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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study in rat spinal cord synaptosomes was to compare the pharmacological characteristics of the serotonin (5-HT)1B receptor defined by [125I]iodocyanopindolol [( 125I] ICYP) binding and the 5-HT autoreceptor defined by inhibition of [3H]-5-HT release. In Percoll gradient Fractions 3 and 4 of spinal cord synaptosomes, a single saturable binding site for [125I]ICYP with a maximum binding of 70 and 134 fmol/mg, respectively, was demonstrated in the presence of 30 microM isoproterenol. The Kd of 0.16 nM did not vary between fractions. Competition for [125I]ICYP binding by various 5-HT agonists and antagonists also indicated a single site model based on a Hill coefficient of approximately 1.0. The most potent compounds at displacing [125I]ICYP binding were RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), 5-carboxyamidotryptamine HCl, 5-methoxytryptamine, 5-HT and CGS 12066B (7-trifluoromethyl-4(4 methyl-1-pyrolo[1,2-a]-quinoxaline malate). [125I]ICYP binding was not altered by compounds with activity at 5-HT1A, 5-HT1C, 5-HT2, 5-HT3 or alpha-2 receptor sites. Similar to the pharmacological characteristics of the 5HT1B site defined by [125I]ICYP, compounds most active at inhibiting 15 mM K(+)-stimulated release of [3H]-5-HT were RU24969 = 5-carboxyamidotryptamine HCl = CGS 12066B greater than 5-methoxytryptamine greater than 5-HT. Compounds with activity at 5-HT1A, 5-HT1C, 5-HT2 or 5-HT3 sites were inactive. A correlation analysis of selective 5-HT1B compounds comparing the pKD for displacement of [125I]ICYP vs. the IC50 for inhibition of [3H]-5-HT release demonstrated the pharmacological similarity of the presynaptic inhibitory 5-HT autoreceptor and the 5-HT receptor site defined by [125I]ICYP binding in spinal cord synaptosomes (r = 0.791, P = .0193). Although [125I]ICYP binding was unaltered, alpha-2 agonists such as clonidine, norepinephrine and UK 14304 [5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) as well as the alpha-2 antagonists rauwolscine and yohimbine also decreased the K(+)-stimulated release of [3H]-5-HT and phentolamine, an alpha-2 antagonist increased release. The action of these alpha-2 compounds to alter [3H]-5-HT release suggests the presence of heteroreceptors localized on 5-HT terminals in the spinal cord. These results point out that [125I]ICYP identifies the 5-HT1B receptor, and affinity of compounds for this site predicts action at the 5-HT1B autoreceptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of 5-hydroxytryptamine1B receptors in rat spinal cord via [125I]iodocyanopindolol binding and inhibition of [3H]-5-hydroxytryptamine release. 173 11

RDC4 is a guanine nucleotide-binding protein-coupled receptor clone originally isolated from a canine thyroid cDNA library by Libert and colleagues [Science (Washington D. C.) 244:569-572 (1989)]. We have isolated the corresponding genomic clone for RDC4, have expressed this clone in murine LM (tk-) fibroblasts, and have determined that it encodes a serotonin 5-hydroxytryptamine1D (5-HT1D) receptor. RDC4 is an intronless gene encoding a protein of 377 amino acids, which exhibits greatest sequence identity (43%) to the 5-HT1A receptor and lower overall homology to other serotonergic and catecholaminergic receptors. Membranes prepared from murine LM (tk-) fibroblasts stably transfected with this clone were shown to bind [3H]5-HT in a saturable manner and displayed an apparently homogeneous population of high affinity (Kd = 3.6 nM, Bmax = 275 fmol/mg of protein) [3H]5-HT binding sites. High affinity [3H] 5-HT binding was unchanged using assay conditions [1 microM (+/- )-pindolol and 1 microM (R)-(+/- )-SCH 23390) to pharmacologically mask 5-HT1A, 5-HT1B, and 5-HT1C receptors. Serotonergic ligands displaced specific [3H]5-HT binding with a rank order of potency expected of a 5-HT1D receptor subtype, 5-carboxyamidotryptamine greater than 5-HT greater than yohimbine greater than 8-hydroxy-2-(di-n-propylamino)tetralin greater than ketanserin = spiperone greater than zacopride. Further, transfected cells responded to addition of 5-HT by decreasing the level of forskolin-stimulated cAMP accumulation. These data indicate that the gene RDC4 encodes a functional 5-HT1D receptor.
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PMID:Expression and pharmacological characterization of a canine 5-hydroxytryptamine1D receptor subtype. 175 39

