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)

In order to test the hypothesis that a 5-hydroxytryptamine (5-HT)-induced increase in vascular permeability results from a cascade triggered by activation of the synthesis of nitric oxide (NO), the vascular permeability was investigated using the Pontamine sky blue leakage method in male mice. Subcutaneous injection of 5-HT induced a dose-related increase of vascular permeability at the injection site. The vascular permeability induced by 5-HT was inhibited by pretreatment with intraperitoneal injection of ketanserin (5-HT2A antagonist) and methysergide (5-HT1/2A antagonist), less efficiently by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine (NAN-190) (5-HT1A antagonist), but not by granisetron (5-HT3 antagonist). Increase in vascular permeability induced by 5-HT was inhibited by concurrent intravenous administration of NO synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and methylene blue but not by the inactive enantiomer NG-nitro-D-arginine methyl ester (D-NAME). These results suggest that 5-HT increases vascular permeability by activating the 5-HT receptors and that endogenous NO is involved in this effect of 5-HT.
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PMID:Possible role of nitric oxide in 5-hydroxytryptamine-induced increase in vascular permeability in mouse skin. 753 Dec 92

The present study assessed compounds displaying affinity for 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors for their ability to substitute for, enhance or antagonize the discriminative stimulus effects of cocaine (10 mg/kg) in rats. In substitution tests, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.2-1.6 mg/kg), the 5-HT1A/B receptor agonists RU 24969 (0.25-2 mg/kg) and CGS 12066B (2-16 mg/kg), the 5-HT1B/2C receptor agonists m-chlorophenylpiperazine (mCPP; 0.25-2 mg/kg) and m-trifluoromethylphenylpiperazine (TFMPP; 0.125-2 mg/kg), the 5-HT2A/2C receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane ([+/-]-DOB; 0.0625-0.5 mg/kg), the 5-HT2C receptor agonist MK 212 (0.25-1 mg/kg) and the nonselective 5-HT receptor agonist quipazine (1-8 mg/kg) engendered 30% to 70% cocaine-appropriate responding. The DA receptor antagonists SCH 23390 (0.025 or 0.05 mg/kg) and haloperidol (0.125 or 0.25 mg/kg) failed to block the partial substitution of RU 24969 (1 mg/kg) for cocaine. In combination tests, a fixed dose of either quipazine (4 mg/kg), RU 24969 (0.25, 0.5 or 1 mg/kg) or TFMPP (0.5 mg/kg) but not 8-OH-DPAT (0.4 mg/kg) or CGS 12066B (16 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.625-5 mg/kg). In contrast, coadministration of either mCPP (0.25-2 mg/kg) or MK 212 (0.125-2 mg/kg) plus a dose of cocaine (5 mg/kg) that produced > 85% cocaine-appropriate responding when given alone partially antagonized cocaine; mCPP (1 mg/kg) also produced a rightward shift in the cocaine dose-response curve. Neither 8-OH-DPAT (0.2-1.6 mg/kg), (+/-)-DOB (0.125-0.5 mg/kg) nor quipazine (2-8 mg/kg) blocked the cocaine stimulus. The 5-HT1A receptor antagonist NAN 190 (0.2-0.8 mg/kg), the 5-HT2A/2C receptor antagonist LY 53857 (0.5-4 mg/kg) and the 5-HT/DA receptor antagonist pirenperone (0.5-4 mg/kg) neither substituted for nor enhanced cocaine; however, pirenperone but not NAN 190 or LY 53857 partially blocked the cocaine (10 mg/kg) response. Although 5-HT receptor compounds do not substitute for cocaine, several 5-HT receptor agonists (i.e., the indole derivative RU 24969 and the arylpiperazines mCPP, MK 212, TFMPP and quipazine), but not antagonists, differentially modulate the stimulus effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. 756 16

