Corticotropin-releasing Factor Neuronal Systems Research Articles

The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies.

The unique distribution of corticotropin-releasing factor (CRF) and its receptors within the central nervous system, its pre-eminent role in mediating the endocrine, behavioural, autonomic and immunological effects of stress and its potent effects after direct administration into the CNS all support the hypothesis that alterations in CRF neuronal systems contribute to the pathophysiology of depression and certain anxiety disorders. This report summarizes a series of preclinical and clinical investigations which have sought to test the hypothesis that CRF-containing neurons show alterations in depression and anxiety, and that drugs used to treat these disorders alter CRF neuronal circuits. Direct injection of CRF into the locus ceruleus or nearby parabrachial nucleus evokes an anxiogenic response. Stress increases CRF concentrations in the locus ceruleus, whereas alprazolam, a benzodiazepine anxiolytic, decreases the concentration of the peptide in the same area. Clinical studies reveal that drug-free depressed patients show: (1) hyperactivity of the hypothalamo-pituitary-adrenal axis; (2) increased CRF concentrations in the cerebrospinal fluid; (3) a blunted release of ACTH in response to CRF; (4) a reduced density of CRF receptors in the frontal cortex; (5) pituitary and adrenal gland hypertrophy. These findings are all concordant with hypersecretion of CRF from hypothalamic and extrahypothalamic CRF neurons in depression.

The CRF 1 receptor antagonist, R121919, attenuates the severity of precipitated morphine withdrawal

Corticotropin-releasing factor (CRF) regulates the hypothalamic–pituitary–adrenal axis, coordinates the mammalian stress response, and acting primarily via the CRF 1 receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, the behavioral and autonomic activation that occurs following withdrawal in drug dependent animals resembles the mammalian stress response. Concordant with this view is evidence of enhanced CRF transcription, release and activity following withdrawal from several drugs of abuse. Conversely, CRF receptor antagonists have been demonstrated to reduce the severity of many drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed during withdrawal. To extend these findings, we investigated whether pretreatment with a selective CRF 1 receptor antagonist, R121919, is capable of similarly decreasing the autonomic, behavioral and neuroendocrine activation observed following precipitation of morphine withdrawal in dependent rats. The results indicate that pretreatment with R121919 attenuates the global severity of the precipitated morphine withdrawal syndrome as measured by the Gellert–Holtzman scale. In addition, rats pretreated with R121919 prior to precipitation of morphine withdrawal demonstrated decreased hypothalamic–pituitary–adrenal axis activation, as measured by plasma ACTH concentrations, and decreased early expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA. These findings suggest that activation of CRF neuronal systems via the CRF 1 receptor may be one element of the neurobiological mechanisms activated during drug withdrawal and that CRF 1 receptor antagonists may have a potential therapeutic role in the treatment of human drug withdrawal syndromes.

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.

The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal

Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF(1) receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation. To extend these findings, we investigated whether pretreatment with the selective CRF(1) receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats. Pretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam. These results indicate that the activation of CRF neuronal systems may be a common neurobiological mechanism in withdrawal from drugs of abuse and moreover, that the CRF(1) receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF(1) receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes.

Spontaneous Withdrawal from the Triazolobenzodiazepine Alprazolam Increases Cortical Corticotropin-Releasing Factor mRNA Expression

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg x kg(-1) x d(-1)), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.

Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse

Background Previous studies indicate that adverse childhood events are associated with persistent changes in corticotropin-releasing factor neuronal systems. Our aim was to determine whether altered glucocorticoid feedback mediates the neuroendocrine sequelae of childhood trauma. Methods Standard and low-dose dexamethasone suppression tests (DST) were performed in women with a history of child abuse ( n = 19), child abuse and major depression ( n = 16), major depression and no childhood trauma ( n = 10), and no history of mental illness or childhood trauma ( n = 19). Secondary analysis with posttraumatic stress disorder (PTSD) as the organizing diagnosis was also conducted. Results In the low-dose DST, depressed women with a history of abuse exhibited greater cortisol suppression than any comparator group and greater corticotropin suppression than healthy volunteers or nondepressed abuse survivors. There were no differences between nondepressed abuse survivors and healthy volunteers in the low-dose DST or between any subject groups in the standard DST. The PTSD analysis produced similar results. Conclusions Cortisol supersuppression is evident in psychiatrically ill trauma survivors, but not in nondepressed abuse survivors, indicating that enhanced glucocorticoid feedback is not an invariable consequence of childhood trauma but is more related to the resultant psychiatric illness in traumatized individuals.

