Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review provides an overview of preclinical and clinical evidence of a role for the neuroactive peptides cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, neurokinin [NK] A and B), and natriuretic peptides in anxiety and/or stress-related disorders. Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of these compounds in anxiety disorders have been unsuccessful so far. However, future investigations using CCK receptor antagonists with better pharmacokinetic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti-anxiety agents. Results obtained with peptide CRF receptor antagonists in animal models of anxiety convincingly demonstrated that the blockade of central CRF receptors may yield anxiolytic-like activity. However, the discovery of nonpeptide and more lipophilic CRF receptor antagonists is essential for the development of these agents as anxiolytics. Similarly, there is clear preclinical evidence that the central infusion of NPY and NPY fragments selective for the Y1 receptor display anxiolytic-like effects in a variety of tests. However, synthetic nonpeptide NPY receptor agonists are still lacking, thereby hampering the development of NPY anxiolytics. Unlike selective NK1 receptor antagonists, which have variable effects in anxiety models, peripheral administration of selective NK2 receptor antagonists and central infusion of natriuretic peptides produce clear anxiolytic-like activity. Taken as a whole, these findings suggest that compounds targeting specific neuropeptide receptors may become an alternative to benzodiazepines for the treatment of anxiety disorders.
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PMID:Is there a future for neuropeptide receptor ligands in the treatment of anxiety disorders? 1034 56

Selective, nonpeptide antagonists for tachykinin receptors first became available ten years ago. Of the three known tachykinin receptors, drug development has focused most intensively on the substance P-preferring receptor, neurokinin(1) (NK(1)). Although originally studied as potential analgesic compounds, recent evidence suggests that NK(1) receptor antagonists may possess antidepressant and anxiolytic properties. If confirmed by further controlled clinical studies, this will represent a mechanism of action distinct from all existing antidepressant agents. As reviewed in this chapter, the existing preclinical and clinical literature is suggestive of, but not conclusive, concerning a role of substance P and NK(1) receptors in the pathophysiology of depression and/or anxiety disorders. The ongoing clinical trials with NK(1) receptor antagonists have served as an impetus for much needed, basic research in this field.
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PMID:Neurokinin(1) receptor antagonists as potential antidepressants. 1126 80

The tachykinin neuropeptide substance P and its receptor neurokinin 1 have been implicated in the regulation of many physiological and pathological processes, including the control of emotional behaviors. The present study examines mice with a targeted deletion of the Tac1 gene, which encodes the neuropeptides substance P and neurokinin A, in animal models relevant to depressive illness and anxiety. In depression-related paradigms, Tac1-deficient mice were more active in the Porsolt's forced-swimming test and the tail-suspension test, and they did not become hyperactive after bulbectomy. Tac1 mutant mice were also less fearful in several animal models of anxiety. They were more active and less affected by the light conditions in the central area of the open-field arena; they showed more social interactions in an aversive environment, they were more active in the open areas of an elevated zero-maze, and they had a reduced latency to feed in the Thatcher-Britton conflict paradigm. These results demonstrate that tachykinins are powerful mediators of depression-like or anxiety-related behaviors in mice. The tachykinin system therefore may play an important role in the regulation of emotional states and the development of anxiety disorders and depression.
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PMID:Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. 1242 62