1. We investigated the effects of serotonin (5-hydroxytryptamine, 5-HT) on whole-cell barium currents through calcium channels in visualized neonatal rat hypoglossal motoneurones (HMs) in a thin brainstem slice preparation. 2. High voltage-activated (HVA) currents were elicited by depolarizing voltage steps from -70 to 0 mV; low voltage-activated (LVA) currents were evoked using steps to between -30 and -40 mV from hyperpolarized potentials (< -80 mV). 5-HT (1.0 microM) inhibited HVA currents by at least 10% in 70% of HMs tested (n = 99); in those responsive neurones, 5-HT decreased HVA current by 22 +/- 1.3% (mean +/- S.E.M.). In contrast, 5-HT had no effect on LVA current amplitude in HMs (n = 7). 3. Calcium current inhibition was mimicked by 5-carboxamidotryptamine maleate (5-CT), a 5-HT1 receptor agonist, and by R(+)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), a specific 5-HT1A agonist; N-(3-trifluoromethylphenyl) piperazine hydrochloride (TFMPP), a 5-HT1B agonist, was without effect. The effect of 5-HT was blocked by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine hydrobromide (NAN-190) but not by ketanserin, a 5-HT2A/2C antagonist. Although R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A/2C agonist, mimicked the current inhibition by 5-HT, it was ineffective in the presence of NAN-190. These data indicate that 5-HT1A receptors mediate calcium current inhibition by 5-HT. 4. Following application of either omega-conotoxin-GVIA (omega-CgTX) or omega-agatoxin-IVA (omega-Aga-IVA), to block N- and P-type components of calcium current, the 5-HT-sensitive current was reduced; 5-HT had no effect on the current remaining after application of both toxins. Thus, 5-HT inhibits both N- and P-type calcium currents in neonatal HMs. 5. Inhibition of HVA current by 5-HT was irreversible, and subsequent applications of 5-HT were occluded, when GTP gamma S was substituted for GTP in the pipette. In addition, inhibition of HVA current by 5-HT was relieved following depolarizing prepulses. These data indicate that inhibition of calcium channels by 5-HT is mediated by G proteins. 6. Under current clamp, both 5-HT and 8-OH-DPAT decreased the amplitude of the after-hyperpolarization (AHP) that followed action potentials, indicating involvement of a 5-HT1A receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of N- and P-type calcium currents and the after-hyperpolarization in rat motoneurones by serotonin. 756 6

Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha 1-, alpha 2-, and beta-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT1A sites (8.10 < or = pKis < or = 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.
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PMID:Characterization of potent and selective antagonists at postsynaptic 5-HT1A receptors in a series of N4-substituted arylpiperazines. 756 40

1-(2-Methoxyphenyl)-4-[(phthalimido)butyl] piperazine (NAN-190) and 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5] decane-7,9-dione (buspirone) are 5-HT1A receptor partial agonists which decrease 5-hydroxytryptamine (5-HT) release in vivo. In order to assess whether these ligands decrease 5-HT release by stimulating 5-HT1A receptors we examined the ability of the selective 5-HT1A receptor antagonist N-tert-butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride (WAY-100135) to block their inhibitory effects on 5-HT. NAN-190 (0.1 mg/kg s.c.) and buspirone (1.0 mg/kg s.c.) significantly decreased extracellular levels of 5-HT in hippocampal dialysates. WAY-100135 (10.0 mg/kg s.c.) attenuated the effect of buspirone but had no significant effect on the NAN-190-induced decreased in 5-HT release. These data demonstrate that buspirone is an agonist at the somatodendritic 5-HT1A receptor but that the inhibitory effects of NAN-190 on 5-HT release may be mediated via a mechanism other than, or in addition to, 5-HT1A receptor agonism.
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PMID:Differential effects of WAY-100135 on the decrease in 5-hydroxytryptamine release induced by buspirone and NAN-190. 760 Dec 15

