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)

We have investigated the distribution of [3H]5-carboxamidotryptamine ([3H]5-CT) binding sites by in vitro autoradiography on sections of guinea-pig and rat brain. In saturation studies, the ligand recognised a saturable, homogeneous population of binding sites with an affinity ranging from 0.19-0.45 nM depending on the region. The labelling pattern was heterogeneous, and the displacement pattern with different competing drugs selective for different 5-HT receptor subtypes was complex. [3H]5-CT appeared to label 5-HT1B/5-HT1D sites in the substantia nigra, globus pallidus and caudate/putamen, as the binding in these regions was displaced by the 5-HT1B/1D receptor selective agents sumatriptan, CP-122,288 and GR-127,935. In the hippocampus and lateral septum, the very dense [3H]5-CT binding was displaced with high affinity by the 5-HT1A receptor selective agonist 8-hydroxy-dipropylaminotetralin ((+/-)-8-OH-DPAT), dihydroergotamine and 5-HT. In contrast the affinity of the 5-HT1 receptor antagonists spiperone and methiothepine was much lower than their previously published potency at 5-HT1A receptors. The affinity of agonists, taken together with the fact that the distribution of these [3H]5-CT sites overlaps that of [3H]8-OH-DPAT binding sites in serial sections, suggest that these sites correspond to 5-HT1A receptors. Their atypical properties deserve further investigations. While [3H]5-CT binding at 5-HT1B/1D sites and these atypical 5-HT1A sites was inhibited by the GTP analogue 5'-beta, gamma-imidotriphosphate, [3H]5-CT binding in the superficial cortical layers and in midline thalamic nuclei was insensitive to this agent. It was however displaced by low concentrations of spiperone, clozapine and methiothepine, but not by sumatriptan, CP-122,288, GR-127,935 or dihydroergotamine. This binding profile is similar to that of 5-HT7 receptors, while the spatial distribution of these sites matches the known distribution of 5-HT7 messenger RNA. We did not find evidence of [3H]5-CT labelling to 5-HT5 receptors, in spite of their reported high affinity for this ligand. It is concluded that [3H]5-CT, in the presence of selective blockers, can be used to investigate the properties of 5-HT1A, 5-HT1B/1D and 5-HT7 receptors in the rodent brain, although further studies are required to explain the atypical features of [3H]5-CT binding in 5-HT1A receptors containing regions.
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PMID:Autoradiographic visualisation of [3H]5-carboxamidotryptamine binding sites in the guinea pig and rat brain. 749 19

5-HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes. At present 15 receptor subtypes of three groups has been recognized. The 5-HT1 subfamily of receptors contains subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F; activation of all of them results in the inhibition of adenylylcyclase. The subfamily of 5-HT2 contains subtypes 5-HT2A, 5-HT2B, and 5-HT2C; their activation leads to the stimulation of PLC. Finally, subfamily of miscellaneous 5-HT receptors contains subtypes 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7; some of them has been cloned, however, our knowledge on their function is still minimal. 5-HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease. 5-HT plays an important role in depression; to cure this disease, drugs which increase levels of this neurotransmitter are used. A new drug group called Selective Serotonin Reuptake Inhibitors (SSRI) has been recently discovered. These drugs block the reuptake of 5-HT into nerve endings. There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential.
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PMID:[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes]. 758 16

Serotonergic neurotransmission represents a complex mechanism involving pre- and post-synaptic events and distinct 5-HT receptor subtypes. Serotonin (5-HT) receptors have been classified into several categories, and they are termed as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 type receptors. 5-HT1 receptors have been further subdivided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. 5-HT2 receptors have been divided into 5-HT2A, 5-HT2B and 5-HT2C receptors. All 5-HT2 receptor subtypes are linked to the multifunctional phosphoinositide (PI) signalling system. 5-HT3 receptors are considered ion-gated receptors and are also linked to the PI signalling system by an unknown mechanism. The 5-HT2A receptor subtype is the most widely studied of the 5-HT receptors in psychiatric disorders (for example, suicide, depression and schizophrenia) as well as in relation to the mechanism of action of antidepressant drugs. The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear. These 5-HT receptors also play an important role in alcoholism. It has been shown that 5-HT2A, 5-HT2C and 5-HT3 antagonists cause attenuation of alcohol intake in animals and humans. However, the exact mechanisms are unknown. The recent cloning of the cDNAs for 5-HT2A, 5-HT2C and 5-HT3 receptors provides the opportunity to explore the molecular mechanisms responsible for the alterations in these receptors during illness as well as pharmacotherapy. This review article will focus on the current research into the pharmacological properties, molecular biology, and clinical correlates of 5-HT2A, 5-HT2C and 5-HT3 receptors.
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PMID:Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. 778 83