Exposure to hostile conditions initiates responses organized to enhance the probability of survival. These coordinated responses, known as stress responses, are composed of alterations in behavior, autonomic function and the secretion of multiple hormones. The activation of the renin-angiotensin system and the hypothalamic-pituitary-adrenocortical axis plays a pivotal role in the stress response. Neuroendocrine components activated by stressors include the increased secretion of epinephrine and norepinephrine from the sympathetic nervous system and adrenal medulla, the release of corticotropin-releasing factor (CRF) and vasopressin from parvicellular neurons into the portal circulation, and seconds later, the secretion of pituitary adrenocorticotropin (ACTH), leading to secretion of glucocorticoids by the adrenal gland. Corticotropin-releasing factor coordinates the endocrine, autonomic, behavioral and immune responses to stress and also acts as a neurotransmitter or neuromodulator in the amygdala, dorsal raphe nucleus, hippocampus and locus coeruleus, to integrate brain multi-system responses to stress. This review discussed the role of classical mediators of the stress response, such as corticotropin-releasing factor, vasopressin, serotonin (5-hydroxytryptamine or 5-HT) and catecholamines. Also discussed are the roles of other neuropeptides/neuromodulators involved in the stress response that have previously received little attention, such as substance P, vasoactive intestinal polypeptide, neuropeptide Y and cholecystokinin. Anxiolytic drugs of the benzodiazepine class and other drugs that affect catecholamine, GABA(A), histamine and serotonin receptors have been used to attenuate the neuroendocrine response to stressors. The neuroendocrine information for these drugs is still incomplete; however, they are a new class of potential antidepressant and anxiolytic drugs that offer new therapeutic approaches to treating anxiety disorders. The studies described in this review suggest that multiple brain mechanisms are responsible for the regulation of each hormone and that not all hormones are regulated by the same neural circuits. In particular, the renin-angiotensin system seems to be regulated by different brain mechanisms than the hypothalamic-pituitary-adrenal system. This could be an important survival mechanism to ensure that dysfunction of one neurotransmitter system will not endanger the appropriate secretion of hormones during exposure to adverse conditions. The measurement of several hormones to examine the mechanisms underlying the stress response and the effects of drugs and lesions on these responses can provide insight into the nature and location of brain circuits and neurotransmitter receptors involved in anxiety and stress.
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PMID:Neuroendocrine pharmacology of stress. 1260 Jul 14

Recent advances in neuroscience and understanding in the etiology of anxiety have led researchers to new targets for treatments that are proving to be at least as effective as benzodiazepines, which have been the traditional treatment for anxiety for over 40 years. The gamma-aminobutyric acid (GABA) system has long been targeted in anxiety interventions via benzodiazepines, but better understanding of its role in anxiety disorders has led to the development of partial benzodiazepine-GABA receptor antagonists and agents that target specific subunits of the GABA-A receptor and that manipulate GABA levels. The recognition that antidepressants are effective in anxiety even in nondepressed patients has caused researchers to develop antianxiety agents that affect the serotonin and norepinephrine systems. Other neurotransmitter systems such as corticotropin-releasing factor and substance P appear to be abnormally regulated in patients with anxiety disorders, so antagonists of these neurotransmitters may prove to be beneficial anxiolytics. Meanwhile, antistress and antianxiety effects through neurogenesis may be possible with the use of agents that decrease glutamate neurotransmission, such as metabotropic glutamate receptor agonists. Finally, the stimulation of neurotrophic factors, such as brain-derived neurotrophic factor, which appears to enhance neurogenesis, may also prove to have anxiolytic effects.
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PMID:New molecular targets for antianxiety interventions. 1266 31

Substance P (SP) is a neuropeptide which is widely distributed in the periphery and the central nervous system (CNS), where it is co-localised with other neurotransmitters such as serotonin or dopamine and where it acts as a neuromodulator. SP has been proposed to play a role in the aetiopathology of asthma, inflammatory bowel disease, emesis, psoriasis, as well as neuropsychiatric disorders including pain syndromes (e.g. migraine and fibromyalgia) and affective disorders, anxiety disorders, schizophrenia and Alzheimer's disease. This review focuses on the role of SP in the pathogenesis of affective disorders. It summarises the current knowledge on measurements of SP in the CSF and serum in patients with depressive disorders or fibromyalgia, effects of SP-application in humans, SP-receptor expression in postmortem brains and the modulation of SP levels in the course of antidepressant treatment. It also discusses the promise of substance P-receptor antagonists (SPA) for the treatment of affective disorders and their proposed mechanism of action. In summary, much more research is needed to elucidate the role of SP in the pathogenesis of depression. SPA are promising as future drugs for the treatment of affective disorders, but current clinical trials have yet to be completed to draw a firm conclusion. Key words: substance P, neurokinin1-receptor, affective disorders, depression, review.
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PMID:Substance P and Substance P receptor antagonists in the pathogenesis and treatment of affective disorders. 1269 75

