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)

NIH-3T3 fibroblasts have been transfected with human serotonin 5-HT1A receptors. Clonal cell lines expressed between 40 and 500 fmol receptor/mg. 5-HT1A agonists strongly inhibited nonstimulated- as well as forskolin- or isoproterenol-stimulated adenylyl cyclase. The effects of 5-HT1A receptor activation on cell growth were investigated. 5-HT1A agonists accelerated cell division, generated foci, and increased DNA synthesis. The stimulation of [3H]thymidine incorporation was much stronger when tyrosine kinase receptors were activated concomitantly. Cyclic AMP (cAMP) elevating agents inhibited DNA synthesis induced by all mitogens tested. The mitogenic activity of 5-HT1A agonists did not seem to be linked to adenylyl cyclase inhibition because 1) we were not able to measure any decrease in intracellular cAMP levels under the conditions of DNA synthesis assay and 2) 2',5'-dideoxyadenosine, which strongly inhibited adenylyl cyclase, was not mitogenic and did not modify the mitogenic effects of 5-HT1A agonists. Pertussis toxin completely blocked potentiation of epidermal growth factor effect induced by 8-hydroxy-di-(n-propyl)aminotetralin, a 5-HT1A agonist, but only partially blocked the one induced by insulin. In conclusion, in transfected NIH-3T3 cells, transforming and mitogenic effects of 5-HT1A agonists involve a pertussis toxin-sensitive G protein but do not seem to be linked to adenylyl cyclase inhibition.
Mol Biol Cell 1992 Sep
PMID:Activation of 5-HT1A receptors expressed in NIH-3T3 cells induces focus formation and potentiates EGF effect on DNA synthesis. 133 92

1. Vasoactive intestinal polypeptide (VIP) stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) production by cultured GH4ZD10 cells with an EC50 value of about 7 nM. The extracellularly recovered cyclic AMP predominated, and was reduced by co-incubation with 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT), whereas dopamine (0.1-30 microM) did not reduce VIP-stimulated cyclic AMP production. 2. The responses to 5-HT and 8-OH-DPAT were blocked by (-)-alprenolol and NAN 190. The antagonism by (-)-alprenolol was competitive in nature with a pA2 value of 7.0. 3. The responsiveness of the cells to 5-HT agonists was highly dependent upon the culturing conditions used. Thus, 8-OH-DPAT inhibition of VIP (30 nM)-stimulated cyclic AMP production decreased with increasing passage number of the cells. Reduction of the zinc concentration used to promote expression of the 5-HT1A receptor gene produced a greater sensitivity of the cells to 5-HT agonists. 4. Under such conditions, the following efficacies (5-HT = 100) were found: lisuride 106, (+)-lysergic-acid diethylamide 100, 5-methoxy-N,N-dimethyltryptamine 98, RU 24949 98, 5-carboxamidotryptamine 97, (+/-)-8-OH-DPAT 90, (+)-8-OH-DPAT 87, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine 86, flesinoxan 79/88, (-)-8-OH-DPAT 62, buspirone 43/50, ipsapirone 46. Spiroxatrine and spiperone had a low intrinsic activity, but reduced the response to 5-HT. These efficacies are similar to those reported in the literature for post-synaptically localized 5-HT1A receptors in the rat hippocampus. Thus, the GH4ZD10 cells serve as a useful in vitro model system for these receptors.
Br J Pharmacol 1992 Sep
PMID:GH4ZD10 cells expressing rat 5-HT1A receptors coupled to adenylyl cyclase are a model for the postsynaptic receptors in the rat hippocampus. 133 Jan 57

Administration of various doses of clonidine increased plasma growth hormone levels. Pretreatment with the alpha 2 adrenergic antagonists, yohimbine and 1-(2-pyrimidyl)piperazine, completely blocked clonidine's effect on growth hormone levels. Pretreatment with the 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL-72222, the 5-HT1A/5-HT2 antagonist, spiperone, and the mixed beta adrenergic/5-HT1B antagonists, l-propranolol and CGP361A, did not attenuate clonidine-induced increases in growth hormone levels. In contrast, pretreatment with the non-selective 5-HT1/2 antagonist, metergoline, and the 5-HT1C/5-HT2-selective antagonist, mesulergine, reduced clonidine-induced increases in growth hormone levels 81 to 87% without affecting clonidine-induced decreases in locomotor activity. Two other 5-HT1C/5-HT2 antagonists, ritanserin and mianserin, also attenuated (47%) clonidine-induced increases in growth hormone levels. Pretreatment with the noradrenergic neurotoxin, DSP4, did not block clonidine's effect on growth hormone levels. Clonidine administration decreased locomotor activity in both the Fawn-Hooded and the Wistar rat strains to the same extent. On the other hand, clonidine administration failed to increase growth hormone levels in the Fawn-Hooded rat strain. These findings suggest that clonidine stimulates growth hormone secretion by activation of alpha 2 adrenergic heteroreceptors present on 5-HT nerve terminals which, in turn, enhance 5-HT activity via stimulation of postsynaptic 5-HT1C receptors to promote growth hormone releasing factor. Furthermore, either 5-HT1C receptors or alpha 2 adrenergic heteroreceptors or both are functionally sub-sensitive in the Fawn-Hooded rat strain relative to the Wistar rat strain.
J Pharmacol Exp Ther 1992 Sep
PMID:Functional subsensitivity of 5-hydroxytryptamine1C or alpha 2 adrenergic heteroreceptors mediating clonidine-induced growth hormone release in the Fawn-Hooded rat strain relative to the Wistar rat strain. 135 49