The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems.

Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the endocrine, autonomic, and behavioral responses to stress. Dysregulation of both hypothalamic and extrahypothalamic CRF systems have been reported in patients with major depression and post-traumatic stress disorder. Moreover, effective treatment of these conditions leads to normalization of these CRF systems. Although there is virtually no data concerning alterations of CRF systems in bipolar disorder (manic depressive illness), previous work indicates that valproic acid, an anticonvulsant also effective in the treatment of acute mania, alters central CRF neuronal systems. In the current studies, we chronically administered valproic acid and lithium, two clinically effective mood stabilizers, in nonstressed rats to extend our previous findings. Chronic valproic acid administration decreased CRF mRNA expression in the paraventricular nucleus of the hypothalamus; lithium administration increased CRF mRNA expression in the central nucleus of the amygdala. Although valproic acid increased CRF(1) receptor mRNA expression in the cortex, CRF(1) receptor binding was decreased in both the basolateral amygdala and cortex, suggesting that chronic valproate treatment may in fact dampen the overall tone in this central stress pathway. Valproate treatment decreased CRF(2A) mRNA expression in both the lateral septum and hypothalamus, although CRF(2A) receptor binding was unchanged. Lithium administration decreased CRF(1) mRNA expression in both the amygdala and frontal cortex, but CRF(1) receptor binding also remained unchanged. These results suggest that the therapeutic actions of these mood stabilizers may, in part, result from their actions on central CRF neuronal systems. The distinct actions of each drug on CRF systems may underlie their synergistic clinical effects.

Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment.

In a series of experiments, we tested the hypothesis that chronic antidepressant drug administration reduces the synaptic availability of corticotropin-releasing factor (CRF) through one or more effects on CRF gene expression or peptide synthesis. We also determined whether effects of acute or chronic stress on CRF gene expression or peptide concentration are influenced by antidepressant drug treatment. Four-week treatment with venlafaxine, a dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor, and tranylcypromine, a monoamine oxidase inhibitor, resulted in an attenuation of acute stress-induced increases in CRF heteronuclear RNA (hnRNA) synthesis in the paraventricular nucleus (PVN). Trends toward the same effect were observed after treatment with the 5-HT reuptake inhibitor fluoxetine, or the NE reuptake inhibitor reboxetine. CRF mRNA accumulation in the PVN during exposure to chronic variable stress was attenuated by concurrent antidepressant administration. Basal CRF hnRNA and mRNA expression were not affected by antidepressant treatment in the PVN or in other brain regions examined. Chronic stress reduced CRF concentrations in the median eminence, but there were no consistent effects of antidepressant drug treatment on CRF, serum corticotropin, or corticosterone concentrations. CRF receptor expression and basal and stress-stimulated HPA axis activity were unchanged after antidepressant administration. These results suggest that chronic antidepressant administration diminishes the sensitivity of CRF neurons to stress rather than alters their basal activity. Additional studies are required to elucidate the functional consequences and mechanisms of this interaction.

The role of corticotropin-releasing factor in depression and anxiety disorders.

Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears to mediate not only the endocrine but also the autonomic and behavioral responses to stress. Stress, in particular early-life stress such as childhood abuse and neglect, has been associated with a higher prevalence rate of affective and anxiety disorders in adulthood. In the present review, we describe the evidence suggesting that CRF is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression, resulting in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid (CSF) concentrations of CRF. This increase in CRF neuronal activity is also believed to mediate certain of the behavioral symptoms of depression involving sleep and appetite disturbances, reduced libido, and psychomotor changes. The hyperactivity of CRF neuronal systems appears to be a state marker for depression because HPA axis hyperactivity normalizes following successful antidepressant treatment. Similar biochemical and behavioral findings have been observed in adult rats and monkeys that have been subjected to early-life stress. In contrast, clinical studies have not revealed any consistent changes in CSF CRF concentrations in patients with anxiety disorders; however, preclinical findings strongly implicate a role for CRF in the pathophysiology of certain anxiety disorders, probably through its effects on central noradrenergic systems. The findings reviewed here support the hypothesis that CRF receptor antagonists may represent a novel class of antidepressants and/or anxiolytics.