The affinity of a new serotonin (S) derivative, serotonin-O-carboxymethyl-glycyl-tyrosinamide (S-CM-GTNH2), for the various 5-hydroxytryptamine (5-HT)1 receptor subtypes was tested using quantitative autoradiography on rat and guinea pig brain sections. In the rat, S-CM-GTNH2 is 57 and 24 times more potent at 5-HT1B sites (IC50 = 28 nM) than at 5-HT1A (IC50 = 1600 nM) and 5-HT1C sites (IC50 = 670 nM), respectively. In the guinea pig, the affinity of S-CM-GTNH2 for 5-HT1D sites (IC50 = 67 nM) is 21 times higher than at 5-HT1A sites (IC50 = 1400 nM). S-CM-GTNH2 shows a low affinity (less than 10 microM) for 5-HT2 and 5-HT3 binding sites. This new ligand is therefore highly specific for 5-HT1B and 5-HT1D binding sites and can be used to further characterize the involvement of these subtypes in physiological studies focusing particularly on behavioral effects.
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PMID:Pharmacological characterization of serotonin-O-carboxymethyl-glycyl-tyrosinamide, a new selective indolic ligand for 5-hydroxytryptamine (5-HT)1B and 5-HT1D binding sites. 176 84

The effects of a number of 5-HT receptor ligands were examined on nonopioid defensive analgesia in male DBA/2 mice. MDL 73005EF (0.05-1.0 mg/kg), a selective 5-HT1A receptor agonist, potently and dose-dependently inhibited the analgesic consequences of social defeat. CGS 12066B (0.5-10.0 mg/kg) and MK-212 (0.3-10.0 mg/kg), selective agonists for 5-HT1B and 5-HT1C sites, respectively, failed to influence this particular form of adaptive pain inhibition. Two 5-HT2/1C receptor antagonists, ritanserin (0.05-10.0 mg/kg) and ICI 169.369 (0.3-10.0 mg/kg), were also devoid of specific effects upon defensive analgesia. Both ritanserin and ICI 169,369 were found to have intrinsic analgetic efficacy and to induce behavioural changes indicative of increased defensiveness. These data, together with previous findings, confirm the specific involvement of 5-HT1A receptor mechanisms in the analgesic consequences of social defeat in male mice. Results are discussed in relation to the role of anxiety in adaptive pain inhibition.
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PMID:Differential effects of novel ligands for 5-HT receptor subtypes on nonopioid defensive analgesia in male mice. 179 10

We have compared the ability of the new putatively specific 5-HT1B receptor agonist CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b] pyrid-5-one) and the structurally related mixed 5-HT1A/5-HT1B receptor ligand RU 24969, to influence 5-HT release in brain in vivo, using microdialysis techniques in chloral hydrate-anaesthetised rats. CP-93,129 (3 or 10 microM, via the dialysis perfusion medium) caused a concentration-dependent and methiothepin (10 microM)-sensitive suppression of ventral hippocampal 5-HT output. The effect of RU 24969 on 5-HT output was dependent on whether or not the 5-HT reuptake blocker citalopram was present in the perfusion medium. Thus, RU 24969 (0.1 microM) induced a decrease, or an increase followed by a decrease (1 microM), in 5-HT output in the absence of citalopram, but monotonically decreased (1 microM) 5-HT release when citalopram (1 microM) was present. CP-93,129 decreased dialysate 5-HT in either condition. Our findings are consistent with the characterisation of CP-93,129 as a 5-HT1B receptor agonist, and may thus represent in vivo support for 5-HT1B autoreceptor-mediated feedback control of 5-HT release in the rat brain. The 5-HT1B selectivity of CP-93,129, and its lack of 5-HT reuptake blocking properties, suggests that the compound compares favourably with other purported 5-HT1B receptor agonists.
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PMID:The putative 5-HT1B receptor agonist CP-93,129 suppresses rat hippocampal 5-HT release in vivo: comparison with RU 24969. 179 66