The binding profile of [3H]8-hydroxy-2-(di-N-propylamino)-tetralin ([3H]8-OH-DPAT) to serotonin1A (5-HT1A) sites in rat hippocampal, frontocortical and striatal membranes has been compared. In these regions, [3H]8-OH-DPAT labels both a high and a low-affinity binding site; the affinity values for each of the two sites are comparable in the different brain regions, but have different maximal capacity. By modifying the experimental conditions in a series of hippocampal membrane preparations, reciprocal changes in the proportion of the two sites were observed suggesting that they represent, at least in this region, different conformations or affinity states of a single receptor protein. In contrast to the lower affinity state, it appears that the high-affinity state is stabilized by coupling with a G-protein. Evidence supporting this statement is provided by addition of the guanine nucleotide Gpp(NH)p, breakage of labile disulfide bonds using N-ethylmaleimide and increasing membrane rigidity with ascorbate-induced lipid peroxidation, conditions which all reduced the density of receptors in the high-affinity state. Moreover, the high-affinity state appears to be stabilized at the expense of the lower affinity state in the presence of Mn2+. On the other hand, a complete shift to the low-affinity binding state was observed after a 24 h in vivo treatment with inhibitors of monoamine oxidase A (phenelzine or clorgyline) but not of monoamine oxidase B (deprenyl). This disappearance of the high-affinity state with a concomitant increase in the binding capacity of the low-affinity state was reproduced by inhibiting monoamine oxidase A in vitro, as well as by reducing preincubation washout periods. Also, competitors of the [3H]8-OH-DPAT binding site, such as serotonin and unlabelled 8-OH-DPAT, display two affinity states while others like (+/-)-propranolol, tryptamine and spiperone recognize a single affinity component. These results suggest that the 5-HT1A binding site may exhibit at least two different affinity states depending upon its microenvironment and the intrinsic activity of the ligand used.
Brain Res 1992 Sep 11
PMID:Further evidence for differential affinity states of the serotonin1A receptor in rat hippocampus. 135 3

Constriction of carotid arteriovenous anastomoses is a common property of several antimigraine drugs. The present study concerns the effects of tertatolol (0.1, 0.3, 1 and 3 mg/kg i.v.), a novel beta-adrenoceptor antagonist with an agonist action on 5-HT1A receptors, on systemic haemodynamics and carotid blood flow distribution in the anaesthetized pig. Two other beta-adrenoceptor antagonists, one (propranolol) with and one (pindolol) without antimigraine actions, were compared (doses: 0.03, 0.1, 0.3 and 1 mg/kg i.v.) with tertatolol in this animal experimental model of migraine. While the beta-adrenoceptor antagonist with partial agonist action, pindolol, increased heart rate and cardiac output, propranolol and tertatolol decreased these variables moderately. Mean arterial blood pressure also decreased with the two highest doses of propranolol and with the highest dose of tertatolol. The calculated total peripheral conductance decreased with the first three doses of tertatolol. Carotid haemodynamic variables were not affected by pindolol, except for some increase in the nutrient fraction after the highest dose. Propranolol and especially tertatolol decreased both total carotid blood flow and arteriovenous anastomotic blood flow without affecting the nutrient fraction. In the case of tertatolol, blood flow decreases were accompanied by similar decreases in vascular conductance, indicating active arteriovenous anastomotic constriction. It is therefore suggested that tertatolol may prove effective in the treatment of migraine.
Eur J Pharmacol 1992 Sep 10
PMID:Effects of tertatolol, a beta-adrenoceptor antagonist with agonist affinity at 5-HT1A receptors, in an animal model of migraine: comparison with propranolol and pindolol. 135 48

