Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to a genetic contribution to the vulnerability for mood and anxiety disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), a preeminent role of early adverse life events in the pathogenesis of these disorders has been postulated. Corticotropin releasing factor (CRF), which has been conclusively documented to be the major regulator of the mammalian stress response, may be the seminal neurobiological substrate mediating the effects of early life stress on subsequent psychopathology. Central administration of CRF produces many of the physiological and behavioral effects of stress and of anxiety and depression. Clinical studies have provided evidence for increased activation of CRF neuronal systems in both MDD and PTSD. Similar hyperactivity of CRF neurons and sensitization of the pituitary-adrenal stress response has been observed in adult animals exposed to stress early in life. We propose that early adverse life events might render the human individual vulnerable to the effects of stress later in life, resulting in an increased risk for developing psychopathology via long-lived alterations in CRF-containing neural circuits. Based on these findings, new therapies including early intervention can now be developed to treat individuals exposed to severe stress early in life.
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PMID:Persistent changes in corticotropin-releasing factor systems due to early life stress: relationship to the pathophysiology of major depression and post-traumatic stress disorder. 923 Jun 30

Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for understanding brain systems that are important for anxiety, it is equally clear that a richer animal model of human anxiety disorders would include measures of both stimulus-specific fear and something less stimulus specific, more akin to anxiety. Studies in patients with posttraumatic stress syndrome indicate these individuals seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones, touch) activates the central nucleus of the amygdala, which in turn activates hypothalamic and brain stem target areas involved in specific signs of fear. Somewhat less explicit information, such as that produced by exposure to a threating environment for several minutes or by intraventricular administration of the peptide corticotropin-releasing hormone may activate a brain area closely related to the amygdala, called the bed nucleus of the stria terminalis, which in turn activates hypothalamic and brain stem target areas involved in specific signs of fear or anxiety. Because the nature of this information may be less specific than that produced by an explicit cue, and of much longer duration, activation of the bed nucleus of the stria terminalis may be more akin to anxiety than to fear.
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PMID:Are different parts of the extended amygdala involved in fear versus anxiety? 986 67

To assess cell-mediated immunity in depression and anxiety disorders and to elucidate whether immunodysfunction might be related to a high opioid activity, a prospective study of patients with major depression (n = 34) or anxiety disorders (n = 21) was performed. Cellular immunity tests, the in vitro effects of naloxone on monocytes, and beta-endorphin plasma levels were investigated. Peripheral blood mononuclear cells and some monocyte parameters were determined by flow cytometry. Natural killer (NK) cell activity was studied by cytotoxicity, gamma-interferon production by a standard bioassay, monocytic phagocytosis by ingestion of Candida albicans and latex, and blastogenesis by stimulation with phytohaemaglutinin. In major depression and anxiety: 1) a marked reduction in the number of monocytes that ingested particles and expressed cytoskeletal intermediate filaments and surface structures (CR1 receptors and HLA-DR antigens); 2) a monocytosis that was not able to normalize the count of functioning monocytes; 3) an in vitro correction of the monocyte dysfunction by naloxone; 4) a decrease in NK cell number and activity; and 6) an anergy to candidin and tuberculin and a diminished lectin-induced blastogenesis were observed. Some of these immune changes correlated closely with plasma beta-endorphin abnormally high in all the cases. In conclusion, a naloxone-reversible monocyte dysfunction, associated to decreased NK activity and cell-mediated hypersensitivity, was found together with high of beta-endorphin plasma levels. In addition, results suggest that these immunological alterations may be useful in the clinical management of patients with these psychiatric diseases.
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PMID:Opioid peptides and immunodysfunction in patients with major depression and anxiety disorders. 1022 12

Although there is a close correspondence between fear and anxiety, and the study of fear in animals has been extremely valuable for understanding the neural basis of anxiety, it is also clear that a richer animal model of human anxiety disorders would include measures of both stimulus-specific fear and something less stimulus specific, more akin to anxiety. Patients with posttraumatic stress syndrome seem to show normal fear reactions but abnormal anxiety measured with the acoustic startle reflex. Studies in rats, also using the startle reflex, indicate that highly processed explicit cue information (lights, tones) activates the central nucleus of the amygdala, which projects to and modulates the acoustic startle pathway in the brain stem. Less explicit information, such as that produced by exposure to a threatening environment or by intraventricular administration of corticotropin-releasing hormone, may activate another part of the extended amygdala, the bed nucleus of the stria terminalis, which also projects to the startle pathway. Because this information may be less specific and of long duration, activation of the bed nucleus of the stria terminalis may mediate anxiety, whereas activation of the central nucleus of the amygdala may mediate stimulus-specific fear.
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PMID:The extended amygdala: are the central nucleus of the amygdala and the bed nucleus of the stria terminalis differentially involved in fear versus anxiety? 1041 55