Four major families of serotonin (5-hydroxytryptamine; 5-HT) receptors have been identified: 5-HT1, 5-HT2, 5-HT3 and 5-HT4. At this time, there is a general consensus that the 5-HT1 family can be further subdivided into 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT1P subpopulations. In addition, there are several other populations of less well-defined 5-HT receptors. The purpose of this presentation is to discuss 5-HT receptor nomenclature and the agents that are commonly used to investigate each receptor population in as much as it will serve to provide background for the remainder of the symposium. There is presently available an abundance of serotonergic agents; however, these agents are only semiselective, and none can be considered truly selective for a particular population of 5-HT receptors. As useful as these agents have been for the identification and characterization of 5-HT receptors, there remains a need for the development of new, more selective ligands.
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PMID:Serotonin receptors and their ligands: a lack of selective agents. 181 55

The 5-hydroxytryptamine (5-HT) receptor by which 5-HT can evoke nonadrenergic noncholinergic (NANC) relaxations in isolated guinea-pig proximal colon was characterized using a variety of 5-HT receptor agonists and antagonists. In the presence of atropine (0.2 microM), guanethidine (5 microM) and ketanserin (10 microM), a concentration-dependent relaxation was obtained with 5-HT (apparent mean pEC50 value 6.43), 5-CT (5.64) and 5-CH3-T (5.02); 8-OH-DPAT, TFMPP, GR43175 and 5-OCH3-N,N-DMT (up to 100 microM) did not relax the guinea-pig proximal colon. The nonselective 5-HT receptor antagonist, metitepine (0.1 microM), the 5-HT1C/5-HT2 receptor antagonists, mianserin (1 microM) and pizotifen (0.1 microM), and the 5-HT1A/5-HT2 receptor antagonists spiperone (3 microM) shifted the concentration-response curves for 5-HT to the right. The 5-HT1A/5-HT1B receptor antagonist, cyanopindolol (0.3 microM) and a selective 5-HT3 receptor antagonist, ICS205-930 (1 microM) failed to block the 5-HT-induced NANC relaxation. In conclusion, the experiments with agonists and antagonists are compatible with the view that a 5-HT1-like receptor is involved in 5-HT-induced NANC relaxations of the guinea-pig proximal colon.
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PMID:Characterization of 5-hydroxytryptamine-induced relaxations of guinea-pig proximal colon. 181 62

This study pharmacologically characterizes a novel behavioral response as a potential in vivo model of serotonin (5-HT)1A receptor-mediated activity. In rats restrained in horizontal cylinders, the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin HBr (8-OH-DPAT), dose-dependently (0.04-10.0 mg/kg s.c.) elicited spontaneous tail-flicks (STFs). This action was mimicked by other ligands possessing high affinity and high efficacy at 5-HT1A sites: RU 24969 [(5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole], lisuride, (+)-lysergic acid diethylamide and 5-methoxy-N,N-dimethyltryptamine hydrogen oxalate. The response could not be elicited by CGS 12066B [7-trifluormethyl-4-(4-methyl-l-piperazonyl)-pyrrolol- [1-2-a] quinoxaline dimaleate], mCPP 1-(3-chlorophenyl)-piperazine-2-HCl, TFMPPm-trifluromethylphenylpiperazine HCl, MK 212 [6-chloro-2-(l-piperzinyl)pyrazine], quipazine and DOI (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl, which act in vivo as agonists at 5-HT1B, 5-HT1C and/or 5-HT2 receptors, or by the 5-HT3 agonist, 2-methyl-5-HT. p-chloroamphetamine, which releases endogenous 5-HT, also evoked STFs; in contrast, d-amphetamine, a preferential releaser of catecholamines, was inactive, as were agonists and antagonists at alpha-1, alpha-2, beta-1, beta-2, dopamine D1 and D2 sites. 8-OH-DPAT-elicited STFs were blocked by the 5-HT1/2 antagonist, methiothepin, but not by the 5-HT1C/5-HT2 antagonists, mianserin, ritanserin and ICI 169,369 [2-(2-dimethylaminoetheylthio)-3-phenylquinoline] nor by the 5-HT3 antagonists, GR 38032F [(1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-l-yl)methyl]-4H- carbazol-4-one HCl], ICS 205,930 [(3 alpha-tropanyl)-1H-indol-3-carboxylic acid ester] and MDL 72222 [(1 alpha H, 3 alpha, 5 alpha H)-tripan-3-yl-3,5- dichlorobenzoate]. beta-Blockers with 5-HT1A affinity i.e., (-)-alprenolol, (+/-)-isamoltane and, stereoselectivity, (-)-but not (+)-pindolol, blocked the action of 8-OH-DPAT. Spiperone and spiroxatrine, D2 antagonists with high 5-HT1A affinity, also inhibited 8-OH-DPAT-induced STFs. Selective beta-blockers and D2 antagonists with low 5-HT1A affinity were inactive. 5-HT1A partial agonists, the pyrimidinylpiperazines, buspirone, gepirone and ipsapirone, the halogenated phenylpiperazine, LY 165,163 [1-(2-(4-aminophenyl) ethyl-4-(3-trifluoromethylphenyl)-piperazine], and the benzodioxane, MDL 72832 [8-(4-(1,4-benzodioxan-2-yl-methylamino)-butyl-8-azaspiro-(4 ,5)-decane- 7,9-dione] did not elicit STFs and antagonized the effect of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:5-hydroxytryptamine (5-HT)1A receptors and the tail-flick response. I. 8-hydroxy-2-(di-n-propylamino) tetralin HBr-induced spontaneous tail-flicks in the rat as an in vivo model of 5-HT1A receptor-mediated activity. 182 33