1. With the use of a thin brain stem slice preparation, we recorded in visualized neonatal rat hypoglossal motoneurons unitary glycinergic inhibitory postsynaptic currents (IPSCs) that were evoked by extracellular stimulation of nearby interneurons. We found that 10 microM serotonin (5-HT) presynaptically inhibited this glycinergic synaptic transmission by 85.5%. 2. In the somata of presynaptic interneurons, 5-HT1A receptor activation potentiated inwardly rectifying K+ channels and inhibited voltage-activated calcium channels. 3. In contrast, the 5-HT1B receptor was primarily responsible for inhibition of evoked glycinergic IPSCs; a selective 5-HT1B receptor agonist, N-(3-trifluoromethylphenyl)piperazine (TFMPP, 10 microM), inhibited synaptic transmission by 97.3%. On the other hand, 5-HT1A receptor activation by (+)-8-OH-dipropylaminotetralin (8-OHDPAT, 1 microM) inhibited IPSCs by only 24.1%. A 5-HT1A antagonist, 1-(2-methyoxyphenyl)-4-[4-(2-phthalimido)-butyl]piperazine hydrobromide (NAN-190, 1 microM), had no effect on synaptic inhibition by 5-HT. 4. In the presence of tetrodotoxin (TTX) as well as TTX with cadmium (50 microM), we found that 5-HT1B receptor activation by TFMPP reduced the frequency of spontaneous miniature IPSCs (mIPSCs) without changing their mean amplitude. The results suggested that the 5-HT1B receptors activated at the presynaptic terminal inhibited synaptic transmission independent of inhibiting calcium influx through voltage-activated calcium channels. 5. These results indicate that activation of inwardly rectifying K+ channels and inhibition of voltage-activated calcium channels by 5-HT1A receptor activation do not constitute a main pathway for presynaptic inhibition by 5-HT of glycinergic synaptic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presynaptic inhibition by serotonin of glycinergic inhibitory synaptic currents in the rat brain stem. 760 65

Serotonergic agents (uptake inhibitors, receptor ligands) cause significant craniofacial malformations in cultured mouse embryos suggesting that 5-hydroxytryptamine (serotonin) (5-HT) may be an important regulator of craniofacial development. To determine whether serotonergic regulation of cell migration might underly some of these effects, cranial neural crest (NC) explants from embryonic day 9 (E9) (plug day = E1) mouse embryos or dissociated mandibular mesenchyme cells (derived from NC) from E12 embryos were placed in a modified Boyden chamber to measure effects of serotonergic agents on cell migration. A dose-dependent effect of 5-HT on the migration of highly motile cranial NC cells was demonstrated, such that low concentrations of 5-HT stimulated migration, whereas this effect was progressively lost as the dose of 5-HT was increased. In contrast, most concentrations of 5-HT inhibited migration of less motile, mandibular mesenchyme cells. To investigate the possible involvement of specific 5-HT receptors in the stimulation of NC migration, several 5-HT subtype-selective antagonists were used to block the effects of the most stimulatory dose of 5-HT (0.01 microM). Only NAN-190 (a 5-HT1A antagonist) inhibited the effect of 5-HT, suggesting involvement of this receptor. Further evidence was obtained by using immunohistochemistry with 5-HT receptor antibodies, which revealed expression of the 5-HT1A receptor but not other subtypes by migrating NC cells in both embryos and cranial NC explants. These results suggest that by activating appropriate receptors 5-HT may regulate migration of cranial NC cells and their mesenchymal derivatives in the mouse embryo.
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PMID:Serotonin regulates mouse cranial neural crest migration. 763 65

The memory effects of agonists and antagonists of some serotonin (5-HT)-receptor subtypes were studied in experiments on rats using the method for passive avoidance with punishment reinforcement (step-down). The 5-HT1A-receptor agonist buspirone (1 mg/kg i.p.) elicited behavioural responses which suggested the lack of pronounced effect on learning and retention; the 5-HT1A-receptor antagonists NAN-190 (1 mg/kg i.p.) and pindolol (6 mg/kg i.p.) impaired retention tested 24 hours and 7 days after training as compared to controls. The 5-HT2-receptor antagonist ritanserin (1 mg/kg i.p.) impaired retention tested 24 hours and 7 days after training as compared to controls, while the 5-HT3-receptor antagonist ondansetron (0.1 mg/kg i.p.) improved it. The 5-HT1/5-HT2-receptor antagonist dotarizine (50 mg/kg orally), characterized by a calcium-antagonistic action, too, exerted some facilitating effect on learning. Most of the effects of the 5-HT-receptor agonists and antagonists were changed when the 5-HT concentration in the synaptic region was increased by the 5-HT-uptake inhibitor fluoxetine (20 mg/kg orally). The results suggest different participation of 5-HT1A-, 5-HT2- and 5-HT3-receptors in the mechanisms of memory process and its modulation by the serotonin level in the cerebral serotonergic synapses.
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PMID:Effects of agonists and antagonists of some serotonin-receptor subtypes on memory and their modulation by the 5-HT-uptake inhibitor fluoxetine. 764 8

