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)

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a 5-HT1A receptor-selective agonist that has recently been reported to trigger adrenal catecholamine release and hyperglycemia. The aim of this study was to analyze in the conscious rat whether the 5-HT1A receptor subtype is involved in these effects. 8-OH-DPAT (0.1-1 mg/kg, i.v.) evoked dose-dependent increases in plasma adrenaline and glucose concentrations. Increases in plasma adrenaline levels peaked 5 min after administration of 8-OH-DPAT; in contrast, plasma glucose levels rose throughout the 20 min period of analysis. Prior administration of (-)pindolol, a beta-adrenoceptor antagonist that blocks 5-HT1A receptors, markedly diminished the rise in plasma adrenaline levels and abolished the hyperglycemia triggered by 8-OH-DPAT. On the other hand, neither the selective beta 1-adrenoceptor antagonist, betaxolol, the selective beta 2-adrenoceptor antagonist, ICI 118.551, nor the 5-HT2 receptor antagonist, ketanserin, affected 8-OH-DPAT-induced increases in plasma adrenaline levels. In addition, except for ICI 118.551 pretreatment, which delayed the hyperglycemic effect of 8-OH-DPAT, none of these antagonists affected the rise in glycaemia evoked by 8-OH-DPAT. The data suggest that the adrenaline-releasing and a major part of the hyperglycemic effects of 8-OH-DPAT are mediated by activation of 5-HT1A receptors.
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PMID:Evidence that 5-HT1A receptors are involved in the adrenaline-releasing effects of 8-OH-DPAT in the conscious rat. 197 Jun 16

The response of guinea pig trachea to 5-hydroxytryptamine (serotonin; 5-HT) was investigated by studying tracheal strips suspended in organ chambers for isometric tension measurements. Serotonin concentrations of 0.1 to 10 microM produced concentration-dependent contractions, whereas at higher concentrations (10-300 microM) the agonist caused concentration-dependent relaxations. The 5-HT2 antagonist ketanserin shifted the bimodal 5-HT response-curve to the right (pA2 for ketanserin was 8.98). The 5-HT1A agonist, (+)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide and 5-HT3 antagonist, ICS 205930 (3-tropanyl-indole-3-carboxylate) had no effect on the 5-HT-response curve. Incubation with atropine resulted in a depression of the maximal contractility and an increase in the EC50 without changing the bimodal nature of the concentration-response curve. Hexamethonium was able to block the atropine effect without significantly affecting the 5-HT concentration-response curve. Neither the constriction nor the relaxation was altered by propranolol, chlorpheniramine or capsaicin pretreatment. Histamine and carbachol preconstricted airways were also relaxed by 5-HT in a concentration-dependent fashion and this relaxation was antagonized by ketanserin (pKb for ketanserin in histamine preconstricted airways was 9.4). Epithelial denudation did not inhibit the 5-HT-induced relaxation. 5-HT stimulated inositol-monophosphate production which also exhibited a bimodal response and correlated well with the functional response. The above findings suggest that 5-HT causes both constriction and relaxation of the guinea pig airway, and that both responses are antagonized by a 5-HT2 receptor blocker. In addition, part of the constrictor response of 5-HT is mediated through a cholinergic preganglionic pathway. Finally, inositol-monophosphate production induced by 5-HT correlates with the functional response.
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PMID:Serotonin induces constriction and relaxation of the guinea pig airway. 197 97