Phylogenetic comparisons between homologous proteins can provide information on the rates of molecular evolution of the proteins. G protein-coupled receptors are a "superfamily" of proteins which exist in species ranging from yeast to man. Based on an analysis of the percentage of amino acid homology between various species, the rate of molecular evolution of G protein-coupled receptors can be estimated at approx 1% per 10 million years. Based on this assumption, the primordial 5-HT receptor must have evolved more than 700-800 million years ago since the 3 major classes of G protein-coupled 5-HT receptors (i.e. 5-HT1, 5-HT2 and 5-HT6 receptors) are less than 25% homologous. 5-HT5, 5-HT7, 5-HTsnail, 5-HTdro and 5-HT1A receptors differentiated approx 600-700 million years ago, the time period during which vertebrates diverged from invertebrates. The mammalian 5-HT receptor subtypes have differentiated over the past 90 million years. Thus, although a recent flurry of "new" 5-HT receptors have appeared in the literature, the first "primordial" 5-HT receptor evolved over 750 million years ago, a date which likely predates the evolution of muscarinic, dopaminergic and adrenergic receptor systems. This analysis also predicts that a significant number of both mammalian and invertebrate G protein-coupled 5-HT receptor subtypes remain to be identified.
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PMID:The molecular evolution of G protein-coupled receptors: focus on 5-hydroxytryptamine receptors. 798 68

We assayed [3H]5-hydroxytryptamine ([3H]5-HT) binding in rat hypothalamic membranes to confirm the possible of measuring 5-HT7 receptors. Binding was tested in the presence of 3 microM (+/-)-pindolol, a concentration higher than previously suggested for the same purpose (0.1 micron). This higher concentration was, however, needed to fully saturate 5-HT1A and 5-HT1B receptors without interaction with 5-HT7 receptors. Under these conditions, [3H]5-HT binding could be further inhibited with methiothepin (used to determine nonspecific binding) and with 5-HT, with an IC50 of 1.4 nM and a slope of 1. The inhibition curves of (+/-)-8-hydroxy-dipropylaminotetralin, ritanserin, and mianserin were shallow (slopes, 0.35-0.58) and could be better analyzed with the two-site model, indicating that the pindolol-insensitive [3H]5-HT binding sites in rat hypothalamic membranes are heterogeneous. Although the IC50 of the compounds tested suggests that one population of sites is actually associated with 5-HT7 receptors, our data clearly indicate that this binding assay does not selectively label 5-HT7 receptors in native tissues. These results challenge a previous report and suggest that the proposed down-regulation of 5-HT7 receptors after fluoxetine treatment should be considered with caution. The development of more selective and sensitive binding assays will probably offer significant advantage.
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PMID:Are 5-hydroxytryptamine7 receptors involved in [3H]5-hydroxytryptamine binding to 5-hydroxytryptamine 1nonA-nonB receptors in rat hypothalamus? 864 96

In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.
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PMID:Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium. 869 81

The mechanism of analgesic action of acetaminophen (paracetamol) remains unknown. However, a central component distinct from that of the NSAIDs (non-steroidal antiinflammatory drugs) seems likely. A recent report (NeuroReport 6:1546-1548, 1995) suggests the involvement of 5-HT3 receptors. In the present study, we measured the affinity of acetaminophen at 5-HT3, as well as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2, 5-HT2C, 5-HT4, 5-HT6, 5-HT7 and eleven other receptor sites and at serotonin and norepinephrine reuptake sites. At 10 microM, acetaminophen inhibited less than 10% specific radioligand binding at any site. These findings: (i) suggest that acetaminophen's effect on serotonergic pathways is indirect, and (ii) circumscribe acetaminophen's possible central analgesic mechanism(s).
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PMID:Lack of binding of acetaminophen to 5-HT receptor or uptake sites (or eleven other binding/uptake assays). 869 17