5-Methoxy-N,N-dimethyltryptamine (5-MeODMT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) facilitate motoneuron excitability through 5-HT1C/5-HT2 receptors in rats. Using spinal cord slices prepared from adult rats, we recorded unitary cell discharges, evoked by local stimulation of the adjacent site, extracellularly in the motor nuclei of the ventral horn. 5-MeODMT, DOI, 5-hydroxytryptamine (5-HT), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and tandospirone facilitated the probability of firing in the motor nuclei, with 5-MeODMT and DOI being the most potent. The effect of 5-MeODMT was significantly suppressed by ketanserin (a 5-HT2 receptor-selective antagonist), spiperone (a 5-HT1A/5-HT2 receptor antagonist) and cyproheptadine (a 5-HT1C/5-HT2 receptor antagonist), but not by 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, a 5-HT3 receptor-selective antagonist) or pindolol (a 5-HT1A/5-HT1B receptor antagonist). This suggests that 5-HT2 and/or 5-HT1C receptors are involved in the facilitatory effects of 5-HT receptor agonists on the synaptic activity of ventral horn cells.
Eur J Pharmacol 1992 Sep 22
PMID:5-HT2/5-HT1C receptor-mediated facilitatory action on unit activity of ventral horn cells in rat spinal cord slices. 135 51

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared with the relatively resistant Fischer F344/N rat, is related to a hyporesponsive hypothalamopituitary-adrenal axis to inflammatory and other stress mediators. Because serotonin (5-HT) and the 5-HT1A receptor are important stimulators of this axis, we have investigated the levels of 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites, 5-HT1A mRNA, 5-HT, and 5-hydroxyindoleacetic acid in various brain regions of Lewis, outbred Harlan Sprague Dawley, and Fischer F344/N rats. Lewis rats expressed significantly fewer hippocampal and frontal cortical 8-[3H]-hydroxy-2,3-(di-n-propylamino)tetralin binding sites and less 5-HT1A mRNA than Harlan Sprague Dawley and Fischer F344/N rats. Adrenalectomy increased the number of 8-[3H]hydroxy-2,3-(di-n-propylamino)tetralin binding sites and 5-HT1A mRNA expression in the hippocampus of all three strains. Levels of hippocampal 5-HT in Fischer F344/N rats were significantly greater than levels detected in the same regions from Lewis and Harlan Sprague Dawley rats. Hypothalamic 5-HT and 5-hydroxyindoleacetic acid levels in Harlan Sprague Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindoleacetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the activity and responsiveness of the hypothalamopituitary-adrenal axis.
J Neurochem 1992 Sep
PMID:Hippocampal 8-[3H]hydroxy-2-(di-n-propylamino) tetralin binding site densities, serotonin receptor (5-HT1A) messenger ribonucleic acid abundance, and serotonin levels parallel the activity of the hypothalamopituitary-adrenal axis in rat. 137 29

1. The ability of various anxiolytic and potential anxiolytic agents to modify 5-hydroxytryptamine (5-HT) release in the frontal cortex of the rat was assessed by the microdialysis technique. 2. The benzodiazepine receptor agonist, diazepam (2.5 mg kg-1, i.p.), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.32 mg kg-1, s.c.) and the 5-HT1A receptor partial agonist buspirone (4.0 mg kg-1, i.p.) maximally reduced extracellular levels of 5-HT in the rat frontal cortex by approximately 50-60%, 70-80% and 30-40%, respectively. 3. (R)-zacopride (1.0-100 micrograms kg-1, i.p.) dose-dependently reduced extracellular levels of 5-HT in the rat frontal cortex (approximately 80% maximal reduction) whereas the other 5-HT3 receptor antagonists ondansetron (10 micrograms kg-1, i.p.) and (S)-zacopride (10-100 micrograms kg-1, i.p.) were ineffective. 4. In contrast to (S)-zacopride (100 nM; administered via the microdialysis probe), (R)-zacopride (1.0-100 nM; administered via the microdialysis probe) induced a concentration-dependent reduction in extracellular levels of 5-HT in the rat frontal cortex (approximately 70% maximal reduction). 5. In contrast to ondansetron (100 micrograms kg-1, i.p.), (S)-zacopride (10-100 micrograms kg-1, i.p.) dose-dependently reversed the (R)-zacopride (10 micrograms kg-1, i.p.) induced reduction in extracellular levels of 5-HT in the rat frontal cortex. The highest dose of (S)-zacopride (100 micrograms kg-1, i.p.) completely prevented the (R)-zacopride response.In addition, (S)-zacopride (100 nM; administered via the microdialysis probe) attenuated the inhibitory action of (R)-zacopride (10 nM; administered via the microdialysis probe) on extracellular levels of 5-HT in the rat frontal cortex.6. In conclusion, the present study provides further evidence of the ability of diazepam, 8-OH-DPAT and buspirone to reduce the activity of the central 5-hydroxytryptaminergic system in vivo. Furthermore,the results indicate that the ability of (R)-zacopride to reduce the in vivo release of 5-HT in the rat frontal cortex does not correlate with its 5-HT3 receptor antagonism. However, the differential affinity of (R)- and (S)-zacopride for a (S)-zacopride-insensitive (R)-zacopride site in rat cerebral cortex mirrors the relative activity of the two zacopride stereoisomers to modify the in vivo release of 5-HT in the frontal cortex of the rat and their ability to release suppressed behaviour in animal models of anxiety.
Br J Pharmacol 1992 Sep
PMID:Differential modulation of extracellular levels of 5-hydroxytryptamine in the rat frontal cortex by (R)- and (S)-zacopride. 138 6

