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

The effects of the Ca2+ and 5-HT1 and 5-HT2 receptor antagonist dotarizine and of some other agonists and antagonists of different 5-HT receptor subtypes administered alone or in combination with the 5-HT uptake inhibitor fluoxetine (FLU) on nociception were studied, using a foot-pressure method (analgesy-meter testing). Dotarizine (DOT) administered at a dose of 50 mg/kg for 3 days orally significantly increased the pain threshold. Fluoxetine (FLU) administered at a dose of 10 mg/kg for 3 days also significantly increased the pain threshold. The combination of DOT and FLU abolished the analgesic effects of the two drugs. The 5-HT1A and 5-HT1B/1C receptor agonists buspirone and m-CPP decreased the pain threshold. The antagonists of 5-HT1A(NAN-190),5-HT1/5-HT2(methysergide), 5-HT2 (ritanserin), and 5-HT3 (ondansetron) receptors as well as the agonists of 5-HT2(DOI) and 5-HT3 (mCPBG) receptors increased the pain threshold. Fluoxetine at a single dose of 10 mg/kg differently influenced the effects of the 5-HT agonists and antagonists on nociception. Comparison of the effects of dotarizine with the effects of some of the agonists and antagonists of 5-HT receptor subtypes on the nociceptive and other actions suggests the possibility of a therapeutic value of dotarizine as an antimigraine drug.
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PMID:Effects on nociception of the Ca2+ and 5-HT antagonist dotarizine and other 5-HT receptor agonists and antagonists. 883 Aug 81

Pancreatic ganglia contain 5-hydroxytryptamine (5-HT)-immunoreactive axons, some of which are extensions of myenteric neurons located in the pyloric antrum and proximal duodenum. The present study investigated the effect of 5-HT on the membrane potential of cat pancreatic ganglion neurons by means of intracellular recordings in vitro. Pressure application of 5-HT evoked a fast depolarization in 29 of 147 neurons and a slow depolarization in 89 of 147 neurons. A biphasic response was observed in 10 of 108 neurons. The 5-HT-induced slow depolarizing response was not altered in a low Ca2+ (0.1 mM), high Mg2+ (15 mM) solution nor by hexamethonium (10(-4) M) or atropine (10(-6) M). The fast depolarizing response was associated with a decrease of membrane input resistance (-17.2%). The slow depolarizing response was associated with either a decrease (-19.6%) in 24, an increase (+25.0%) in 20, or without a detectable change of membrane input resistance in 10 out of 54 neurons tested. Conditioning hyperpolarization increased the amplitude of both fast and slow depolarizing responses. A low Na+ (68.5 mM) solution and a high K+ (23.5 mM) solution significantly reduced the amplitude of the slow depolarizing response. A low Cl- (9.6 mM) solution had no significant effect on the slow depolarization. The 5-HT3 receptor antagonist MDL 72222 (Bemesetron) blocked the 5-HT-evoked fast depolarizing response. BRL 24924 (Renzapride) and 5 HT-DP, antagonists for the putative 5-HT1P receptor, blocked the slow depolarizing response. The 5-HT3 receptor agonist 2-methyl-5-HT evoked a fast depolarizing response and MCPP, an agonist for the putative 5-HT1P receptor, evoked a slow depolarizing response. Spiperone (a 5-HT1A receptor antagonist) and mianserin (a 5-HT2 receptor antagonist) had no effect on either depolarizing response to 5-HT. The results show that pancreatic ganglion neurons responded to 5-HT with fast and slow depolarizing responses. The data suggest that these responses were mediated by the 5-HT3 receptor and the putative 5-HT1P receptor, respectively.
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PMID:5-Hydroxytryptamine depolarizes neurons of cat pancreatic ganglia. 886 89

