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)

At birth, the rat renal papilla has the structural composition of the mature inner stripe of the outer medulla. All loops of Henle have the configuration of short loops, and there are no ascending thin limbs. This study examines the role of apoptosis in the differentiation of the loop of Henle and the development of the ascending thin limb in the rat kidney. Kidneys of 20-day-old fetuses and 1-, 3-, 5-, 7-, 14-, and 21-day-old pups were preserved for immunohistochemistry and electron microscopy. Using a preembedding immunoperoxidase method, we identified thick ascending limbs by labeling with antibodies to the serotonin receptor, 5-HT1A, and descending thin limbs were identified by labeling with antibodies to aquaporin-1. Three methods were used to identify apoptotic cells as follows: 1) in situ nick end labeling using the ApopTag kit, 2) toluidine blue staining on plastic sections followed by etching, and 3) transmission electron microscopy. At birth, tubules with 5-HT1A immunoreactivity were present throughout the renal papilla, and there were no ascending thin limbs. From 1 to 14 days of age, staining for apoptosis was observed in numerous cells in the 5-HT1A-positive epithelium, beginning at the papillary tip and ascending to the border between outer and inner medulla. This was associated with transformation from a cuboidal to a squamous epithelium and subsequent disappearance of 5-HT1A immunostaining from the transformed cells. Electron microscopy confirmed the presence of apoptotic cells and phagocytosed apoptotic bodies in the thick ascending limb in the renal papilla. We conclude that the ascending thin limb is derived from the 5-HT1A-positive thick ascending limb by apoptotic deletion of thick ascending limb cells and transformation of the remaining tubule cells into the 5-HT1A-negative ascending thin limb.
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PMID:Role of apoptosis in development of the ascending thin limb of the loop of Henle in rat kidney. 889 13

In order to set up the technique of semi-quantitative in situ hybridisation to detect the serotonin receptor mRNA levels in brain tissue, a panel of three Swiss 3T3 cell clones (named clones 66, 53 and 47) expressing the human 5-HT1A receptor at different densities were used as a model. The clones were generated by limiting dilution from pools of stably transfected cells. In addition membranes were prepared from each clone to perform receptor binding studies. Clones 66, 53, and 47 showed saturable binding for the agonist [3H]-8-OH-DPAT, with receptor densities (Bmax) of 227 +/- 86, 548 +/- 107 and 1505 +/- 212 fmol/mg protein respectively, and with corresponding affinity constants (pKd) of 8.8 +/- 0.1, 9.1 +/- 0.1, and 9.1 +/- 0.1 nM, respectively. Northern blot analysis using a specific probe for the 5-HT1A receptor revealed the presence of a single 1.56 kilobase mRNA species in the 5-HT1A receptor clones but not in control cells. In situ hybridisation studies were performed by measuring the 5-HT1A receptor mRNA levels in these three 5-HT1A transfectants using [35S]alphaCTP labeled riboprobes (sense and anti-sense). The following rank order of receptor mRNA expression was found for clones 66, 53 and 47 respectively: 0.140 +/- 0.001, 0.365 +/- 0.045 and 0.835 +/- 0.115 (relative optical density units). With the sense probe no specific labelling was observed. In conclusion, a positive correlation was found between receptor density (Bmax) and receptor mRNA expression (semi-quantitative in situ hybridisation) using human 5-HT1A receptor clones with different expression levels.
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PMID:Combined in situ hybridisation, northern blot analysis, and receptor binding studies in clones expressing different levels of the human 5-HT1A receptor. 890 56