1. Whole-cell and intracellular recordings were made from neurons in slices of guinea-pig spinal trigeminal nucleus pars caudalis. 2. 5-Hydroxytryptamine (5-HT) hyperpolarized 70% of neurons by activating 5-HT1A receptors. The effect was mimicked by 5-carboxamidotryptamine (5-CT) and (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene hydrobromide (8-OH-DPAT) and antagonized by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)-butyl]-piperazine hydrobromide (NAN 190) and pindobind-5-HT1A. Nine per cent of the neurons were depolarized by 5-HT. 3. In about 20% of recordings, 5-HT also evoked repetitive inhibitory postsynaptic potentials that were mediated by glycine. 4. Noradrenaline (NA) hyperpolarized 71% of neurons. This effect was mediated by activation of alpha 2-adrenoceptors, since 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304) also caused a hyperpolarization and idazoxan (1 microM) blocked the hyperpolarization to both NA and UK14304. Phenylephrine depolarized a subset of neurons and this depolarization was blocked by prazosin, suggesting an action mediated by activation of alpha 1-adrenoceptors. 5. NA also evoked repetitive GABAA-mediated inhibitory postsynaptic potentials in about 20% of recordings. The increase in synaptic activity was mimicked by phenylephrine and blocked by prazosin. 6. These results indicate that there are at least two mechanisms through which 5-HT and NA inhibit neurons: (i) in many cells both 5-HT and NA mediate a hyperpolarization through an increase of a potassium conductance; (ii) 5-HT and NA also activated GABA- and glycine-containing interneurons to cause IPSPs in separate groups of cells.
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PMID:Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus. 765 66

Intracellular electrophysiological methods were used to examine the effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 4-amino-5-chloro-2-methoxy-N-(4-[1-azabicyclo[3,3,1]nonyl]) benzamide hydrochloride (renzapride), cis-4-amino-5-chloro-N[1-[3- (4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl[-2-methoxybenzamide monohydrate (cisapride) and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3- (1-methyl)ethyl-2-oxo-1 H-benzimidazole-1-carboxamidehydrochloride (BIMU 8) on noncholineric slow excitatory postsynaptic potentials (slow EPSPs) in myenteric afterhyperpolarization (AH) neurons of guinea pig ileum. 5-HT (0.01-1 microM) and 5-CT (0.001-0.1 microM) produced a concentration-dependent inhibition of slow EPSPs. The 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimidobutyl]piperazine (NAN-190) produced rightward shifts in 5-HT and 5-CT concentration-response curves; facilitation of slow EPSPs was never observed. 5-MeOT caused a depolarization and inhibited spike afterhyperpolarizations in a concentration-dependent manner but this effect was not blocked by the 5-HT3/5-HT4 receptor antagonist, tropisetron (1 microM). Renzapride (0.01-0.3 microM), cisapride (0.01-1.0 microM) and BIMU 8 (0.01-1.0 microM) did not change the membrane potential of any neuron tested. Renzapride and BIMU 8 did not change the amplitude of slow EPSPs. In 13 of 19 neurons cisapride did not change the amplitude of slow EPSPs; in 6 neurons cisapride (1 microM) reversibly inhibited the slow EPSP. Responses to substance P which mimicked the slow EPSP were not affected by cisapride.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of 5-HT1A and 5-HT4 receptor agonists on slow synaptic potentials in enteric neurons. 766 14


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