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)

The interactions between 14 days of repeated restraint stress and daily administration of imipramine or tianeptine (2 h before the beginning of stress) were investigated in rats to assess responses of 5-HT2 and 5-HT1A receptors and serotonin transporter sites labelled by [3H]paroxetine in the cerebral cortex and hippocampus, two brain regions in which adrenal steroid effects on serotonin receptor-binding have been reported. 5-HT2 sites, labelled by [125I]7-amino-8-iodo ketanserin, were decreased in parietal cerebral cortex layers 3 and 5 by imipramine treatment, but not by tianeptine treatment and not by daily restraint stress. Stress, but not antidepressant, depressed 5-HT1A sites labelled with [3H]8-hydroxy-DPAT in hippocampal fields CA3, CA4 and dentate gyrus. [3H]paroxetine-binding to serotonin transporter sites was decreased by tianeptine treatment as well as by imipramine in both hippocampus and cerebral cortex, with some overlap of the fields that were significantly affected, whereas there were no effects of stress per se and no evidence of a stress x drug interaction. These results are discussed in relation to similarities and differences in the effects of different antidepressant drugs on the serotonergic system of the rat brain. Whereas the actions of imipramine and tianeptine on 5-HT2 and 5-HT1A receptors are specific to each drug, the surprising finding of a similar effect of both drugs to reduce serotonin transporter sites labelled by [3H]paroxetine suggest the possibility of a common action for these two drugs in spite of their opposite effects on serotonin re-uptake.
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PMID:Stress and antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2 receptors and transport sites for serotonin. 836 29

Altered serotonin indices have been reported in the brain of suicide victims. We sought to localize the changes in presynaptic and postsynaptic serotonin receptors and identify an area of prefrontal cortex that may influence suicide risk. Quantitative autoradiography was performed in coronal sections of prefrontal cortex to determine whether serotonin 5-HT1A receptor (postsynaptic in cortex) and serotonin transporter (presynaptic) binding are different in suicide victims compared to matched controls. 5-HT1A receptor binding was higher in 85 of the 103 sampled areas in the suicide group (n = 18 pairs; P < 0.0001). The increase ranged from 17 to 30%. The increase was more pronounced in the ventrolateral prefrontal cortex. Serotonin transporter binding was found to be lower in the suicide group in all but one of the 43 sampled regions (n = 22 pairs; P < 0.0001). The reduction in binding was most pronounced in the ventrolateral prefrontal cortex, where the difference between suicides and controls ranged between 15 and 27%. Serotonin transporter and 5-HT1A binding were negatively correlated (r = -0.35 to -0.44, P = 0.04 to 0.007) within the same brain areas, suggesting common regulatory factors with opposite effects on binding to the two receptors. We conclude that suicide victims have an abnormality in the serotonin system involving predominantly the ventrolateral prefrontal cortex, and hypothesize that the serotonergic dysfunction in this brain region contributes to the risk for suicidal behavior.
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PMID:Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. 854 98

Selective central benzodiazepine agonists, such as clonazepam, are known to modify serotonin and 5-hydroxyindoleacetic content in the brain. In order to further study the effect of this benzodiazepine on serotonin turnover rate, rats received clonazepam, 10 mg/kg for 10 days, and the concentrations of serotonin and 5-hydroxyindoleacetic acid were determined in the hippocampus after inhibition of monoamineoxidase with pargyline. The results indicate a reduction in the turnover rate of the monoamine. In addition, the systemic administration of clonazepam produced a decrease in the Bmax of [3H]DPAT binding to 5-HT1A sites in the hippocampus. By contrast, this effect was not observed if clonazepam was delivered into the dorsal raphe nucleus by osmotic minipumps. The binding of [3H]paroxetine to 5-HT reuptake sites was increased by the treatment with clonazepam. The present observations indicate that clonazepam produces a reduction of serotonin turnover rate in the hippocampus of the rat concomitant with a down-regulation of 5-HT1A binding sites, probably by an effect at the forebrain projections. There is also an up-regulation of the serotonin transporter, which might contribute to a reduction in the synaptic availability of serotonin during clonazepam treatment.
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PMID:Serotonin turnover rate, [3H]paroxetine binding sites, and 5-HT1A receptors in the hippocampus of rats subchronically treated with clonazepam. 857 30