The aim of the present experiments was to investigate whether 8-OH-DPAT, a selective 5-HT1A agonist, could induce vasoconstriction in vivo and, if so, the type of receptors functionally involved. Dose-response curves to bolus intravenous doses of 8-OH-DPAT were established in anesthetized spinally pithed rats. The peak increase in the mean arterial pressure-log dose (microgram/kg) relationship was fitted to a sigmoidal logistic equation. In the control group, the dose-response curve was steep. The half maximal dose was 743 micrograms/kg. The maximal response was 43 mmHg. Ketanserin, a potent 5-HT2 and alpha 1-adrenoceptor antagonist (0.25 mg/kg), essentially abolished the effect of 8-OH-DPAT (maximal rise = 6 mmHg). Ritanserin (0.25 mg/kg) and LY 53857 (100 micrograms/kg), which have relatively weak affinity for alpha 1-adrenoceptors, also markedly reduced the pressor action of 8-OH-DPAT (maximal rise 17 and 9 mmHg). Prazosin, an alpha 1-adrenoceptor antagonist, slightly reduced the maximal response to 8-OH-DPAT (22% reduction). Adrenalectomy did not affect the pressor response (42 mmHg). This excluded a contribution of an acute release of adrenaline in the blood pressure elevation. (-)Propranolol (5 mg/kg), a beta-blocker with a 5-HT1A antagonistic action, affected the 8-OH-DPAT-induced blood pressure elevation (37% reduction). However, two other beta-blockers with a similar 5-HT1A antagonistic property, (-)pindolol (5 mg/kg) and (+/-)cyanopindolol (10 mg/kg), did not (maximal rise 44 and 39 mmHg). Finally, 8-OH-DPAT dose-dependently increased local vascular resistances, with a regional profile similar to that of 5-HT, with the hindquarter being the most sensitive vascular bed. Ketanserin also prevented the vascular effects of 8-OH-DPAT. Our pharmacological analyses of the vascular action of 8-OH-DPAT in the spinally pithed rat indicated that this drug caused dose-related increases in blood pressure. This effect depended on a rise in peripheral vascular resistance, particularly in the hindquarter and kidney beds. Our data suggest that the 5-HT1A agonistic property of 8-OH-DPAT cannot account for this pressor effect which seems to depend on the activation of the vascular 5-HT2 receptor.
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PMID:Evidence that 5-HT2 receptors mediate the pressor effect of 8-OH-DPAT in the spinally pithed rat. 198 65

The genetically dystonic (dt) rat is an animal model of dystonia that displays sustained abnormal movements that include: torticollis, clasping of the hindlimbs, rigidity of the limbs, and contortions of the trunk. Since serotonin (5-HT) has been shown to be involved in some animal models of movement disorders, the functional responsiveness of the 5-HT system in dt rats and phenotypical normal littermates was examined by administering 5-HT agonists selective for different receptor subtypes and observing behavioral responses associated with the activation of specific 5-HT receptor subtypes. The dt rats were 6-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to produce the 5-HT behavioral syndrome. The dt rats demonstrated a diminished head-shaking response following administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB). However, the dt rats also displayed significantly fewer head shakes following mechanical stimulation of the aural pinnae. The inability of the dt rats to demonstrate head-shaking behavior following stimulation of 5-HT2 receptors is probably due to the dt rat's difficulty in producing the motor responses involved in this behavioral response and do not reflect alterations in 5-HT2 receptor sensitivity. These results suggest that the 5-HT system, particularly 5-HT1A receptors, may have an integral role in the abnormal movements displayed by the genetically dystonic rat and movement disorders in general.
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PMID:Altered behavioral responses mediated by serotonin receptors in the genetically dystonic (dt) rat. 201 8

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.
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PMID:Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. 201 33