Effects of generalized convulsive seizures on corticotropin-releasing factor neuronal systems

Most stressors generate a set of endocrine and neural adaptations that form a stress response. The corticotropin-releasing factor neurons of the paraventricular nucleus of hypothalamus integrate endocrine and neural inputs, and cause a cascade of events with resultant increased levels of pituitary adrenocorticotropic hormone and adrenal hormones. Although activation of the hypothalamic-pituitary-adrenal axis is associated with a large variety of stressors, the effects of seizures on hypothalamic corticotropin-releasing factor neurons are essentially unknown. The goal of the present study was to elucidate the effects of generalized convulsive seizures on distinct and separate corticotropin-releasing factor cell populations in brain. Seizure-activated neurons were identified immunocytochemically through their expression of the Fos protein. Seizures were induced by intraperitoneal injection of kainic acid. In the paraventricular nucleus, the vast majority of corticotropin-releasing factor-like parvocellular neurons also expressed Fos-like protein following seizure elicitation. This response was specific to corticotropin-releasing factor neurons of the paraventricular nucleus, as corticotropin-releasing factor neurons in central nucleus of the amygdala or bed nucleus of the stria terminalis did not simultaneously localize Fos following seizures.

Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation.

There is considerable evidence that CRF-containing neurons integrate the endocrine, autonomic, immune, and behavioral responses to stress. In this study we examined long term effects of early stress on developing hypothalamic and extrahypothalamic CRF neural systems in the rat brain and subsequent responses to stress in the adult. Specifically, we sought to determine whether adult male rats previously isolated for 6 h daily during postnatal days 2-20 react in a biochemically distinct manner to a mild foot shock stress compared to controls. Four treatment groups were examined: nondeprived (NDEP)/no shock, NDEP/shock, deprived (DEP)/no shock, and DEP/shock. Compared to the NDEP group, DEP rats exhibited an increase in both basal and stress-induced ACTH concentrations. Moreover, DEP rats exhibited a 125% increase in immunoreactive CRF concentrations in the median eminence and a reduction in the density of CRF receptor binding in the anterior pituitary compared to those in all NDEP rats. Alterations in extrahypothalamic CRF systems were also apparent in DEP vs. NDEP animals, with an observed 59% increase in the number of CRF receptor-binding sites in the raphe nucleus and an 86% increase in immunoreactive CRF concentrations in the parabrachial nucleus. These results indicate that maternal deprivation before weaning in male rats produces effects on CRF neural systems in both the central nervous system and pituitary that are apparent several months later and are probably associated with persistent alterations in behavioral response in adult rats.

Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation

Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation

Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders.

There is increasing evidence for an important role of adverse early experience on the development of major psychiatric disorders in adulthood. Corticotropin-releasing factor (CRF), an endogenous neuropeptide, is the primary physiological regulator of the mammalian stress response. Grown nonhuman primates who were exposed as infants to adverse early rearing conditions were studied to determine if long-term alterations of CRF neuronal systems had occurred following the early stressor. In comparison to monkeys reared by mothers foraging under predictable conditions, infant monkeys raised by mothers foraging under unpredictable conditions exhibited persistently elevated cerebrospinal fluid (CSF) concentrations of CRF. Because hyperactivity of CRF-releasing neurons has been implicated in the pathophysiology of certain human affective and anxiety disorders, the present finding provides a potential neurobiological mechanism by which early-life stressors may contribute to adult psychopathology.

Neuropharmacological and Clinical Aspects of Alcohol Withdrawal

Abnormalities in the function or activity of several neurotransmitter systems have been demonstrated after acute and chronic, exposure to alcohol, and in alcohol withdrawal. The changes can be divided into alterations in function of inhibitory and excitatory systems. Inhibitory dysfunction is indicated by reduced gamma-aminobutyric acid and alpha-2-adrenoceptor activity. In conjunction with, and exacerbating this, is increased activity of excitatory systems, perhaps the most significant of which is the probable potentiation of N-methyl-D-aspartate activity by depletion of magnesium. There is additional, and possibly secondary, overactivity of catecholamine and corticotropin releasing factor neuronal systems. Other, less specific changes include increased numbers of calcium channels, which would increase neuronal excitability. The evidence for these changes is presented, and the implications for new treatment regimes for alcohol withdrawal are discussed.