1. Chinese hamster ovary (CHO) cells have been reported to be devoid of 5-HT receptors and have frequently been used as hosts for the expression of cloned 5-HT receptors. Unexpectedly, 5-HT was found to induce profound inhibition of forskolin-stimulated cyclic AMP production in these cells and the aim of this study was to classify the 5-HT receptor involved. 2. In CHO(dhfr-) cells 5-HT was a potent agonist and caused 80-100% inhibition of forskolin stimulated cyclic AMP production. A study using several 5-HT1 receptor agonists revealed the following potencies (p[A50]): RU24969 (9.09 +/- 0.17) > 5-carboxamidotryptamine (8.86 +/- 0.20) > 5-HT (8.07 +/- 0.05) > CP-93,129 (7.74 +/- 0.10) > sumatriptan (5.93 +/- 0.04). All five agonists achieved a similar maximum effect. Irreversible receptor alkylation studies yielded a pKA estimate of 7.04 +/- 0.34 for 5-HT. 3. The 5-HT1A/1B antagonist, (+/-)-cyanopindolol (4-100 nM), caused parallel rightward shifts of the 5-HT concentration-effect curve with no change in asymptote. Schild analysis yielded a pKB estimate of 8.69 +/- 0.09 (Schild slope 1.13 +/- 0.10). (+/-)-Cyanopindolol actually behaved as a partial agonist with an intrinsic activity of 0.2-0.5 and a p[A50] of 8.55. 4. 5-HT (0.01-10 microM) also elicited a concentration-dependent increase in intracellular [Ca2+] in CHO(dhfr-) cells thus demonstrating that dual coupling is not a phenomenon restricted to systems in which there is overexpression of transfected receptors. 5. This agonist and antagonist profile is consistent with the presence of a 5-HT1B receptor. 8-OH-DPAT (1 microM) and renzapride (3 microM) were without effect on forskolin-stimulated cyclic AMP production and ketanserin (0.3 microM) did not antagonize the inhibition produced by 5-HT, thus excluding the involvement of 5-HT1A, 5-HT4, and 5-HT2 receptors. 6. The possibility that expression of a 5-HT1B receptor was associated with the dhfr- mutation was excluded since RU24969, 5-HT and CP-93,129 were also potent agonists in unmutated, CHO-K1 cells: p[A50] 9.03 +/- 0.03, 8.34 +/- 0.05, 7.69 +/- 0.07 respectively, and (+/-)-cyanopindolol (0.1 microM) shifted the 5-HT curve to the right and yielded a pA2 estimate of 8.70 +/- 0.06. 7. Little or no specific binding of [3H]-5-HT (0.1-200 nM) or of the high affinity ligand [125I]-iodocyanopindolol (0.01-3 nM) to CHO(dhfr-) cell membranes could be detected. 5-HT also failed to elicit any increase in the binding of [35S]-GTP gamma S to CHO membranes. 8. In conclusion, cultured CHO cells express 5-HT1B receptors which are negatively coupled to adenylyl cyclase and positively coupled to increases in intracellular calcium. The absence of radioligand binding was unexpected in view of the high potency of 5-HT and the partial agonist activity of the normally 'silent' competitive antagonist, (+/-)-cyanopindolol. This implies very efficient receptor-effector coupling of a low density of 5-HT1B receptors. Clearly, the absence of detectable radioligand binding cannot be assumed to mean the absence of receptors capable of eliciting a significant functional response.
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PMID:Characterization of a 5-HT1B receptor on CHO cells: functional responses in the absence of radioligand binding. 888 5

