Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticotropin-releasing factor receptor type 1, CRF1, plays a prominent role in the hypothalamic-pituitary-adrenal (HPA) axis and is implicated in the autonomic and behavioral responses to stress. Dysregulation of the CRF system may underlie the pathophysiology of several disorders, including depression and anxiety. The distribution of CRF1 mRNA and CRF1 specific ligand binding has been reported by multiple groups in rodents using in situ hybridization and receptor autoradiography, respectively. More recently, somewhat conflicting rodent anti-CRF1 immunohistochemical studies were reported. In this study we report the generation of an antihuman CRF1 antiserum and provide the first immunohistochemical description of CRF1 distribution in a primate brain, that of the rhesus monkey. The specificity of anti-CRF-R1 antiserum R221 was demonstrated using transfected hCRF1-expressing HEK 293 cells and rhesus monkey pituitary. CRF1-immunoreactive neurons were widespread in the rhesus brain. CRF1 staining was associated with neuronal cell bodies and dendrites and was primarily intracellular, suggesting a high rate of receptor turnover or receptor sequestration. Anti-CRF1 immunoreactivity was most abundant in pituitary, cerebellum, and in portions of brain stem associated with sensorimotor function. CRF1 staining was also observed in cerebral cortex, basal forebrain, portions of the basal ganglia, and thalamus. Staining was relatively low in prefrontal cortex and in limbic areas, which may reflect masking of the N-terminal epitope. The distribution of CRF1 immunoreactivity is suggestive of roles in attentional processing as well as the processing of motor and sensory information.
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PMID:Immunohistochemical visualization of corticotropin-releasing factor type 1 (CRF1) receptors in monkey brain. 1534 73

The studies reviewed indicate that brain stress system play an important role in the acquisition and maintenance of drugs of abuse that target the brain's reward centers. In doing so, they may destabilize these areas, making the perception of pleasure more elusive and difficult to attain. Withdrawal from drugs of abuse leads to the activation of brain CRF systems that may produce the anxiogenic response associated with drug withdrawal. More research, however, is needed to investigate the role of brain stress systems and neuropeptides in other drug withdrawal symptoms such as anhedonia. A better understanding of the brain systems underlying drug withdrawal may help in the development of improved pharmacotherapies that can alleviate drug withdrawal symptoms. The second part of the article indicated that there is a very high comorbidity between depression and drug dependence. The reviewed studies suggest that depressed patients initiate drug-taking behavior to self-medicate the symptoms associated with their psychiatric disorder. Chronic use of drugs of abuse, however, may exacerbate the symptoms of pre-existing mental disorders and subsequently increase drug-taking behavior. Conversely, professional treatment of pre-existing psychiatric disorders may decrease the use of illicit substances.
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PMID:Neurobiological mechanisms in addictive and psychiatric disorders. 1555 Feb 86

The corticotropin releasing factor receptor 1 (CRFR1) belongs to the superfamily of G-protein coupled receptors. Though CRF is involved in the aetiology of several stress-related disorders, including depression and anxiety, details of CRFR1 regulation such as internalization remain uncharacterized. In the present study, agonist-induced internalization of CRFR1 in HEK293 cells was visualized by confocal microscopy and quantified using the radioligand 125I-labelled sauvagine. Recruitment of beta-arrestin 1 in response to receptor activation was demonstrated by confocal microscopy. The extent of 125I-labelled sauvagine stimulated internalization was significantly impaired by sucrose, indicating the involvement of clathrin-coated pits. No effect on the extent of internalization was observed in the presence of the second messenger dependent kinase inhibitors H-89 and staurosporine, indicating that cAMP-dependent protein kinase and protein kinase C are not prerequisites for CRFR1 internalization. Surprisingly, deletion of all putative phosphorylation sites in the C-terminal tail, as well as a cluster of putative phosphorylation sites in the third intracellular loop, did not affect receptor internalization. However, these mutations almost abolished the recruitment of beta-arrestin 1 following receptor activation. In conclusion, we demonstrate that CRFR1 internalization is independent of phosphorylation sites in the C-terminal tail and third intracellular loop, and the degree of beta-arrestin 1 recruitment.
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PMID:Internalization of the human CRF receptor 1 is independent of classical phosphorylation sites and of beta-arrestin 1 recruitment. 1556 Jul 78

CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.
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PMID:The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. 1586 51

Since vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active non-peptide V(1b) receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V(1b) receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V(1b) receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.
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PMID:Non-peptide vasopressin V1b receptor antagonists as potential drugs for the treatment of stress-related disorders. 1589 61

Deficits in the function of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested to predispose to the development of depression and anxiety disorders. This is mirrored in the animal model "Maternal Separation (MS)" where the stress of repeated separation of rat pups from the dam during early postnatal development results in long lasting alterations in HPA axis function. Cholecystokinin increases serum concentrations of stress axis hormones and might be involved in the dam-pup interaction in rats. Therefore, we hypothesized that adult animals, which had been separated daily (postnatal days (PND) 2-14) for 180 min (MS180) would differ in HPA axis responsiveness to an intravenous challenge dose of cholecystokinin tetrapeptide (CCK-4) compared to handled rats, separated for 15 min daily. The study explored the effects of intravenous CCK-4 on elevated plus maze behaviour and HPA axis hormones. MS180 animals displayed reduced general activity but unaltered levels of open arm activity in the elevated plus maze. CCK-4 administration elevated general activity in the handled rats, while leaving MS180 rats unaffected. MS180 rats had increased baseline CRF mRNA expression in the paraventricular nucleus of the hypothalamus. When CRF mRNA was assessed in chronically catheter implanted and single housed rats, lower levels were found in the paraventricular nucleus of MS180 animals compared to handled animals and this parameter was not affected by CCK-4 treatment. Adrenocorticotropin concentrations in serum were equal in MS180 and handled rats and unaffected by CCK-4. Corticosterone serum concentrations were lower in saline treated MS180 rats compared to saline treated handled rats. CCK-4 injection raised serum corticosterone in MS180 rats to levels equal to the handled rats, while leaving handled rats unaffected. We suggest that the lower levels of hypothalamic CRF mRNA and serum corticosterone concentrations in MS180 rats might be due to the experimental set-up with chronic venous catheter implants and single housing. In conclusion, this study supports the hypothesis of elevated CCK sensitivity in separated rats as measured by corticosterone changes thus adding to the existing literature reporting early life stress having long-term impact on HPA axis function.
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PMID:Cholecystokinin tetrapeptide effects on HPA axis function and elevated plus maze behaviour in maternally separated and handled rats. 1592 46

Of all the psychological complications that an individual is likely to present with when confronted with an exceptional event, the Post-Traumatic Stress Disorder is characterized by being progressive, frequent, invalidating, strongly associated with comorbidity, and having the tendency to become chronic if it is not detected clinically. By definition, it is threatening and produces an intense fear reaction. The traumatic event is a situation of extreme stress, not only capable of altering the physical and psychological homeostasis of the individual, but is also recognized as determinant in the aetiopathology of complications. The intensity of this distress can be identified clinically and physiologically, and is currently considered as an important risk factor for the development of PTSD later on, together with other pre-, peri- and post-traumatic factors. In fact, the most studied field is the therapeutic approach, in particular drug treatment, of the fully-constituted disorder, although this actually represents tertiary prevention. Even though primary prevention seems to concern Medicine very little, any prospect of performing secondary prevention should begin by rapid identification of the risk or vulnerability factors and should allow a population at risk from developing complications to be defined. Its potential therapeutic impact brings together psychotherapeutic and drug treatment, since it is only this combination that seems able to allow the most favourable clinical outcome to be achieved for an individual, who is confronted by an out-of-the-ordinary event. The aims of secondary prevention strategies are, for example, to reduce the incidence of acute PTSD in patients seen following the event. The benefits for the individual and for the society can easily be measured in terms of the consequences on his/her social, professional and family life, or in terms of cost. The usefulness of this prevention can also be measured by the possible ways that other conditions, comorbid to PTSD, are controlled, such as anxiety disorders, depression and substance abuse, for example. Secondary prevention strategies may also be aimed at determining the therapeutic impact, by preventing or moderating the appearance of an acute stress, or even by contributing in avoiding the onset of chronic PTSD. Psychopharmacology of the immediate and post-immediate disorders, however, remains a field which has been studied very little. Reduction or control of the high, prolonged level of hyperarousal phenomena or hypersensitization of the hypothalamo-pituitary axis, would contribute to the comfort of the individual, and would participate in the prevention of PTSD. Based on current knowledge of the neurobiology of trauma, we look into the existing and potential pharmacological possibilities. Even though benzodiazepines tend to have an important role, knowledge of other drugs and therapeutic groups is rapidly increasing. In this review, we will see that the efficacy of anti-adrenergic drugs and certain other anxiolytics is now well-documented, this opening the door to their use in the future. Other drug groups offer interesting, well-proven approaches, such as serotoninergic drugs, CRF or NPY antagonists, NMDA antagonists, anticonvulsants or other GABAergic agents. In view of this disorder, which represents a true public health problem, we consider that it is now possible to widen the horizons of our drug therapy, in combination with any necessary psychotherapeutic treatment, to reach the heart of the traumatic event, that often upsets the victims, both by the psychological suffering it induces, and the loss of his/her social, family and professional references and support structures.
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PMID:[From the biology of trauma to secondary preventive pharmalogical measures for post-traumatic stress disorders]. 1595 48

