typifies IBS symptoms are the effects of both psychosocial and infection-related stresses. Indeed, co-morbidity with mood disorders such as depression and anxiety is common in IBS. Accumulating evidence points to a role for a maladaptive stress response in the initiation, persistence and severity of IBS-associated symptom flare-ups. Moreover, mechanistically, the stress-induced secretion of corticotropin-releasing factor (CRF) is known to mediate changes in GI function. Activation of the immune system also appears to be important in the generation of IBS symptoms and increasing evidence now implicates low-grade inflammation or immune activation in IBS pathophysiology. There is a growing body of research focused on understanding at a molecular, cellular and in vivo level, the relationship between the dysregulated stress response and immune system alterations (either individually or in combination) in the etiology of IBS and to the occurrence of symptoms.

Corticotropin-releasing factor secretion from dendritic cells stimulated by commensal bacteria

To study the production and secretion of corticotropin-releasing factor (CRF) by dendritic cells and the influence of commensal bacteria. JAWSII cells (ATCC CRL-11904), a mouse dendritic cell line, were seeded into 24-well culture plates and grown for 3 d. Commensal bacterial strains of Clostridium clostrodiiforme (JCM1291), Bacteroides vulgatus (B. vulgatus) (JCM5856), Escherichia coli (JCM1649), or Fusobacterium varium (F. varium) (ATCC8501) were added to the cells except for the control well, and incubated for 2 h. After incubation, we performed enzyme-linked immunosorbent assay for the cultured medium and reverse transcription polymerase chain reaction for the dendritic cells, and compared these values with controls. The level of CRF secretion by control dendritic cells was 40.4 ± 6.2 pg/mL. The CRF levels for cells incubated with F. varium and B. vulgatus were significantly higher than that of the control (P < 0.0001). CRF mRNA was present in the control sample without bacteria, and CRF mRNA levels in all samples treated with bacteria were above that of the control sample. F. varium caused the greatest increase in CRF mRNA expression. Our results suggest that dendritic cells produce CRF, a process augmented by commensal bacteria.

The central amygdala nucleus via corticotropin-releasing factor is necessary for time-limited consolidation processing but not storage of contextual fear memory

The central nucleus of the amygdala (CeA) is traditionally portrayed in fear conditioning as the key neural output that relays conditioned information established in the basolateral amygdala complex to extra-amygdalar brain structures that generate emotional responses. However, several recent studies have questioned this serial processing view of the amygdalar fear conditioning circuit by showing an influence of the CeA on memory consolidation. We previously reported that inhibition of endogenous CeA secretion of corticotropin-releasing factor (CRF) at the time of contextual training effectively impaired fear memory consolidation. However, the time-dependent range of CeA CRF secretion in facilitating consolidation processing has not been examined. Therefore, to address this issue, we performed CeA site-specific microinjections of CRF antisense oligonucleotides (CRF ASO) at several post-training time intervals. Rats microinjected with CRF ASO at post-training intervals up to 24-h subsequently exhibited significant impairments in contextual freezing retention in contrast to animals treated 96-h after training. To further establish the validity of the results, CeA fiber-sparing lesions were made at two distinct post-training periods (24-h and 96-h), corresponding respectively to the temporal intervals when CeA CRF ASO administration disrupted or had no significant effects on memory consolidation. Similar to the CeA CRF ASO results, CeA lesions made 24-h, but not 96-h, after training induced significant freezing deficits in the retention test. In conclusion, the current results demonstrate: (1) an extended involvement of CeA CRF in contextual memory consolidation and (2) that contextual fear memory storage is not dependent on a functional CeA.

Corticotropin-releasing factor and hypoxic-ischemic brain damage

Corticotropin-releasing factor(CRF)is one neuroendocrine peptide which is closely related with the stress.It has been proved that any stress can lead to the person and animal's blood CRF level increasing,and high-level CRF urges the hypothalamic neuron calcium ion inflow.Newborn pediatricians pay more attention to whether blood CRF level can act as one director of assessing severity of newborn hypoxic-schemic brain damage.This article reviews the CRF and it's acceptors,CRF secretion,CRF physiological action and it's adjustment,and hypoxia-ischemia stress and CRF,in order to provide the theory basis for reviewing the severity of hypoxic-schemic brain damage in neonates. Key words: Corticotropin-releasing factor(CRF); Hypoxia; Hypoxia-ischemia brain damage; Infant,newborn

Infection as a stressor: a cytokine-mediated activation of the hypothalamo-pituitary-adrenal axis?