1. 2,2'-Pyridylisatogen tosylate (PIT) has been reported to be an irreversible antagonist of responses to adenosine 5'-triphosphate (ATP) at metabotropic purinoceptors (of the P2Y family) in some smooth muscles. When a recombinant P2Y1 purinoceptor (derived from chick brain) is expressed in Xenopus oocytes, ATP and 2-methylthioATP (2-MeSATP) evoke calcium-activated chloride currents (ICl,Ca) in a concentration-dependent manner. The effects of PIT on these agonist responses were examined at this cloned P2Y purinoceptor. 2. PIT (0.1-100 microM) failed to stimulate P2Y1 purinoceptors directly but, over a narrow concentration range (0.1-3 microM), caused a time-dependent potentiation (2-5 fold) of responses to ATP. The potentiation of ATP-responses by PIT was not caused by inhibition of oocyte ecto-ATPase. At high concentrations (3-100 microM), PIT irreversibly inhibited responses to ATP with a IC50 value of 13 +/- 9 microM (pKB = 4.88 +/- 0.22; n = 3). PIT failed to potentiate inward currents evoked by 2-MeSATP and only inhibited the responses to this agonist in an irreversible manner. 3. Known P2 purinoceptor antagonists were tested for their ability to potentiate ATP-responses at the chick P2Y1 purinoceptor. Suramin (IC50 = 230 +/- 80 nM; n = 5) and Reactive blue-2 (IC50 = 580 +/- 130 nM; n = 6) reversibly inhibited but did not potentiate ATP-responses. Coomassie brilliant blue-G (0.1-3 microM) potentiated ATP-responses in three experiments, while higher concentrations (3-100 microM) irreversibly inhibited ATP-responses. The results indicated that potentiation and receptor antagonism were dissociable and not a feature common to all known P2 purinoceptor antagonists. 4. In radioligand binding assays, PIT showed a low affinity (pKi < 5) for a range of membrane receptors, including: alpha 1, alpha 2-adrenoceptors, 5-HT1A, 5-HT1B, 5-HT2, 5-HT3, D1, D2, muscarinic, central benzodiazepine, H1, mu-opioid, dihydropyridine and batrachotoxin receptors. PIT showed some affinity (pKi = 5.3) for an adenosine (A1) receptor. 5. In guinea-pig isolated taenia caeci, PIT (12.5-50 microM) irreversibly antagonized relaxations to ATP (3-1000 microM); PIT also directly relaxed the smooth muscle and histamine was used to restore tone. Relaxations to nicotine (10-100 microM), evoked by stimulating intrinsic NANC nerves of taenia caeci preparations in the presence of hyoscine (0.3 microM) and guanethidine (17 microM), were not affected by PIT (50 microM, for 25-60 min). 6. These experiments indicate that PIT causes an irreversible antagonism of ATP receptors but, for recombinant chick P2Y1 purinoceptors, this effect is preceded by potentiation of ATP agonism. The initial potentiation by PIT (and by Coomassie brilliant blue-G) of ATP-responses raises the possibility of designing a new class of modulatory drugs to enhance purinergic transmission at metabotropic purinoceptors.
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PMID:Potentiation by 2,2'-pyridylisatogen tosylate of ATP-responses at a recombinant P2Y1 purinoceptor. 888 4

1. Activation of the enzyme protein kinase C (PKC) partially uncouples receptors from the inhibition of Ca2+ current. We have studied the effect of PKC activation on 5-HT1A receptor coupling of Ca2+ currents and 5-HT-induced K+ current (IK,5-HT) in acutely isolated adult rat dorsal raphe neurones. 2. The phorbol ester 4 beta-phorbol 12-myristate, 13-acetate (PMA; 1 microM) did not significantly alter the peak Ca2+ current. A maximal dose of 5-HT inhibited Ca2+ current on average by 52%; after application of PMA, the inhibition was only 30% and the effect was irreversible for the duration of the experiment. 3. The inactive phorbol ester 4 alpha-phorbol (1 microM) did not reduce the effectiveness of 5-HT. When the kinase inhibitor staurosporine (ST; 200 nM) was added, PMA reduced the effect of 5-HT by only 13.9%. ST partially prevented or reversed the effect of PMA, depending on the order of addition. 4. The voltage-dependent rate or re-inhibition by 5-HT was reduced by PMA, suggesting that fewer activated G-protein subunits are available to interact with Ca2+ channel after the action of PMA. 5. In contrast, PMA (1 microM) did not have a significant effect on IK,5-HT. 6. PKC activation has an inhibitory effect on one branch of the 5-HT1A receptor transduction fork, namely inhibition of Ca2+ influx, but not on the activation of IK,5-HT.
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PMID:Differential effects of protein kinase C activation on 5-HT1A receptor coupling to Ca2+ and K+ currents in rat serotonergic neurones. 891 Feb 1

