Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 the stress-induced hyperthermia (SIH) paradigm in mice, both a benzodiazepine receptor agonist, diazepam, and a 5-HT1A receptor agonist, flesinoxan, reduced the stress-induced increase in rectal temperature. The SIH procedure itself enhanced plasma ACTH and corticosterone levels but not plasma glucose levels. Diazepam (3, 6, and 12 mg/kg p.o.) did neither affect basal plasma ACTH, corticosterone, or glucose levels, nor did it suppress the stress-induced rises in these parameters. Flesinoxan (1, 3, and 10 mg/kg p.o.) enhanced plasma ACTH and corticosterone concentrations under nonstress conditions but did not affect the stress-induced increases in ACTH and corticosterone secretion. No clear effects of flesinoxan on plasma glucose levels were found. Our results indicate that in mice the anxiolytic effects of diazepam and flesinoxan in the SIH paradigm are not paralleled by a blockade of stress-induced increases in plasma ACTH, corticosterone, and glucose levels.
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PMID:Neuroendocrine effects of diazepam and flesinoxan in the stress-induced hyperthermia test in mice. 872 65

Drugs that enhance brain serotonin function (direct agonists, serotonin uptake inhibitors and serotonin releasers) increase serum corticosterone concentration in rats, and in many cases ACTH has been shown to be similarly increased. At least two distinct serotonin receptor subtypes can mediate this effect. One is the 5-HT1A receptor, and the other seems to be a 5-HT2A receptor. Possibly, the 5-HT2C receptor or other receptors can also mediate these effects. The increase in serum corticosterone seems to be one useful marker in characterizing drug effects on serotonergic function. Much needs to be learned about the physiological importance and roles of this serotonergic influence on pituitary-adrenocortical function. Some studies have suggested it may be important in the diurnal rhythmicity of glucocorticoid secretion and perhaps in some stress effects. Serotonergic activation can also increase plasma levels of ACTH and cortisol in humans. Although the effects in humans are less well characterized than in rats, they seem to be useful as a way of probing brain serotonergic function in disease or after drug treatment. As more drugs that act selectively on a single receptor subtype become available for use in humans, more precise information about particular receptor subtypes should be attainable.
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PMID:Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats. 878 5

To test the hypothesis that the mechanisms of 5-HT1 and 5-HT2 receptor-mediated hormonal responses are different, we compared the effects of hypothalamic paraventricular nucleus (PVN) lesions on the ACTH/corticosterone, prolactin and oxytocin responses to the 5-HT1A agonist ipsapirone (1 and 2 mg/kg), the 5-HT2C agonist m-chlorophenylpiperazine (m-CPP, 0.6 mg/kg), which also binds to other 5-HT receptors with lower affinity, and the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg) in chronically cannulated, freely moving male rats. Pharmacological characterization using antagonists with different affinity for 5-HT2A and 5-HT2C receptors revealed that DOI's responses were mediated mainly by 5-HT2A receptors and m-CPP's responses were almost exclusively mediated by 5-HT2C receptors. ACTH/corticosterone responses to ipsapirone, DOI and m-CPP were almost completely blocked after PVN lesions. Prolactin responses were significantly different in lesioned rats only after DOI and m-CPP challenges. Oxytocin responses to ipsapirone and DOI, but not m-CPP were markedly attenuated after PVN lesions. The present findings suggest that the PVN, or neural pathways close to it, mediate corticosterone and in some cases prolactin and oxytocin responses to selective stimulation of 5-HT1A, 5-HT2A, or 5-HT2C receptors.
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PMID:Role of the hypothalamic paraventricular nucleus in 5-HT1A, 5-HT2A and 5-HT2C receptor-mediated oxytocin, prolactin and ACTH/corticosterone responses. 878 18