A potent and selective serotonin (5-HT1A) partial agonist with potential as a human anxiolytic drug was given in oral doses of 0, 5, 15, or 50 mg/kg/day by gavage to Sprague-Dawley rats for 6 or 12 mo. Some animals were allowed 1 mo to recover after each treatment period. The 10-fold increase in dose resulted in a 20-fold increase in drug plasma concentration due to saturable first-pass metabolism. This resulted in disproportionately higher concentrations and greater bioavailability of the 15- and 50-mg/kg/day regimens. Drug exposure was associated with decreased spontaneous activity in the 15- and 50-mg/kg rats. The activity of these rats returned to normal during the recovery period. There were significant (p < 0.05) decreases in mean body weights during the study for 50-mg/kg males, with improvement during the recovery periods. No biologically significant effects were noted in clinical laboratory parameters. Based on organ weight increases and histopathological evaluation, drug-related effects after 6 and 12 mo of treatment were in the pituitary (both sexes) and all treated female reproductive organs. In general, these effects persisted into periods of recovery, except for pituitary hyperplasia, which was not apparent following recovery after treatment for 6 mo. After treatment for 12 mo and the following recovery, there were significant increases in adrenal weights in the 15- and 50-mg/kg/day males with no morphological correlate. There was increased pituitary hyperplasia that persisted through the recovery period in all treated groups in both sexes, but there was no increase in pituitary neoplasms. In treated females, there was also morphologic evidence of persistent diestrus (estrogenic effect) evidenced by endometrial squamous metaplasia, increased corpora lutea, vaginal mucification, and decreased uterine size. The clinical and pathological changes seen with these 2 regimens were considered exaggerated pharmacological effects of the drug on serotonin receptor-rich organs.
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PMID:Effects found in a one-year oral toxicity study in Sprague-Dawley rats of a novel 5-HT1A receptor partial agonist for the treatment of anxiety in humans. 899 11

The serotonergic system appears to play a role in behaviors that involve a high cognitive demand and in memory improvement or recovery from impaired cognitive performance, as made evident after administration of serotonin 5-HT2A/5-HT2C or 5-HT4 receptor agonists or 5-HT1A or 5-HT3 receptor antagonists. These serotonin receptor subtypes are localized on 'cognitive' pathways, with the hippocampus and frontal cortex as the main target structures. A better understanding of the role played by these and other serotonin receptor subtypes in cognition is likely to result from the recent availability of new specific ligands and new molecular tools, such as gene knock-out and transgenic mice.
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PMID:Serotonin receptors in cognitive behaviors. 914 56

The aim of the present study was to compare the effects of citalopram, either alone or combined with 5-HT1A receptor antagonists, on extracellular serotonin levels in brain regions innervated by the dorsal or median raphe nuclei. Using intracerebral microdialysis in awake rats with separate probes in the frontal cortex or dorsal hippocampus, we studied the ability of 8 mg/kg s.c. (-)penbutolol, a beta-adrenoceptor antagonist with antagonist action at 5-HT1A and 5-HT1B receptors, and 0.3 mg/kg s.c. WAY-100635, a selective 5-HT1A receptor blocker, to modify the effect of 1 and 10 mg/kg i.p. citalopram on extracellular serotonin. Both doses of citalopram had more effect on extracellular serotonin levels in the dorsal hippocampus than in the frontal cortex. The effect of 1 mg/kg citalopram was significantly potentiated by (-)penbutolol in the frontal cortex only, but a clear-cut potentiation of the effect of citalopram was seen in both regions at a dose of 10 mg/kg. The effect of 10 mg/kg citalopram was potentiated by WAY-100635 in the frontal cortex but not in the dorsal hippocampus. In a second set of experiments, the combined effect of WAY-100635 and citalopram was studied in the same rat implanted with vertical probes in the striatum and dorsal hippocampus. Citalopram (1 and 10 mg/kg i.p.) raised extracellular serotonin to a similar extent in both regions. However, 0.3 mg/kg s.c. WAY-100635 potentiated the effect of 10 mg/kg citalopram in the striatum but not in the dorsal hippocampus. The results suggest that only a combined blockade of 5-HT1A and 5-HT1B receptors potentiates the effect of citalopram on extracellular concentrations of serotonin in the dorsal hippocampus. The findings may be relevant in designing clinical trials aimed at enhancing the antidepressant action of selective serotonin re-uptake inhibitors by combining them with serotonin receptor antagonists.
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PMID:Effect of 5-HT1A receptor antagonists on citalopram-induced increase in extracellular serotonin in the frontal cortex, striatum and dorsal hippocampus. 922 71