1. Serotonin (5-HT) and selective 5-HT receptor agonists were administered intrathecally (i.t.) in rats, and the antinociceptive efficacy of these agents was assessed on the tail-flick and hot plate tests. 2. The 5-HT receptor agonists examined in this study included the 5-HT1A agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), the 5-HT1B agonist m-trifluoromethylphenylpiperazine (TFMPP), the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT3 agonist phenylbiguanide (PBG). 3. None of these agents produced significant elevations in tail-flick latency (TFL) at doses which produced elevations in hot plate latency (HPL). 4. In contrast, the i.t. dose of 5-HT which elevated TFL also produced analgesia on the hot plate test. 5. Serotonin-induced elevations in TFL were reversed by pindolol, ritanserin and ICS 205-930, suggesting that 5-HT interacts with more than one 5-HT site in the spinal cord to produce analgesia on the tail-flick test. 6. The finding that ritanserin reversed 5-HT-induced elevations in HPL suggests that the 5-HT2 site is primarily responsible for mediating the spinal antinociceptive effects of 5-HT on the hot plate test.
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PMID:Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord. 182 46

The present study was designed to assess whether the antiaggressive effects of eltoprazine are mediated via presynaptic and/or postsynaptic 5-HT1 receptors. We describe the effects of central 5-HT depletion 1) on the behaviour of resident TMD-S3 rats in a territorial situation, 2) on the efficacy of eltoprazine to inhibit offensive aggression, and 3) on the 5-HT1A, 5-HT1B and 5-HT1C receptor binding in brains of rats previously used in behavioural studies. Male resident rats were given combined 5,7-dihydroxytryptamine (5,7-DHT) injections into the dorsal and median raphe nuclei. Two to four weeks after the lesions, rats were confronted with an intruder Wiser rat in their home cage for a 10-min period. The 5,7-DHT treatment resulted in a modest reduction of offensive behaviour, while having no effects on other social and nonsocial behaviours. Oral administration of eltoprazine (1 mg/kg) specifically reduced offensive aggression in both sham- and 5,7-DHT-lesioned animals, leaving social interest and exploration intact or even increasing it. A low dose (0.3 mg/kg) of eltoprazine did not affect the behavioural repertoire of sham-operated rats, whereas this dose significantly reduced offense behaviours in the 5,7-DHT-lesioned residents. Quantitative autoradiographic studies 5 weeks after 5,7-DHT treatment revealed a significant increase in radioligand binding to 5-HT1A, 5-HT1B and 5-HT1C sites in many brain regions studied, except for the raphe nuclei where [3H]8-OH-DPAT binding to 5-HT1A sites was markedly reduced. The concentrations of 5-HT and 5-HIAA in frontal cortex were reduced to approximately 10% of controls. The results indicate that serotonin has a stimulatory rather than an inhibitory influence on offensive aggressive behaviour. Central 5-HT depletion does not prevent the antiaggressive effects of eltoprazine, indicating a role for postsynaptic 5-HT1 receptors in the modulation of offensive aggression. The 5,7-DHT-induced overall upregulation of 5-HT1A, 5-HT1B and 5-HT1C binding sites suggests that these three receptor subtypes receive a tonic serotonergic influence. It is conceivable that this postsynaptic 5-HT1 receptor supersensitivity is reflected by the increased efficacy of eltoprazine to inhibit offensive aggression.
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PMID:Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine. 182 32


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