Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In spite of recent progress in the pharmacotherapy of depression major issues are still unresolved. These include the non-response rate of approximately 30% to conventional antidepressant pharmacotherapy, side effects of available antidepressants and the latency of several weeks until clinical improvement. The only non-pharmacological biological treatment options available so far which exert more rapid antidepressant efficacy are electroconvulsive therapy and, as an augmentation strategy, sleep deprivation. Current pharmacological treatments aim to enhance serotonergic and/or noradrenergic neurotransmission. In spite of emerging knowledge, the crucial mechanisms underlying both non-pharmacological treatments, which are responsible for antidepressant efficacy, are not yet clear so far. In the meantime several new pharmacological principles are under investigation with regard to their putative antidepressant potency. These include 5-HT1A receptor agonists, tachykinin receptor antagonists and various interventions within the hypothalamic-pituitary-adrenal system. While there is evidence for antidepressant properties of these new treatments in animal studies, in case series, in open studies and to some degree also in placebo controlled studies, no definite proof for the antidepressant efficacy of these new pharmacological strategies according to the requirements for evaluation of antidepressant drugs has been furnished so far. In contrast, for the established non-pharmacological treatment strategies including bright light therapy the clinical efficacy has been proven at least in subgroups of depression, but more knowledge of the main mechanisms underlying their antidepressant efficacy is still necessary. In addition new non-pharmacological treatments like repetitive transcranial magnetic stimulation, magnetic seizure therapy and Vagus nerve stimulation are currently under development. Nevertheless, a follow-up of both the new pharmacological strategies and non-pharmacological treatment options is of major importance to provide even better strategies for the clinical management of depression, which also is of great socio-economic impact.
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PMID:Recent progress in pharmacological and non-pharmacological treatment options of major depression. 1647 42

Classical antidepressant drugs such as Selective Serotonin Reuptake Inhibitors (SSRIs) display several disadvantages, e.g., the onset of action (2 to 3 weeks) to start clinical benefits is too long, and a significant proportion of patients do not respond to this monotherapy. Several strategies have been proposed to overcome these problems, notably the use of potentiating agents, which combined with SSRIs, augment or accelerate their established antidepressant activity. Recent clinical trials proposed that compounds with dual action on both central serotonin (5-HT) and noradrenaline (NA) systems would have a faster action than SSRIs alone. Preclinical electrophysiological and neurochemical studies demonstrated that the putative new class of antidepressants, substance P (neurokinin 1) NK1 receptor antagonists, enhance brain monoaminergic neurotransmissions by reducing the sensitivity of 5-HT1A autoreceptors in the Dorsal Raphe Nucleus, and possibly alpha2 autoreceptors in the Locus Coeruleus. However, in several clinical studies, a similar delay of therapeutic effects has been reported with NK1 receptor antagonists and SSRIs. Recently intracerebral in vivo microdialysis studies were performed to examine the effects of genetic or pharmacological blockade of Substance P (SP)/ NK1 neurotransmission on SSRIs-induced increases in extracellular 5-HT levels in awake, freely moving mice. New evidences suggest that the combination of a NK1 receptor antagonist with a SSRI should benefit to depressed patients. This review describes our current knowledge of the role of SP and its preferred NK1 receptors mainly in the modulation of brain serotonergic activity.
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PMID:Microdialysis approach to study serotonin outflow in mice following selective serotonin reuptake inhibitors and substance P (neurokinin 1) receptor antagonist administration: a review. 1647 60

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, alpha-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT2C, 5-HT6) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
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PMID:Innovative approaches for the development of antidepressant drugs: current and future strategies. 1648 68

In addition to its neurotransmitter/modulator role in pain perception, substance P (SP) is involved in a regulation of mood, as antagonists of its neurokinin-1 receptor (NK1r) have been found to have antidepressant-like effects in humans. In rodents, treatment with NK1r antagonists has been shown to increase the firing of dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine, 5-HT) neurons and to induce a desensitization of their 5-HT1A autoreceptors, suggesting local interactions between the SP and 5-HT systems. To search for the presence of NK1r on 5-HT neurons of the DRN, we used light and electron microscopic immunocytochemistry, as well as confocal microscopy, after single- and double-labelling of NK1r and of the biosynthetic enzyme of 5-HT, tryptophan hydroxylase (TpOH). A significant number of 5-HT (TpOH-positive) cell bodies and dendrites endowed with NK1r were thus demonstrated in the caudal part of rat and mouse DRN. As visualized by electron microscopy after gold immunolabelling, NK1r was mostly cytoplasmic in 5-HT neurons, while predominating on the plasma membrane in the case of TpOH-negative dendrites. The proportion of NK1r observed on the plasma membrane of 5-HT neurons was, however, slightly higher in mouse than rat. Thus, in both rat and mouse DRN, a subpopulation of 5-HT neurons is endowed with NK1r receptors and may be directly involved in the antidepressant-like effects of NK1r antagonists. These 5-HT neurons represent a new element in the neuronal circuitry currently proposed to account for the role of SP in mood regulation.
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PMID:Immunocytochemical evidence for the existence of substance P receptor (NK1) in serotonin neurons of rat and mouse dorsal raphe nucleus. 1681 84

Acute injection of imipramine to NPK mice hereditary predisposed to pinching catalepsy reduced immobility in the forced swimming test, but had no effect on catalepsy. Chronic treatment with imipramine reduced the severity of catalepsy and functional activity of 5-HT1A serotonin receptors, but did not modify their expression in the hippocampus. NPK mice can be a convenient model for studies of the effects of antidepressant.
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PMID:Effect of imipramine on the behavior and cerebral 5-HT1A serotonin receptors in mice genetically predisposed to catalepsy. 1692 62