Although considerable progress has been made in characterising the 5-HT1A receptor using agonists, partial agonists or non-selective antagonists, further studies of 5-HT1A receptor function have been hindered by the lack of highly selective antagonists. The term 'silent' antagonist has been used for such compounds in order to distinguish them unequivocally from several 5-HT1A receptor partial agonists which were initially designated 'antagonists'. In this report we provide a comprehensive review of the biochemical, pharmacological and behavioural properties of the first potent, selective and silent 5-HT1A receptor antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride). WAY-100635 had an IC50 (displacement of specific [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus) of 1.35 nM and was > 100-fold selective for the 5-HT1A site relative to a range of other CNS receptors. [3H]WAY-100635 was also characterised as the first 5-HT1A antagonist radioligand, displaying the same regional distribution of binding sites as [3H]8-OH-DPAT in rat brain. As would be expected for the binding of an antagonist to a G-protein-coupled receptor, the Bmax of [3H]WAY-100635 specific binding was consistently 50-60% greater than that of the agonist radioligand, [3H]8-OH-DPAT. Mn2+, but not guanine nucleotides, inhibited [3H]WAY-100635-specific binding. [3H]WAY-100635 was also shown to bind selectively to brain 5-HT1A receptors in vivo, following intravenous administration to mice. In vitro electrophysiological studies demonstrated that WAY-100635 had no 5-HT1A receptor agonist actions, but dose-dependently blocked the effects of agonists at both the postsynaptic 5-HT1A receptor in the CA1 region of the hippocampus, and the somatodendritic 5-HT1A receptor located on dorsal raphe 5-HT neurones. In vivo, WAY-100635 also dose-dependently blocked the ability of 8-OH-DPAT to inhibit the firing of dorsal raphe 5-HT neurones, and to induce the '5-HT syndrome', hypothermia, hyperphagia and to elevate plasma ACTH levels. In the mouse light/dark box anxiety model, WAY-100635 induced anxiolytic-like effects. WAY-100635 had no intrinsic effect on cognition in the delayed-matching-to-position model of short-term memory in the rat, but reversed the disruptive effects of 8-OH-DPAT on motor motivational performance. These data clearly demonstrate that WAY-100635 is the first potent, selective and silent 5-HT1A receptor antagonist. Furthermore, [3H]WAY-100635 is the first antagonist radioligand to become available for 5-HT1A receptor binding studies both in vitro and in vivo. The positive effects of WAY-100635 in an anxiety model also indicate that a postsynaptic 5-HT1A receptor antagonist action may contribute to the anxiolytic properties of 5-HT1A receptor partial agonists.
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PMID:Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist. 878 30

To determine whether emotional stress-induced rises in stress hormone levels are mediated by activation of 5-HT1A receptors, we studied the effects of the selective 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on plasma ACTH, corticosterone, prolactin, and glucose levels in the conditioned ultrasonic vocalisation (USV) model in adult rats. The effects of WAY-100635 on USVs were also investigated in this paradigm. WAY-100635 (0.3, 1, and 3 mg/kg SC) had no clear effects on basal plasma ACTH, corticosterone, and glucose levels, but the 3 mg/kg dose significantly increased the plasma prolactin levels. The increases in plasma ACTH, corticosterone, and prolactin levels induced by the USV procedure were not affected by WAY-100635. This indicates that the 5-HT1A receptor does not play a major role in the distress-induced activation of the hypothalamic-pituitary-adrenal axis and prolactin secretion. The USVs were significantly enhanced by low doses of WAY-100635 (0.03 and 0.3 mg/kg SC), whereas higher doses (1.0 and 3.0 mg/kg SC) had no effect. These findings suggest that blockade of 5-HT1A receptors during stress may enhance the behavioural stress-response.
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PMID:The 5-HT1A receptor is not involved in emotional stress-induced rises in stress hormones. 895 69

Two major classes of antianxiety drugs, benzodiazepines and partial agonists of 5-HT1A receptors, have dissimilar effects on learning. Benzodiazepines induce amnesic effects in humans and animals. In contrast, partial agonists of 5-HT1A receptors do not suppress memory in humans and have variable effects in animal learning models. The two groups of drugs shift activity of the hypothalamic-pituitary-adrenocortical (HPA) axis in opposite ways. Benzodiazepines, given at antianxiety doses, suppress HPA axis excitability. Partial agonists of 5-HT1A receptors facilitate HPA excitability and, at higher doses, directly stimulate ACTH secretion. Assuming that certain components of the HPA axis are involved in memory acquisition, it is hypothesized that antianxiety drugs may affect learning through the regulation of HPA axis excitability.
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PMID:The role of the hypothalamic-pituitary-adrenocortical axis in memory-related effects of anxiolytics. 901 95