Although serotonin has been shown to play an important role in peripheral pain mechanisms, the specific subtypes of serotonin receptors involved in pain and hyperalgesia remain poorly understood. To date, no previous study has attempted to determine the presence of any serotonin receptor subtype in human dorsal root ganglia. In this study, the presence of messenger RNA for eight human serotonin receptor subtypes in lumbar dorsal root ganglia was detected using the method of polymerase chain reaction. Dorsal root ganglia were excised post mortem from four patients. Oligonucleotide primers were chosen based on unique regions of complimentary DNA sequence for eight cloned human serotonin receptor subtypes (i.e. 5-HT1A, 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2C and 5-HT7). The presence of 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A and 5-HT7 receptor subtype messenger RNA was detected in dorsal root ganglia from three of the four subjects. 5-HT1A receptor subtype messenger RNA was detected in one of the four subjects. No 5-HT2C receptor subtype messenger RNA could be detected. Findings from this study may direct further efforts to determine the role of serotonin receptors in the peripheral nervous system.
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PMID:5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study. 931 30

Little is definitively known of the identity or actions of neurotransmitters utilized within mammalian taste buds. Serotonin has been immunocytochemically localized to taste cells of several species but its physiological actions are unknown. Using whole-cell patch clamp recordings on dissociated posterior rat taste cells, data are presented to suggest that exogenously applied serotonin inhibits a calcium-activated potassium current by up to 50%. This current, best visualized at depolarized holding potentials, is both apamin- and charybdotoxin-sensitive. Approximately 60% of the tested taste cells were serotonin sensitive. This inhibition was mimicked by N-(3-trifluoromethylphenyl)piperazine (TFMPP), a general serotonin receptor agonist, by 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, but not by phenylbiguanide, a 5-HT3 receptor agonist. These are the first data to establish a physiological effect of serotonin on mammalian taste cells.
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PMID:Serotonin inhibits calcium-activated K+ current in rat taste receptor cells. 935 53

A series of substituted 4-[2-(5-benzimidazole)ethyl]-arylpiperazines was synthesized by introducing different substituents into position 2 of benzimidazole ring of 4-[2-(N,N-di-n-propyl-amino)ethyl]-1, 2-diaminobenzenes. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nuclei and hippocampi, respectively. Tritiated SCH 23390 (D1 receptor-selective), spiperone (D2 receptor selective) and 8-OH-DPAT (5-HT1A receptor selective) were employed as the radioligands. Only compound 6 expressed a moderate binding affinity at the dopamine D1 receptor, while the remaining ligands were inefficient or weak competitors of [3H]SCH 23390. Compound 12 was an absolutely inactive competitor of all three radioligands. Also, compound 7 was an inefficient displacer of [3H]-8-OH-DPAT. Compound 19 with a Ki value of 3.5 nM was the most potent competitor of [3H]spiperone and compound 13 (Ki = 3.3 nM) was the most efficient in displacing [3H]-8-OH-DPAT from the 5-HT1A serotonin receptor. Ligands 5,6,8-11, and 13-20 expressed mixed dopaminergic/serotonergic activity in nanomolar range of concentrations with varying affinity ratios which strongly depended on the properties of the substituents introduced into position 2 of benzimidazole ring of the parent compounds.
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PMID:Mixed dopaminergic/serotonergic properties of several 2-substituted 4-[2-(5-benzimidazole)ethyl]-1-arylpiperazines. 950 98

Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT2A and 5-HT1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the delta9-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT2A, but not the 5-HT1A, receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.
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PMID:Structural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamide. 953 97

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


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