Infections are associated with increased plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. Hypothalamo-pituitary-adrenal (HPA) responses have also been observed with immunological stimuli that are not infective. Although such responses have been suggested to be mediated by ACTH secreted by lymphocytes, adrenocortical activation by immunological stimuli requires a functional pituitary. The most likely mechanism by which immunological stimuli activate the HPA axis involves production of cytokines by lymphocytes. The prime candidate is interleukin 1 (IL-1), because IL-1 production follows activation of the immune system and IL-1 administration is a potent activator of the HPA axis. However, other cytokines, such as tumour necrosis factor, may also be involved. Most immunological stimuli and IL-1 also activate both peripheral and central noradrenergic neurons. IL-1-induced activation of the HPA axis in vivo depends upon secretion of corticotropin-releasing factor (CRF), an intact pituitary, and the ventral noradrenergic bundle which innervates the CRF-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Besides elevating body temperature, administration of IL-1 elicits a number of behavioural responses in rats and mice, including anorexia, increased sleep time, decreased investigation of novel objects and other animals, increased defensive withdrawal and other behaviours characteristic of sickness. Some of these responses can be reversed by CRF-antagonists and mimicked by CRF administration. Thus, endogenous production of IL-1 can account for a range of physiological and behavioural responses characteristic of sickness. Nevertheless, definitive evidence that IL-1 mediates these responses in sick animals is lacking.

The regulation of hypothalamic corticotropin-releasing factor release: in vitro studies.

Although there are various ways in which the regulation of hypothalamic corticotropin-releasing factor (CRF) may be investigated, the most direct is by the study of CRF secretion from rat hypothalami incubated in vitro. Using this technique, we have found stimulation of secretion by noradrenaline, acetylcholine, serotonin, neuropeptide Y, and interleukins 1 and 6; inhibitory modulation was shown by GABA, substance P, atrial natriuretic peptide, opioid peptides and precursors of nitric oxide. Studies of these interactions demonstrated certain non-linear characteristics which may allow appropriate mathematical models to be devised; this may aid in our understanding of clinical disorders associated with CRF excess.

Central and feedback regulation of hypothalamic corticotropin-releasing factor secretion.

Physical, emotional and metabolic stressors activate the hypothalamo-pituitary-adrenal (HPA) axis via multiple neural pathways. Final hypothalamic coding of stressor-induced adrenocorticotropic hormone (ACTH) secretion is mediated by differential release of ACTH secretagogues. These include, but may not be limited to, corticotropin-releasing factor (CRF), arginine vasopressin, oxytocin and, possibly, adrenaline. Among these substances, CRF serves as the predominant regulatory factor of this axis because its presence is obligatory for the action of intrinsically weaker secretagogues. Because neural input-encoding qualities of individual stressors utilize, in part, stimulus-specific pathways, the effectiveness of glucocorticoid negative feedback in modulating ongoing and subsequent activity of the HPA axis is dependent upon the type of stressor and the nature of the neural pathways mediating the initial activity. Studies suggest that responses to physical stressors (for example, haemorrhage) are resistant to classical intermediate feedback, whereas those to emotional/cognitive stressors (such as a novel environment) are strongly susceptible to feedback. Overall functional characteristics of the HPA axis in adult organisms are at least partially a result of neonatal experience. In the adult differences in hypothalamic CRF mRNA levels, median eminence peptide content and pituitary responsiveness to stressors can be correlated with aspects of neonatal experience.

Superposição entre depressão atípica, doença afetiva sazonal e síndrome da fadiga crônica

We reviewed previous studies that have described an association between abnormal functioning of the hypothalamic-pituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category. The literature data on the overlap between the key-words were reviewed, summarized and discussed. Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems. Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning common symptom clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin realising factor activity.

Insomnia: Pathophysiology and implications for treatment

Interest in developing a greater understanding of the pathophysiogical mechanisms underlying primary insomnia has increased. Recent evidence indicates that there may be some neuroendocrine and clinical similarities between primary insomnia and major depressive disorder, that abnormal corticotropin releasing factor (CRF) activity occurs in major depression, and that CRF hyperactivity appears to mediate the hyperarousal seen in primary insomnia. These findings all point to the possibility of hypothalamic-pituitary-adrenal (HPA) axis and CRF overactivity in both disorders. More recent findings have strengthened the evidence that primary insomnia may be linked with mood disorders and is associated with HPA axis overactivity and excess secretion of CRF, adrenocorticotropin releasing hormone, and cortisol. These insights have implications for managing chronic primary insomnia, such as use of antiglucocorticoid agents.