Clinical studies suggest that 5-HT1A receptor function may be blunted in depression, while 5-HT1A agonists may possess antidepressant activity. Preclinical findings implicate changes in 5-HT1A receptor sensitivity in the mechanism of antidepressant action. The hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression could be related to those observations, since 5-HT1A receptors are inhibited by glucocorticoids. To evaluate the interaction of the HPA and 5-HT1A systems, we pretreated 15 unipolar depressed patients and 12 healthy control subjects with the antiglucocorticoid ketoconazole (KTCZ) prior to administration of a test dose of the 5-HT1A agonist ipsapirone (IPS). Neuroendocrine (ACTH, cortisol, growth hormone), physiological (hypothermia), and behavioral responses to IPS were assessed. As expected, KTCZ inhibited cortisol biosynthesis, but non-HPA responses to IPS were not enhanced. This study failed to show that glucocorticoid modulation of 5-HT1A receptor function is altered in depression.
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PMID:Effects of antiglucocorticoid treatment on 5-HT1A function in depressed patients and healthy subjects. 932 49

In the first study the possible role of the hypothalamic paraventricular nucleus (PVN) in 5-HT1A receptor agonist-induced neuroendocrine responses was tested. Surgical lesions of the PVN completely blocked ACTH and corticosterone and markedly attenuated oxytocin but not prolactin responses to ipsapirone, providing evidence for a crucial role of the PVN in these responses. In the second study we have compared the effectiveness of intracerebroventricular and intravenous administration of 8-OH-DPAT in frequently used behavioural models of 5-HT1A receptor activation, namely lower lip retraction, body temperature and tail flick responses. We have found marked differences in the rates of effectiveness. We conclude that these models measure the activation of different subsets with clearly separate location of 5-HT1A receptors.
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PMID:Studies on the sites and mechanisms of 5-HT1A receptor-mediated in vivo actions. 932 12

The aminomethylchroman derivative BAY x 3702 (R-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d] isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT)1A receptor ligand [calf hippocampus: Ki: 0.19 nM; reference compounds 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT1A receptors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relatively high to moderate affinity to the following receptors: alpha-1 and alpha-2 adrenergic (Ki: 6 and 7 nM, respectively); 5-HT7- and 5-HT1D (7 and 36 nM); dopamine D2- and D4 (48 and 91 nM); sigma sites (176 nM) and 5-HT2C (310 nM); others: > 10 microM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonist (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide trihydrochloride (WAY-100635). At those receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D receptors) or an antagonist (alpha-1, alpha-2 and D2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY x 3702 (0.5 microgram/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY x 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY x 3702 (ED50: 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY x 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED50: 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with high potency and intrinsic activity.
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PMID:Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist. 949 70

We investigated the involvement of serotonin (5-HT) and 5-HT receptors in mediation of stress-induced ACTH secretion in adult male rats, which were pretreated by 5-HT antagonists before restraint-, ether-, cold swim-stress or endotoxin. All stressors potently increased plasma ACTH. Lesion of 5-HT neurons with 5, 7-dihydroxytryptamine injected intracerebroventricularly, into the paraventricular nucleus or into the raphe nuclei, inhibited the restraint stress-induced ACTH response by 50%. Restraint increased the content of 5-HT and its metabolite 5-hydroxyindole acetic acid, in the raphe nuclei, whereas the other stressors had no such effect. Pretreatment with the 5-HT1A receptor antagonist WAY 100635 inhibited the restraint stress- and endotoxin-induced ACTH secretion by 50%. The 5-HT1+2 antagonist methysergide or the 5-HT2 antagonist ketanserin inhibited the restraint- or ether stress-induced ACTH response, and eliminated the endotoxin-induced ACTH response. The 5-HT2 receptor antagonist LY 53857 blocked only the endotoxin-induced ACTH response. Pretreatment with the 5-HT3 receptor antagonist ondansetrone had no effect on stress-stimulated ACTH secretion. The 5-HT3+4 receptor antagonist tropisetrone inhibited the restraint- and ether stress-induced response. The ACTH response to swim stress was not affected by any of the antagonists used. It is concluded that the 5-HT1A, the 5-HT2A and the 5-HT2C receptor, but not the 5-HT3 receptor are involved in the stress-induced ACTH secretion. An involvement of the 5-HT4 receptor is possible. Furthermore, that serotonergic neurons in the raphe nuclei are activated during restraint stress, and that these neurons and neurons in PVN of the hypothalamus, are important for the mediation of the restraint stress-induced ACTH response.
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PMID:Serotonergic involvement in stress-induced ACTH release. 980 68


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