The health burden of stress-related diseases, including depression and anxiety disorders, is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in mediating the response to stress and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of depression and anxiety disorders. In preclinical models, pharmacological and/or genetic manipulation of substance P, corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y and galanin function alters anxiety- and depression-related responses. Recently, specific and highly potent small-molecule neuropeptide receptor agonists and antagonists have been developed that can readily cross the blood-brain barrier. Clinical assessment of several compounds is currently underway, with antidepressant efficacy confirmed in double-blind, placebo-controlled trials of tachykinin NK(1) (substance P) receptor antagonists, and preliminary evidence of antidepressant activity in an open-label trial of a CRF(1) receptor antagonist.
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PMID:Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. 1512 Apr 87

Benzodiazepines are effective and widely used in anxiety disorders, but they produce sedation and dependency. Molecular studies have shown that binding benzodiazepines to GABAA receptors containing the Alpha1 subunit mediates the sedative properties of benzodiazepines. Other strategies are being developed including the use of the selective GABA reuptake inhibitor tiagabine and the voltage gated calcium ion channel ligand pregabalin. Several novel strategies are being developed based on preclinical observations, including corticotrophin-releasing factor (CRF) antagonists, substance P antagonists, and drugs inhibiting glutamate neurotransmission.
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PMID:[New molecular targets in pharmacological treatment of anxiety disorders]. 1550 88

Tachykinins play an important role as peptide modulators in the CNS. Based on the concentration and distribution of the peptides and their receptors, substance P (SP) and its cognate receptor neurokinin 1 (NK1R) seem to play a particularly important role in higher brain functions. They are expressed at high levels in the limbic system, which is the neural basis of emotional responses. Three different lines of evidence from physiological studies support such a role of SP in the regulation of emotionality: (1) stress is often associated with elevated level of SP in animals and humans; (2) systematic and local injections of SP influence anxiety levels in a dose-dependent and site-specific manner; (3) NK1 receptor antagonists show anxiolytic effects in different animal models of anxiety. Although these studies point to the NK1 receptor as a promising target for the pharmacotherapy of anxiety disorders, high affinity antagonists for the human receptors could not be studied in rats or mice due to species differences in the antagonist binding sites. However, studies on anxiety and depression-related behaviors have now been performed in mouse mutants deficient in NK1 receptor or SP and NKA. These genetic studies have shown that anxiety and depression-related phenotypes are profoundly affected by the tachykinin system. For example, NK1R-deficient mice seem to be less prone depression-related behaviors in models of depression, and one study also provided evidence for reduced anxiety levels. Mice deficient in SP and NKA behaved similarly as the NK1R knockouts. In animal models of anxiety they performed like wildtype mice treated with anxiolytic drugs. In behavioral paradigms related to depression they behaved like wildtype animals treated with antidepressants. In summary, the genetic studies clearly show that the SP/NK1 system plays an important role in the modulation of emotional behaviors.
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PMID:Mutagenesis and knockout models: NK1 and substance P. 1659 57

The neuropeptide substance P (SP) has been found to be possibly involved in the etiology of affective and anxiety disorders. However, the molecular mechanisms underlying this involvement are still poorly understood. In this study, we used macroarrays to investigate the differential gene expression profile induced by SP, particularly of genes which have been shown to be involved in the pathophysiology of affective disorders. As a model system, we used the human astrocytoma cell line U373 MG as well as primary rat astroglial cells, which both are known to express functional neurokinin-1 receptors (NK-1-R) and to secret various cytokines upon stimulation with SP. Among several regulated genes, we found that SP (100 and 1000 nM) induced the expression of the corticotropin-releasing factor receptor 1 (CRF1 receptor). Further analyses revealed that this induction was mediated (a) via NK-1-R, as the selective NK-1-R-antagonist L-733,060 (1 microM) strongly inhibited SP-induced CRF1 receptor expression, and (b) intracellularly, by protein kinase C, p42/44 and p38 mitogen-activated protein kinases (MAPK), as shown by using specific inhibitors of signal transduction pathways. In conclusion, this study demonstrates that SP induces CRF1 receptor expression in cells of the CNS, which may be of potential interest for a better understanding of the interplay between SP and the stress hormone axis and, thus, diseases like affective or anxiety disorders. Further studies are needed to substantiate this link in vivo.
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PMID:Substance P induces expression of the corticotropin-releasing factor receptor 1 by activation of the neurokinin-1 receptor. 1680 14


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