Citalopram together with fluoxetine, fluvoxamine, paroxetine and sertraline belong to the group of SSRIs, so named because of their pharmacological action as selective serotonin reuptake inhibitors in rat brain synaptosomes-their potency of inhibiting noradrenaline uptake is low and, from a clinical point of view, irrelevant. In contrast to classical tricyclic antidepressants and some antipsychotics, the SSRIs have little affinity for the dopamine D2 receptors, 5-HT1A and 5-HT2A receptors, alpha 1-receptors, beta-receptors, muscarinic receptors and histamine H1 receptors. Several authors have examined whether SSRIs are ligands of other receptors, including the 5-HT3-5-HT7 receptors and their subtypes, and the NMDA receptor, and whether chronic treatment with SSRIs modifies the affinity and binding capacity of these receptors. The SSRIs differ by their pharmacokinetics and pharmacogenetics of metabolism and by their cytochrome P450 isozyme inhibition properties. Some situations are presented in which plasma level monitoring of SSRIs is recommended, despite the lack of clearly defined "therapeutic windows'.
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PMID:Pharmacology and pharmacokinetics of citalopram and other SSRIs. 873 38

The present results show that under constant darkness the endogenous circadian pacemaker located in the suprachiasmatic nuclei can be affected by administration of 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), a well known 5-HT1A/5-HT7 receptor agonist. A single i.p. injection (0.1 ml) with 8-OH-DPAT (5 mg/kg) induced significant phase-advances of hamster locomotor activity at circadian time (CT) 6 and 8 and a significant phase-delay at CT11. Saline injections by themselves induced a significant phase-advance at CT10-11. The dose-response curve for 8-OH-DPAT showed a maximal phase-shifting effect for doses of at least 2.5 mg/kg at CT8. Thus, in golden hamsters. (1) 8-OH-DPAT has a chronobiological effect with sensitivity depending upon the circadian time of injection, and (2) a single saline injection is able to induce regular phase-advances at the end of the subjective day (CT10-11).
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PMID:Phase-shifting effect of 8-OH-DPAT, a 5-HT1A/5-HT7 receptor agonist, on locomotor activity in golden hamster in constant darkness. 876 77

Stimuli that make hamsters active, such as dark pulses or triazolam administration, also phase shift their circadian clocks, producing phase advances during the subjective day and phase delays during the subjective night. Activity or its correlate appears to be important in producing the shifts because preventing locomotion blocks the phase shifts associated with these stimuli. The physiological basis of clock resetting induced by activity is not fully understood. The serotonergic (5-HT) projection from the raphe to the suprachiasmatic nucleus (SCN) is a possible route by which nonphotic information could reach the pacemaker. Administration of 8-HYDROXY-2-(DI-N-PROPYLAMINO) TETRALIN HYDROBROMIDE (8-OH-DPAT), a 5-HT1A and 5-HT7 receptor agonist, at circadian time (CT) 8 produces phase advances in the circadian rhythms of hamsters. Before concluding that 5-HT mediates the effect of activity on the pacemaker, it must be shown that 5-HT agonist do not produce shifts simply because they make animals more active. Therefore, we investigated the contribution of activity to 8-OH-DPAT-produced shifts. Preventing hamsters from moving around after administering 8-OH-DPAT did not abolish phase shifts. Moreover, higher doses of 8-OH-DPAT diminished activity on the day of injection but did not affect the amplitude of phase shifts. Suprisingly, quipazine (a non specific 5-HT agonist), when injected in the middle of subjective day did not phase shift the activity rhythm of hamsters, as it has been reported to do in rats.
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PMID:Serotonergic stimulation and nonphotic phase-shifting in hamsters. 883 98


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