Effect of ethanol on the regulation of corticotropin-releasing factor (CRF) gene expression

Ethanol stimulates hypothalamic–pituitary–adrenal axis activity in vivo. To determine the cellular and molecular mechanisms through which ethanol regulates corticotropin-releasing factor (CRF) gene expression, we compared the effect of ethanol and forskolin on CRF peptide secretion and messenger RNA levels in hypothalamic primary cell cultures, and on CRF promoter activity in the NG108-15 cell line. CRF secretion, mRNA levels, and gene transcription significantly increased in response to ethanol or forskolin. Mutation of the cAMP-response element (CRE) reduced luciferase activity under basal conditions as well as in response to forskolin or ethanol. On the other hand, plasmid with five CRE repeats yielded dramatically elevated basal luciferase activity and significantly increased upregulation by ethanol. Inclusion of adenosine deaminase reduced the promoter response to ethanol. Finally a PKA inhibitor and a cAMP antagonist both decreased ethanol-induced CRF peptide secretion, gene expression, and transcription. These results suggest that ethanol upregulates CRF expression through cAMP/PKA-dependent pathways.

Melatonin attenuates stress‐induced defecation: lesson from a rat model of stress‐induced gut dysfunction

Melatonin is known to alleviate stress and modulate gut motility. We investigated the modulating effects of melatonin on stress-induced gut dysfunction. One hundred Wistar rats were randomly assigned to five equal groups, receiving intraperitoneal injections of 0, 1, 10, 100 or 1000 microg kg(-1) melatonin, respectively. Fifteen minutes later, each group was divided again into four subgroups receiving no treatment, 0.25 mg luzindole (a non-selective melatonin receptor antagonist) intraperitoneally, wrap-restraint stress, and 10 mg kg(-1) serotonin intraperitoneally, respectively. Two hours later, serum serotonin, corticotropin-releasing factor (CRF) and melatonin levels, and faecal output were recorded. Results showed that intraperitoneal melatonin increased faecal output, but this effect was abolished by luzindole. In wrap-restraint group, prior intraperitoneal melatonin at doses of 100 or 1000 microg kg(-1) significantly inhibited stress-induced defecation. This effect was associated with corresponding reductions in serum serotonin and CRF concentrations. In serotonin-treated group, serotonin-induced defecation was also inhibited by melatonin. In conclusion, melatonin exhibited an excitatory effect on bowel output in rats placed under resting state, while attenuated defecation in those subjected to wrap-restraint stress or serotonin treatment. The inhibitory effects of melatonin on stress-induced defecation may stem from its antagonistic effect on stress-induced enhancement of serotonin and CRF secretion.

Central Neuropeptide B Administration Activates Stress Hormone Secretion and Stimulates Feeding in Male Rats

Neuropeptide B (NPB) was identified to be an endogenous, peptide ligand for the orphan receptors GPR7 and GPR8. Because GPR7 is expressed in rat brain and, in particular, in the hypothalamus, we hypothesized that NPB might interact with neuroendocrine systems that control hormone release from the anterior pituitary gland. No significant effects of NPB were observed on the in vitro releases of prolactin, adrenocorticotropic hormone (ACTH) or growth hormone (GH) when log molar concentrations ranging from 1 pM to 100 nM NPB were incubated with dispersed anterior pituitary cells harvested from male rats. In addition NPB (100 nM) did not alter the concentration response stimulation of prolactin secretion by thyrotropin-releasing hormone, ACTH secretion by corticotropin-releasing factor (CRF) and GH secretion by GH-releasing hormone. However, NPB, when injected into the lateral cerebroventricle (i.c.v.) of conscious, unrestrained male rats, elevated prolactin and corticosterone, and lowered GH levels in circulation. The threshold dose for the effect on corticosterone and prolactin levels was 1.0 nmol, while that for the effect on GH release was 3.0 nmol NPB. Pretreatment with a polyclonal anti-CRF antiserum completely blocked the ability of NPB to stimulate ACTH release and significantly inhibited the effect of NPB on plasma corticosterone levels. NPB administration i.c.v. did not significantly alter plasma vasopressin and oxytocin levels in conscious rats. It did stimulate feeding (minimum effective dose 1.0 nmol) in sated animals in a manner similar to that of the other endogenous ligand for GPR7, neuropeptide W. We conclude that NPB can act in the brain to modulate neuroendocrine signals accessing the anterior pituitary gland, but does not itself act as a releasing or inhibiting factor in the gland, at least with regard to prolactin, ACTH and GH secretion.