The pharmacological characteristics of hindlimb scratching induced by serotonergic compounds were studied. We conclude that hindlimb scratching induced by serotonergic compounds is mediated by a serotonin1D (5-HT1D) or 5-HT1D-like receptor outside the blood-brain barrier because hindlimb scratching could be induced by s.c. injection of 5-methoxytryptamine (5-MeOT), 5-carboxamidotryptamine (5-CT), bufotenine, 5-hydroxytryptamine (5-HT) and tryptamine. These compounds have high affinity for 5-HT1A and 5-HT1D receptors. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the 5-HT1C receptor agonist MK 212, and the mixed 5-HT1C/5-HT2 receptor agonists (dl)-1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and quipazine did not induce hindlimb scratching. Rather, the latter compounds attenuated 5-MeOT-induced hindlimb scratching. The 5-HT releasing compounds fenfluramine and p-chloroamphetamine (PCA) inhibited whereas the 5-HT re-uptake inhibitors fluvoxamine and indalpine potentiated 5-MeOT-induced hindlimb scratching. 5-MeOT-induced hindlimb scratching could be inhibited dose dependently by the alpha 2-adrenoceptor blockers yohimbine and rauwolsince, which also have high affinity for 5-HT1D receptors, whereas the alpha 2-adrenoceptor blocker piperoxan only weakly counteracted hindlimb scratching. Haloperidol, apomorphine, morphine, clonidine and methiothepin strongly attenuated hindlimb scratching, atropine, naloxone and ICS 205930 attenuated it weakly whereas domperidone, methylatropine and mepyramine were inactive in doses up to 10 mg/kg. Hindlimb scratching induced by 5-MeOT was potentiated by the 5-HT receptor antagonists metergoline, methysergide, mesulergine, mianserin, ritanserin and xylamidine. Hindlimb scratching was not induced by i.c.v. injection of 5-MeOT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A peripheral 5-HT1D-like receptor involved in serotonergic induced hindlimb scratching in rats. 206 Jun 1

The study concerns the effects of indorenate, a tryptamine derivative with antihypertensive properties as well as high affinity for the 5-HT1A binding site, on carotid haemodynamics in anaesthetized pigs. Intracarotid infusions of indorenate (0.3, 1.0, 3.0 and 10.0 micrograms.kg-1.min-1 for 10 min each) caused dose-related decreases in total common carotid artery blood flow due almost exclusively to a reduction in arteriovenous anastomotic flow. These effects of indorenate were not appreciably modified after treatment with the 5-HT2 receptor antagonist ketanserin (0.5 mg.kg-1 i.a.), but were markedly reduced after treatment with methiothepin (1.0 mg.kg-1 i.a.), which antagonizes not only 5-HT2 receptors, but also the putative 5-HT1A, 5-HT1B 5-HT1C and 5-HT1D subtypes of 5-HT1-like receptors. Nonetheless, metergoline (1 mg.kg-1 i.a.), a drug with higher affinity than methiothepin for the above 5-HT1 receptor subtypes, failed to significantly modify the responses to indorenate. It is therefore concluded that, like 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), indorenate reduces both total common carotid and cephalic arteriovenous anastomotic blood flow in the pig by stimulating 5-HT1-like receptors; these receptors, however, do not seem to correspond to either 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites.
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PMID:Constriction of porcine arteriovenous anastomoses by indorenate is unrelated to 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptor subtypes. 207 52

Recently, the family of G protein-coupled serotonin (5-hydroxytryptamine[5-HT]) receptors has begun to yield to molecular analysis. The cloning of the 5-HT1C and 5-HT2 receptors has provided a structural basis for the similarities observed in their pharmacologic properties. Furthermore, pharmacologic characterization of the transfected human 5-HT2 receptor has answered two outstanding questions regarding this receptor. First, the few amino acid differences that exist between the human and the rat genes are sufficient to account for the species differences seen in their pharmacologic properties. Second, the single protein encoded by the human 5-HT2 receptor gene is capable of binding both [3H]DOB and [3H]ketanserin. Analysis of the effects of guanine nucleotides provides further evidence that this single protein binds both ligands, that this receptor has high- and low-affinity states, and that these states are partially interconvertible. Furthermore, the close relationship between the adrenergic receptors and the 5-HT1A receptor has been reaffirmed by the recent cloning of a new adrenergic receptor subtype, alpha 2B, by use of the 5-HT1A receptor sequence. Finally, the detailed level of structural information now available on serotonin receptors has yielded valuable information about the ligand binding site and about the possible functional significance of differing rates of evolutionary change in various parts of the gene.
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PMID:The molecular biology of serotonin receptors. An overview. 207 70