Clinical and preclinical data suggest that unrestrained secretion of corticoctropin-releasing hormone (CRH) in the CNS produces several signs and symptoms of depression and anxiety disorders through continuous activation of CRH(1) receptors. This led to the development of drugs that selectively antagonize CRH(1) receptors suppressing anxiety-like behavior in rats and also in monkey models of anxiety. These findings led to a clinical development program exploring the antidepressive potential of R121919, a water-soluble pyrrolopyrimidine that binds with high affinity to human CRH(1) receptors and is well absorbed in humans. This compound was administered to 24 patients with a major depressive episode primarily in order to investigate whether its endocrine mode of action compromises the stress-hormone system or whether other safety and tolerability issues exist. The patients were enrolled in two dose-escalation panels: one group (n=10) where the dose range increased from 5-40 mg and another group (n=10) where the dose escalated from 40 to 80 mg within 30 days each. Four patients dropped out because of withdrawal of consent to participate (three cases) or worsening of depressive symptomatoloy in one case. We found that R121919 was safe and well tolerated by the patients during the observation period. Moreover, the data suggested that CRH(1)-receptor blockade does not impair the corticotropin and cortisol secretory activity either at baseline or following an exogenous CRH challenge. We also observed significant reductions in depression and anxiety scores using both, patient and clinician ratings. These findings, along with the observed worsening of affective symptomatology after drug discontinuation, suggests that the pharmacological principle of CRH(1)-receptor antagonism has considerable therapeutic potential in the treatment and the prevention of diseases where exaggerated central CRH activity is present at baseline or following stress exposure.
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PMID:Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. 1086 11

Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.
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PMID:Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys. 1092 83

Neurotransmitter-neuroendocrine and cardiovascular responses to the administration of a psychologically stressful mixed-model test (Mental Arithmetic, Stroop Color Word Interference Task, Trier Social Stress Test) were examined in 20 male peripubertal subjects affected by anxiety disorder (group A: 14 with generalized anxiety disorder, 6 with generalized anxiety disorder and separation anxiety disorder) and 20 junior school adolescents, matched for age, without overt psychological disorders (group B). Plasma levels of norepinephrine (NE), epinephrine (EPI), adrenocorticotropic hormone (ACTH), beta-endorphin (beta-EP), cortisol (CORT), growth hormone (GH), prolactin (PRL) and testosterone (Te) were measured immediately before the beginning of the tests and 30 min later at their end. Mean prestress values of GH, PRL, beta-EP and ACTH were significantly higher in anxious subjects than in controls. There was no difference in NE, EPI, CORT and Te prestress levels in the two groups. After the psychological stress session NE, GH and Te concentrations increased significantly in anxious subjects (A), but not in controls. In contrast, beta-EP and PRL decreased significantly during the psychological stress session in anxious subjects, and were unaffected by stress in the subjects without anxiety. No significant changes were found in ACTH, CORT and EPI during the challenge either in anxious subjects or in controls, which may be attributed to the late time of poststress blood sampling. In contrast to controls, heart rate and systolic blood pressure increased significantly in anxious subjects after psychological stress testing. Our data support the hypothesis that the hyperactivity of the noradrenergic system in response to stress is associated with anxiety disorders in adolescents and might influence the responses of GH and Te. High prestress basal values of stress hormones seem to be induced in anxious subjects by the anticipation of the task or by a persistent hyperactivity of the noradrenergic system. Further studies are needed to investigate in more detail the involvement of the HPA axis in anxious adolescents by a more refined resolution of time points of blood sampling.
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PMID:Neuroendocrine responses to psychological stress in adolescents with anxiety disorder. 1094 Jul 63