During enrichment of the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-binding serotonin 5-HT1A receptors from sheep brain gray matter (membrane isolation, detergent solubilization and reconstitution into vesicles) a consistent and striking increase in the composition of saturated fatty acids was observed in phospholipids which were coisolated with the receptors. A rapid procedure has been developed for the methylation of free and phospholipid linked fatty acids which were thus analyzed by gas chromatography-mass spectrometry (GC/MS). Esterification of free fatty acids and transesterification of phospholipid linked fatty acids were achieved with 14% boron trifluoride in methanol (BF3-CH3OH) in 20 s and 50 s, respectively, under low power microwave irradiation (60 W) with a post-reaction cooling of less than 5 min. This is in contrast to the conventional method of heating in a boiling water bath for 10-15 min with BF3-CH3OH which is inevitably preceded by time-consuming and inconvenient clamping of vials and followed by cooling for 10 min before the vials can be safely opened. Analysis of fatty acid profiles in phosphatidylethanolamine (PE) and phosphatidylcholine (PC) from egg yolk, phosphatidylinositol (PI) from bovine liver and phosphatidylserine (PS) from bovine brain by both techniques showed comparable results. During detergent solubilization of sheep brain gray matter, the overall proportion of saturated fatty acids in PE (major lipid), PI, PC (major lipid) and PS increased from 50-60% in sheep brain phospholipids to 70-75% in 1.5% CHAPS solubilized, reconstituted and biologically active serotonin 5-HT1A preparations. In sharp contrast, the proportions of saturated fatty acids in 1.5% Triton X-100 solubilized PE (48.1%) (major lipid), PI (63.6%), PC (60.6%) (major lipid) and PS (62.2%) were not significantly different from those in the original sheep brain membranes. Strikingly, this was coupled with the occurrence of very low levels of 5-HT1A receptor activity in the Triton X-100 solubilized preparations. The abundance of 5-HT1A sites in the enriched vesicles obtained only from the CHAPS-solubilized preparations was further confirmed by specific radiolabeling of a 58-kDa polypeptide by the 5-HT1A specific ligand p-aminophenylethyl-m-trifluoromethylphenylpiparazine (PAPP) which was coupled to a 125I-labeled, photoreactive, heterobifunctional cross-linker, sulfosuccinimidyl-2-(p-azidosalicylamido)ethyl-1,3'-dithiopropiona te (SASD). Thus CHAPS-solubilized 5-HT1A receptor preparations are depleted in the more rigid lipids such as sphingolipids and cholesterol, (Banerjee et al. (1990) Biochim. Biophys. Acta 1044, 305-314), but are enriched in vesicle-stabilizing, phospholipid-linked saturated fatty acids which in turn probably stabilize the heptahelical, membrane bound 5-HT1A receptor.
Biochim Biophys Acta 1992 Sep 21
PMID:Enrichment of saturated fatty acid containing phospholipids in sheep brain serotonin receptor preparations: use of microwave irradiation for rapid transesterification of phospholipids. 139 Aug 37

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT1B and 5-HT1D sites, Serotonin-5-O-Carboxymethyl-Glycyl[125I]Tyrosinamide ([125I]GTI). [125I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, Bmax = 191 +/- 47 fmol/mg protein, pKD (-log mol/l) = 8.50 +/- 0.13, n = 5. The pharmacological profile of [125I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT1D sites (using either [3H]5-HT or [125I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamido-tryptamine greater than 5-HT = dihydroergotamine greater than or equal to ergotamine greater than or equal to sumatriptan greater than or equal to CGS 12066 greater than or equal to metergoline greater than yohimbine greater than or equal to methysergide greater than ICYP greater than 8-OH-DPAT greater than or equal to CP 93129 greater than (-)pindolol greater than ketanserin greater than isamoltane greater than mesulergine greater than corynanthine greater than buspirone greater than MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and mesulergine (in order to mask 5-HT1A and 5-HT1C binding sites) and [125I]CYP (iodocyanopindolol) in the presence of 3 mumol/l isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask beta adrenoceptor and 5-HT1A binding sites). There was no detectable specific binding of [125I]CYP through the brain, thus excluding the presence of 5-HT1B sites in rabbit brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Naunyn Schmiedebergs Arch Pharmacol 1992 Sep
PMID:"5-HT1R" or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain. 140 10


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