We review our results from the first computational simulations of a mechanism by which ligands can activate a 5-HT1A receptor, and relate the findings to information on the structure and function of the authentic receptor. The computational exploration of the recognition and activation mechanisms is carried out inside a protein selected as a model for the receptor based on cognate physicochemical and experimental data. A similar approach is applied to the 5-HT2 receptor. The interaction mechanisms at the two 5-HT receptor subtypes differ in the nature of the forces determining ligand-receptor interactions and the types of receptor activation mechanisms they entail. The main molecular property related to recognition at 5-HT1A receptors was shown to be the directional character of the electrostatic potential generated by the ligands in the molecular region corresponding to the indole in 5-HT. The corresponding recognition site was shown to have properties of a positively-charged (imidazolium) form of the side chain of a His residue. The mechanism of recognition at the 5-HT1A receptor was shown to be electrostatic, and conducive to a triggering of the receptor response through the change in the electronic structure of the imidazolium recognition site when it interacts with an activating ligand (agonist). This effect was shown to induce a proton transfer from the ring to a neighboring residue to which it can be hydrogen-bonded in the resting state. We show how this model for recognition and activation defines in molecular terms the mechanisms underlying the classical pharmacologic properties of agonists, partial agonists, and antagonists. The molecular correlates of pharmacologic efficacy emerge from the calculations of the effect of the ligands on the barriers for proton transfer, and on the energy drive for the proton transfer reaction. A different model is proposed for selective recognition at the 5-HT2 receptors, based on structural details of 5-HT-binding peptides. The recognition site is considered to consist of two aromatic residues separated by a hydrophilic residue. In contrast to the model for 5-HT1A, the recognition is based on the interaction of neutral molecules and the stabilization is provided by dispersion forces. The resulting activation mechanism is based on a structural rearrangement. These detailed descriptions of elements in the ligand-receptor interactions at the two receptor subtypes lead to a new basis for rational design of receptor-selective compounds with predetermined efficacy.
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PMID:On the structural and mechanistic basis of function, classification, and ligand design for 5-HT receptors. 207 75

The mechanisms by which imipramine and dihydroergosine stimulate the 5-HT syndrome in rats and inhibit the head-twitch response in rats and mice were studied. Imipramine- and dihydroergosine-induced stimulation of the 5-HT syndrome was inhibited stereoselectively by propranolol, a high affinity ligand for 5-HT1 receptor sites, but not by ritanserin, a specific 5-HT2 receptor antagonist. (-)-Propranolol potentiated the inhibitory effect of imipramine, but not of dihydroergosine on the head-twitch response, while ritanserin was without effect. Neither imipramine nor dihydroergosine were able to stimulate the 5-HT syndrome in the animals pretreated with p-chlorophenylalanine. As expected, 8-OH-DPAT, a selective 5-HT1A receptor agonist, stimulated, and 5-HT1B agonists CGS 12066B and 1-(trifluoromethylphenyl)piperazine (TFMPP) failed to stimulate the 5-HT syndrome induced in rats by pargyline and 5-HTP administration. A higher dose of ritanserin inhibited the syndrome. While 8-OH-DPAT alone produced all behavioral components of the 5-HT syndrome, dihydroergosine or imipramine alone even at very high doses never produced tremor or a more intensive forepaw padding as seen when these drugs were given in combination with pargyline and 5-HTP. A single administration of (-)-propranolol also inhibited the head-twitch response. This effect lasted in mice longer than after ritanserin administration. In in vitro experiments dihydroergosine expressed approximately twenty-fold higher affinity for 3H-ketanserin binding sites than imipramine. The results suggest that imipramine and dihydroergosine possess two components--one stimulating the 5-HT syndrome in rats by a presynaptic, presumably 5-HT1A-mediated mechanism, and the other inhibiting 5-HT2 binding sites.
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PMID:Do imipramine and dihydroergosine possess two components--one stimulating 5-HT1 and the other inhibiting 5-HT2 receptors? 211 65


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