Hypothalamic CRF plays a central role in the coordination of endocrine and behavioral responses to stress and it is also involved in the pathophysiology of several neuropsychiatric diseases including depression, anxiety and addiction. In the mammals, the CRF family of peptides includes CRF, urocortin (Ucn), Ucn I, and Ucn II while was enriched with new members, the urocortins. Their biological effects are mediated by the CRF1 and CRF2 receptors, which belong to the G-protein-coupled receptor super family. Multiple research groups have demonstrated during the last decade the expression of the CRF peptides and their receptors in several components of the immune system and their participation in the ad hoc regulation of inflammatory phenomena. Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse. In the gastrointestinal tract, these compounds open new therapeutic options in the treatment of lower-GI inflammatory diseases associated to CRF, such as the chronic inflammatory bowel syndromes, irritable bowel disease and ulcerative colitis while Ucn, Ucn I, Ucn II or synthetic non-peptide CRF2 agonists may be useful in the treatment of upper-GI inflammatory diseases. In human endometrium, CRF1 antagonists may be used as abortive agents interfering with the inflammatory phenomena taking place during the implantation of the conceptus. They thus may represent a new class of nonsteroidal inhibitors of implantation. These two examples illustrate the potential therapeutic significance of the CRH in regulating inflammatory phenomena in an ad hoc approach without affecting the rest of the immune system.
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PMID:The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. 1597 83

The purpose of this preliminary study was to evaluate the relationship between a possible biochemical marker of stress, 24-h urinary concentrations of Corticotropin Releasing Factor-Like Immunoreactivity (CRF-LI), and ratings of stress-related symptoms like depression and anxiety, as well as to evaluate pain and emotional reactions in patients with fibromyalgia (FM). Another purpose was to study the effects of massage and guided relaxation, with respect to change in the same variables. Urine sampling and ratings were performed before treatments, after and 1 month after completed treatments. Concentrations of CRF-LI was analysed with radioimmnoassay technique. For the assessment of depression, anxiety and pain the CPRS-A questionnaire was used and for rated pain and emotional reactions the NHP questionnaire was used. The 24-h urinary concentration of the CRF-LI was found to be related to depression, mood and inability to take initiative. After treatment the urinary CRF-LI concentrations and the rated levels of pain and emotional reactions were found to have decreased. In conclusion, the 24-h urinary CRF-LI concentration may be used as a biochemical marker of stress-related symptoms such as depression in patients with FM and possibly also other conditions characterized by chronic pain. Therapies such as massage and guided relaxation may be tried for the amelioration of pain and stress but further studies are required.
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PMID:Corticotropin releasing factor in urine--a possible biochemical marker of fibromyalgia. Responses to massage and guided relaxation. 1671 15

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety.
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PMID:Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. 1687 Jan 85


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