The saturation parameters and the pharmacological characteristics of the binding of the serotonin 1A (5-HT1A) receptor agonist [3H]8-hydroxy-2-(di-N-propylamino)tetralin ([3H]8-OH-DPAT), as well as the effects of nucleotides and divalent cations (Mg2+, Mn2+) on it, were compared in some human postmortem brain regions: the main cortical areas, hippocampus and striatum. [3H]8-OH-DPAT labelled a single population of recognition sites with the highest maximal capacity (Bmax) in the hippocampus and the lowest affinity in the striatum. Among the various cortical areas, the frontal cortex exhibited the highest Bmax. The pharmacological profile of the [3H]8-OH-DPAT binding sites was consistent with the labelling of the 5-HT1A receptor in the hippocampus and cortex, whereas the striatal site shared strong similarity to the presynaptic serotonin transporter. Modulation of [3H]8-OH-DPAT binding by divalent cations and nucleotides was detectable and stable in autopsy brains. In particular, nucleotide effects were area-dependent: guanosine thiotriphosphate (GTP gamma S) reduced [3H]8-OH-DPAT binding to the same extent in the hippocampus and frontal cortex, while having no effect in the striatum. Divalent cation effects depended also upon the brain area: in the striatum, they inhibited [3H]8-OH-DPAT binding, while stimulating it in the hippocampus and, with less extent, in the frontal cortex. In summary, these findings suggest that the [3H]8-OH-DPAT binding and its modulatory parameters in human brain tissues seem to show similarities but also some differences with respect to those determined in the rat brain. Furthermore, postmortem stability of GTP and divalent cation sensitive 5-HT1A receptors underlines the need for further studies on the regulatory and functional properties of this receptor in the human brain.
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PMID:Further characterisation of [3H]8-hydroxy-2-(di-N-propylamino)tetralin binding sites in human brain postmortem. 901 62

Significant progress has been made in understanding psychosocial, psychological, and environmental factors associated with suicide; however, it is only recently that attention has been paid to the understanding of the neurobiology of suicide. There are several studies that implicate the serotonin (5-HT) system in suicide. Initial evidence was obtained from observations of low 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of depressed patients with a previous history of suicide attempts. Several strategies have been used to examine the serotonergic system in suicidal behavior, which include the determination of serotonin and its metabolites in CSF and postmortem brain tissues as well as serotonin receptor subtypes in postmortem brain tissues, and in platelets of suicidal patients. The neuroendocrine strategy, often termed the "window to the brain," has been extensively used for studying the serotonergic system in suicide. This chapter will review the results obtained from neuroendocrine and serotonin studies in platelets. Initial studies in platelets focussed on determining serotonin uptake and serotonin transporter binding sites in platelets of depressed and suicidal patients. Whereas several studies have found decreased imipramine binding sites of platelets of depressed patients, imipramine binding sites in platelets of suicidal patients showed inconsistent results. Similarly, no consistent changes in 5-HT uptake have been observed in platelets obtained from suicidal patients compared to nonsuicidal patients. On the other hand, studies of platelet 5-HT2A receptors appear to be quite encouraging. Initially, several investigators indicated that they found an increase in platelet 5-HT2A receptors in depressed patients. Subsequently, it was shown that platelet 5-HT2A receptors in suicidally depressed patients were significantly higher compared to nonsuicidally depressed patients and normal control subjects. It has also been shown that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis, similar to platelets. 5-HT2A receptors have also been shown to be increased in the postmortem brain of suicide victims by several investigators, although some investigators do not find such an increase. The neuroendocrine strategy provides an important method for studying serotonin function in the central nervous system of depressed and suicidal patents. Using a serotonergic probe of 5-HT1A receptors, several investigators examined ipsapirone-induced prolactin release in suicidal patients and did not find it different that that of control subjects. On the other hand, fenfluramine, which causes release of serotonin and blocks serotonin uptake, causes a decreased release of prolactin in depressed patients compared to normal control subjects. Furthermore it has been shown by some investigators that fenfluramine-induced prolactin release is also decreased in suicidal patients compared to normal control subjects. In summary, platelet and neuroendocrine studies have provided initial evidence sufficient to suggest serotonergic abnormalities in suicidal patients. Most earlier evidence is based on CSF 5-HIAA studies, but it appears that 5-HT2A receptors in both platelet and postmortem brain samples are increased in suicidal patients. The observation that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis provides a very useful potential biological marker for identifying suicidal patients.
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PMID:Altered serotonin function in suicide. Evidence from platelet and neuroendocrine studies. 961 99

Alterations in serotonergic and noradrenergic receptor binding in membrane homogenates from the brain of suicide victims suggest a biological substrate for the vulnerability to commit suicide. We and others have employed high-resolution quantitative autoradiography of full coronal sections of the prefrontal cortex to map the locus of maximal change in receptor binding. We found alterations in binding to the serotonin transporter, the 5-HT1A, and the 5-HT2A receptors primarily in the ventral and ventrolateral prefrontal cortex of suicide victims. Importantly, these changes are often modest in magnitude and anatomically restricted to one or two Brodmann areas. Furthermore, we have found that care in case selection is essential, because sex, age, drugs, and comorbid diagnoses contribute to receptor binding. The implications for in vivo imaging are considerable, directing the focus of such studies toward the ventrolateral prefrontal cortex. However, because ligands are limited, as is the resolution of current methods, including PET, automated analyses that produce statistical images, rather than manual selection of individual slices, will likely lack the ability to detect the discrete receptor changes found postmortem. Alternatively, the advantages of examining large numbers of subjects, imaging the entire brain, obtaining detailed clinical information in the living patient, and magnifying the changes with neuropharmacological challenges present a promising outlook for making major advances into the identification of brain abnormalities associated with suicide risk.
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PMID:Postmortem findings in suicide victims. Implications for in vivo imaging studies. 961 4