Ontogeny of corticotropin-releasing factor effects on locomotion and foraging in the Western spadefoot toad ( Spea hammondii)

We investigated the effects of corticotropin-releasing factor (CRF) and corticosterone (CORT) on foraging and locomotion in Western spadefoot toad ( Spea hammondii) tadpoles and juveniles to assess the behavioral functions of these hormones throughout development. We administered intracerebroventricular injections of ovine CRF or CRF receptor antagonist αhelical CRF (9-41) to tadpoles and juveniles, and observed behavior within 1.5 h after injection. In both premetamorphic (Gosner stage 33) and prometamorphic (Gosner stages 35–37) tadpoles, CRF injections increased locomotion and decreased foraging. Injections of αhelical CRF (9-41) reduced locomotion but did not affect foraging in premetamorphic tadpoles, but dramatically increased foraging in prometamorphic tadpoles compared to both placebo and uninjected controls. Similarly, αhelical CRF (9-41) injections stimulated food intake and prey-catching behavior in juveniles. These results suggest that in later-staged amphibians, endogenous CRF secretion modulates feeding by exerting a suppressive effect on appetite. By contrast to the inhibitory effect of CRF, 3-h exposure to CORT (500 nM added to the aquarium water) stimulated foraging in prometamorphic tadpoles. These tadpoles also exhibited a CORT-mediated increase in foraging 6 h after CRF injection, which was associated with elevated whole-body CORT content and blocked by glucocorticoid receptor (GR) antagonist (RU486) injections. Thus, exogenous CRF influences locomotion and foraging in both pre- and prometamorphic tadpoles, but endogenous CRF secretion in relatively unstressed animals does not affect foraging until prometamorphic stages. Furthermore, the opposing actions of CRF and CORT on foraging suggest that they are important regulators of energy balance and food intake in amphibians throughout development.

Local γ‐aminobutyric acid and glutamate circuit control of hypophyseotrophic corticotropin‐releasing factor neuron activity in the paraventricular nucleus of the hypothalamus

Paraventricular corticotropin-releasing factor (CRF) neurons play a pivotal role in regulating neuroendocrine responses to stress. The mechanisms by which synaptic inputs control the activity of these neurons are not well understood. The present study was undertaken to determine the role of the intrinsic gamma-aminobutyric acid (GABA)- and glutamatergic neural circuits of the hypothalamic paraventricular nucleus (PVN) in the control of CRF neural activity. We show that in organotypic cultures of the PVN, blockade of the intrinsic GABAergic neurotransmission by the GABAA receptor antagonist bicuculline resulted in a significant increase in CRF secretion. The bicuculline-induced CRF secretory activity was abolished by the coadministration of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Electrical stimulation of the CRF cell division elicited glutamatergic extracellular field potentials that were dramatically enhanced by bicuculline and were suppressed by CNQX. These results show that the functional activity of CRF neurons in organotypic cultures of the PVN is under a tonic inhibitory influence of an intrinsic GABAergic circuit. Suppression of GABAergic transmission appears to have a permissive role for inducing an increased secretory activity of CRF neurons that is driven by an excitatory glutamatergic network via AMPA/kainate receptors.

Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects

BackgroundRecent studies have reported a high comorbidity between posttraumatic stress disorder (PTSD) and psychotic symptoms, and it has been hypothesized that PTSD with comorbid psychosis is a severe form of PTSD. Few studies have examined the neurobiology of PTSD with comorbid psychosis. If PTSD with secondary psychotic symptoms (PTSD-SP) is a severe form of PTSD, then it might be expected to show more extreme perturbations in the neuroendocrine patterns that characterize PTSD. MethodsPatients with PTSD with secondary psychotic symptoms (PTSD-SP), PTSD without psychosis, and healthy comparison subjects were compared for differences in cerebrospinal fluid concentrations of corticotropin-releasing factor (CRF) and somatotropin-release-inhibiting hormone (SRIF). ResultsThe PTSD-SP subjects had significantly higher mean levels of CRF than either the PTSD or control subjects (p < .01). The three groups showed similar SRIF levels. ConclusionsThese data implicate abnormalities in the secretion of CRF with the production of secondary psychotic symptoms in PTSD. This finding supports the validity of PTSD-SP as a PTSD subtype and as a severe form of PTSD.