Intrathecal (i.t.) administration into mice of S-(+)-fenfluramine (0.01-0.1nmol), a serotonin (5-hydroxytryptamine, 5-HT) releaser, produced a behavioral response consisting of scratching, biting and licking. Here, we report the behavioral characteristics and the involvement of interactions between 5-HT and substance P (SP) systems in the S-(+)-fenfluramine-induced behavioral response. The S-(+)-fenfluramine-induced behavioral response peaked at 5-15min and almost disappeared at 20min after injection. The behavior induced by S-(+)-fenfluramine (0.1nmol) was dose-dependently inhibited by an intraperitoneal injection of morphine (0.02-0.5mg/kg), suggesting that the behavioral response is related to nociception. The S-(+)-fenfluramine-induced nociceptive behavior was significantly inhibited by pretreatment with 5-HT antiserum and co-administration of ketanserin, a selective 5-HT2 receptor antagonist. However, WAY-100635, a selective 5-HT1A receptor antagonist, and ramosetron, a selective 5-HT3 receptor antagonist, were not active. On the other hand, SP antiserum and RP67580, a selective neurokinin-1 (NK1) receptor antagonist, significantly inhibited S-(+)-fenfluramine-induced nociceptive behavior. These results suggest that i.t.-administered S-(+)-fenfluramine releases SP through the activation of 5-HT2 receptors subsequent to 5-HT release, and, as a result, produces nociceptive behavior.
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PMID:S-(+)-fenfluramine-induced nociceptive behavior in mice: Involvement of interactions between spinal serotonin and substance P systems. 1714 Jun 59

Preclinical studies suggest that substance P (SP) neurokinin 1 (NK1) receptor antagonists are efficient in the treatment of anxiety and depression. This therapeutic activity could be mediated via stimulation of serotonin (5-HT) neurons located in the dorsal raphe nucleus (DRN), which receive important SP-NK1 receptor immunoreactive innervations. The present study examined the effects of intraraphe injection of SP on extracellular 5-HT levels in the frontal cortex, ventral hippocampus, and DRN by using intracerebral microdialysis in conscious mice. Intraraphe SP injection dose dependently decreased cortical 5-HT release, whereas no effects were detected in the ventral hippocampus. Cortical effects were blocked by the selective NK1 receptor antagonist N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine (GR205171) and completely dampened in mice lacking NK1 receptors. Furthermore, genetic (in knockout 5-HT1A(-/-) mice) or pharmacological inactivation of 5-HT1A autoreceptors blocked cortical responses to SP. Contrasting with its cortical effects, intraraphe SP injection increased 5-HT outflow in the DRN in wild-type mice; this effect was potentiated by a local perfusion of the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Finally, SP-induced changes in frontal cortex and DRN dialysate 5-HT levels were blocked by the DRN perfusion of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate ionotropic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These data support the hypothesis that SP-induced over-activation of 5-HT1A autoreceptors within the DRN limits cortical 5-HT release. A better knowledge of the complex relationship between tachykininergic, serotonergic, and glutamatergic systems within the DRN might help better understand the pathophysiology and subsequent treatment of depression.
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PMID:Substance P neurokinin 1 receptor activation within the dorsal raphe nucleus controls serotonin release in the mouse frontal cortex. 1789 Mar 58

Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.
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PMID:Neurokinin 1 receptor antagonism promotes active stress coping via enhanced septal 5-HT transmission. 1795 16

Over the last half of the 20th century, there have been a series of psychopharmacologic strategies for treatment of depression. As we approach the next century, new therapies in varying stages of American release are being developed. This review will focus on information available for the following proposed antidepressants: 1) reboxetine, a norepinephrine selective reuptake inhibitor; 2) milnacipran, a combined serotonin/norepinephrine reuptake inhibitor; 3) a new enantiomer of fluoxetine, a selective serotonin reuptake inhibitor; 4) duloxetine, another combined serotonin/norepinephrine reuptake inhibitor; 5) sunepitron, a combined 5-HT1A agonist and a2 antagonist; and 6) MK-869, a substance P inhibitor. Finally, other possible developing directions will be reviewed, including corticotropin-releasing factor.
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PMID:Psychopharmacology of depression in the next millennium. 1843 95

Natural defense-inducing stimuli are being increasingly exploited as a means to investigate the neural mechanisms underlying normal and pathological anxiety, as well as for the screening of new compounds with potential therapeutic use in human anxiety disorders. Such an approach, frequently used in rodents, has recently been employed in the Marmoset Predator Confrontation Test (MPCT). In this method, marmoset monkeys are individually confronted with a taxidermized predator (wild oncilla cat) in a previously habituated maze environment, while several easily discernable fear/anxiety-related behaviors are measured. Confrontation with the cat stimulus significantly altered ongoing behaviors, each habituating distinctively during repeated exposures; e.g. complete rapid habituation (alarm call), complete slow habituation (exploration, vigilance) or only partial habituation (proximity avoidance). Pharmacological validating studies with diazepam and buspirone induced a significant dose-dependent reversal of the fear-induced proximic avoidance and scratching/scent-marking behaviors, while exploration (smell/lick the maze, leg stand) was found to increase. The neuropeptide substance P and the selective 5-HT1A receptor antagonist WAY100635 resulted in a similar anxiolytic-like profile. The response pattern observed was not influenced by social isolation, handling/manual restraint, novel environment exposure or habituation to the stimulus or its location. Persistent defensive behavior and response pattern to diazepam was observed when naive versus MPCT-experienced marmosets were tested following a recent predatory stress. Taken together, the results indicate that the MPCT is a valuable experimental procedure to measure fear and anxiety-related behaviors in nonhuman primates.
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PMID:Predatory stress as an experimental strategy to measure fear and anxiety-related behaviors in non-human primates. 1875 22


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