Hyperactivity of central corticotropin-releasing hormone (CRH) circuits appears to contribute to the symptomatology of affective and anxiety disorders and therefore CRH receptor antagonists have attracted attention as potential therapeutic agents. R121919, a novel high-affinity nonpeptide CRH(1) receptor antagonist, displaced (125)I-oCRH in rat pituitary, cortex and amygdala, but not in choroid plexus or cerebral blood vessels in vitro and in vivo, which is consistent with CRH(1) receptor antagonism. In vivo, R121919 significantly inhibited stress-induced corticotropin release in rats selectively bred for high- and low-anxiety-related behaviour but displayed anxiolytic effects in high-anxiety rats only. These data, corroborated by ex vivo receptor occupancy studies, suggest that this animal model is appropriate for the evaluation of CRH(1) receptor antagonists and that compounds such as R121919 will be beneficial whenever the central stress hormone system is hyperactive.
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PMID:The anxiolytic effect of the CRH(1) receptor antagonist R121919 depends on innate emotionality in rats. 1116 42

There is some evidence that a traumatic life event can induce long-term alterations in corticotropin-releasing hormone (CRH) producing neurons in humans, which may play a role in the pathophysiology of anxiety disorders, including post-traumatic stress disorder (PTSD). To study the long-term effects of a traumatic event on brain CRH-immunoreactivity (CRH-ir) and phospho-cAMP response element binding protein-immunoreactivity (P-CREB-ir), rats were exposed to a single session of foot shocks (preshocked) or no shocks (control). Two weeks later half of the control rats and half of the preshocked rats received an electrified prod in the home cage for 15 min and behavior was recorded. Fifteen minutes after the removal of the prod rats were perfused and brain sections were stained for CRH-ir and P-CREB-ir. There was no basal difference between preshocked and control rats in brain CRH-ir and P-CREB-ir. Exposure to the electrified prod induced a significant increase in CRH-ir in the paraventricular nucleus of the hypothalamus, the median eminence and the central amygdala in preshocked rats, but not in control rats. The electrified prod increased the number of P-CREB-ir neurons in the paraventricular nucleus of the hypothalamus and the locus coeruleus, but the preshock experience did not affect this response. In an additional experiment with a similar design plasma hormone levels were measured 14 days after the foot shocks. The preshock experience sensitized the shock prod-induced ACTH and corticosterone response. No behavioral differences between preshocked and control rats were found during the shock prod tests. We suggest that long-term stress-induced changes in neuropeptide dynamics of CRH-ir neurons may play a role in long-term stress-induced neuroendocrine sensitization.
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PMID:Stress-induced sensitization of CRH-ir but not P-CREB-ir responsivity in the rat central nervous system. 1145 29

Although selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs) are widely used in the chronic treatment of several anxiety disorders, increased anxiety has been observed in some patients at the beginning of treatment with these compounds. Similar increases in anxiety-related behaviors have been observed in animal studies following a single injection with SSRIs. The mechanism underlying this effect is unclear. The aim of the present study was to investigate the effects of a variety of psychoactive compounds on the anxiogenic-like activity of fluoxetine. The drugs used included the benzodiazepine diazepam, the 5-HT1A receptor partial agonist buspirone, the 5-HT1A receptor antagonists pindolol and WAY-100635, the non-selective 5-HT2 receptor antagonists methiothepin, mianserin and ritanserin, the non-selective dopamine (DA) receptor antagonist haloperidol, the D1 antagonist SCH23390, the selective D2 antagonist raclopride, the D2/3 agonist quinelorane, the cholecystokininB (CCK(B)) receptor antagonist LY 288513, and the corticotropin-releasing factor1 (CRF1) receptor antagonist CP-154,526. Experiments were performed in the free-exploration test. This model is based on the strong neophobic reactions exhibited by BALB/c mice when confronted simultaneously with a familiar and a novel environment. When administered alone, diazepam (1 and 2 mg/kg), buspirone (1 mg/kg) and mianserin (0.3 mg/kg) produced anxiolytic-like effects as they significantly increased exploratory activity of the novel compartment. In contrast, fluoxetine (20 mg/kg) almost completely suppressed exploration of the novel area. Diazepam reversed the anxiogenic-like as well as the locomotor impairment induced by fluoxetine, while quinelorane blocked only the anxiogenic action of fluoxetine. None of the other compounds was able to counteract this effect. Taken together, these results suggest that dopaminergic mechanisms may underlie, at least in part, the behavioral effects of fluoxetine in the free-exploration test, whereas 5-HT1A 5-HT2, CCK(B) and CRF1 receptors may not be involved primarily in these effects.
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PMID:An investigation of the mechanisms responsible for acute fluoxetine-induced anxiogenic-like effects in mice. 1148 52


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