In this study, we investigated the serotonin transport mechanisms in rainbow trout (Oncorhynchus mykiss) peripheral blood Lymphocytes. We have observed that the transport of serotonin is a membrane transport process that have the properties of a secondary active transport system. The binding isotherm of [3H]-paroxetine, a serotonin transport blocker, demonstrated a high-affinity binding site with a positive type of cooperativity, Hill coefficient being higher than unity. Known specific inhibitors of the mammalian serotonin transporter significantly inhibited the uptake process in fish lymphocytes. In order to demonstrate the physiological relevance of the serotonin transporter in T-cell activation, we conducted experiments on lymphocytes activated or not by phytohemagglutinin (PHA), a T-cell mitogen. We have observed that addition of PHA for 24hrs, increased the Vmax but not the Km of this transporter. Serotonin uptake inhibitors diminished the PHA-activated proliferation of fish lymphocytes. The intracellular concentrations of cAMP were found to regulate the serotonin uptake and the PHA-stimulated proliferation as the agents known to augment cAMP stimulated serotonin uptake, and inhibited the lymphoproliferation. Inhibitory effects of increased cAMP on the proliferation were reversed by the addition of the nanomolar concentrations of 8-OH-DPAT, a 5-HT1A receptor agonist which is known to diminish the intracellular cAMP concentrations, suggesting that serotonin also regulates PHA-induced proliferation via 5-HT1A membrane receptors in an autocrine manner. These results all together demonstrate that fish lymphocytes possess an active serotonin transporter that is implicated in the proliferation of these immunocompetent cells.
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PMID:Characterisation of serotonin transport mechanisms in rainbow trout peripheral blood lymphocytes: role in PHA-induced lymphoproliferation. 1022 67

Serotonin (5-HT) plays a crucial neuromodulatory role in numerous physiological and behavioral functions, and dysfunction of the serotonergic system has been implicated in several psychiatric disorders. Despite the widespread importance of the central serotonergic neurotransmitter system, little is known about the molecular mechanisms controlling the development of 5-HT neurons. We previously identified an ETS domain transcription factor, Pet-1, that is expressed in a small number of tissues, including the brain. Here, we show that expression of Pet-1 RNA in the brain is restricted to, and marks, the entire rostrocaudal extent of rat serotonergic hindbrain raphe nuclei. Remarkably, Pet-1 RNA colocalizes with tryptophan hydroxylase-positive neurons in raphe nuclei but not with their nonserotonergic neuron or non-neuronal neighbors. Pet-1 RNA is limited to two domains in the developing hindbrain, which precedes the appearance of 5-HT in each domain by approximately a half day. Conserved Pet-1 binding sites are present in or near the promoter regions of the human and mouse 5-HT1a receptor, serotonin transporter, tryptophan hydroxylase, and aromatic L-amino acid decarboxylase genes whose expression is characteristic of the serotonergic neuron phenotype. These sites are capable of supporting transcriptional activation through interactions with the Pet-1 ETS domain and can function as enhancers. Together, our findings establish Pet-1 as an early and precise marker of 5-HT neurons and suggest that it functions specifically in the differentiation and maintenance of these neurons.
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PMID:The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. 1057 32

Effects of thyroid hormone deficiency on 5-HT1A receptors, 5-HT2A receptors and serotonin transporter in the brain were studied in thyroidectomised Wistar rats receiving an iodine-free diet and receiving 15 micrograms/kg of thyroxine for 21 days. Binding of 3H-8-OH-DPAT to 5-HT1A receptors and 3H-cytalopram to serotonin transporter were unchanged in hypothyroid rats as compared to the control. 3H-ketanserin binding to 5-HT2A receptors was significantly decreased in the frontal cortex in hypothyroid rats. The cortical 3H-ketanserin binding in thyroidectomised rats was normalised after thyroxine replacement. The data suggest that the decrease in the cortical 5-HT2A receptors is the main consequence of impairing effect of hypothyroidism on serotonin neurotransmission.
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PMID:[Effect of hypothyroidism on 5-HT1A-, 5-HT2A-receptors and serotonin transporter in the rat brain]. 1080 28

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.
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PMID:New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants. 1123 Oct 49


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