Contractile responses to serotonin (5-HT) of fundic smooth muscle strips isolated from both control and streptozotocin (STZ)-induced diabetic rats were investigated. Contrary to carbachol (CCh) which causes contractile hyperactivity in DM, 5-HT response tended to decrease in DM compared to that of the control. Pindolol (10(-5)M) increased the value of EC50 of the concentration-response to 5-HT about 2.5 times in both the control and DM. After treatment with pindolol, the maximal tension to 5-HT in DM significantly decreased compared to that of the control. Pindolol showed no effect on the contractile response to CCh. Pindolol significantly inhibited the relaxation caused by isoproterenol in DM more than in the control. Mianserin (10(-5) M) increased the EC50 of the response to 5-HT about 2-2.5 times in both groups, but did not cause a significant difference between the control and DM. The Ca(2+)-induced contraction caused hyperreactivity in DM in the presence of 10(-6) M CCh, but that in DM was not significantly different from the control in the presence of 10(-6) M 5-HT. Pretreatment of phorbol 12-myristate 13-acetate (PMA, 10(-5) M) significantly attenuated the response to 5-HT in the control, but not in DM. Results suggest that the contractile response to 5-HT in DM is related to the altered Ca2+ signal transduction system via disturbed protein kinase C (PKC) activity, and that there are alterations of receptor characteristics and of the density in 5-HT receptor subtypes, especially 5-HT1A, during DM development.
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PMID:Alteration of contractile properties to serotonin in gastric fundus smooth muscle isolated from streptozotocin (STZ)-induced diabetic rats. 891 Feb 54

The effect of 5-HT and its 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on excitatory transmission in CA1 pyramidal cells was studied. Using concentrations of 5-HT within a range of 10-50 microM we observed no change in excitatory postsynaptic potentials (EPSPs) in CA1 cells evoked by Schaffer collateral stimulation. However, at higher concentrations, > or = 100 microM, 5-HT caused a significant decrease (30-40%) in EPSP/Cs, an effect that was also mimicked by 50 microM 8-OH-DPAT. A presumed presynaptic Ca2+ entry was measured in stratum radiatum following repetitive stimulation of the Schaffer collaterals with all excitatory synaptic transmission blocked. Both 5-HT and 8-OH-DPAT reduced this Ca2+ entry. These results suggest that 5-HT acts at presynaptic 5-HT1A receptors to reduce Ca2+ entry and thereby glutamatergic synaptic transmission.
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PMID:Serotonin and 8-OH-DPAT reduce excitatory transmission in rat hippocampal area CA1 via reduction in presumed presynaptic Ca2+ entry. 892 88

The effect of repeated treatment with various antidepressant drugs on the reactivity of CA1 neurons to the 5-HT4 receptor agonist zacopride was examined. Zacopride decreased the calcium-activated afterhyperpolarization and adaptation, it also elicited a slow membrane depolarization associated with an increase in input resistance. All those effects may have contributed to the zacopride-induced increase in the amplitude of population spikes, evoked in the CA1 cell layer by stimulation of the Schaffer collateral/commissural pathway. The later effect of zacopride was concentration-dependent and was antagonized by the 5-HT4 receptor antagonist DAU 62805. Repeated (14 days, twice daily), but not single, administration of the antidepressant drugs imipramine, citalopram, fluvoxamine and paroxetine (10 mg/kg) attenuated the effect of zacopride on population spikes. Because inhibitory 5-HT1A and excitatory 5-HT4 receptors are colocalized on pyramidal neurons, and our previous data demonstrated an increase in the 5-HT1A receptor-mediated inhibition after repeated treatment with antidepressants, we conclude that treatment with antidepressant drugs may enhance the inhibitory effect of 5-HT directly, by increasing the 5-HT1A receptor responsiveness, and indirectly, by inducing subsensitivity to the 5-HT4 receptor activation.
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PMID:Repeated treatment with antidepressant drugs induces subsensitivity to the excitatory effect of 5-HT4 receptor activation in the rat hippocampus. 900 37

Fast cyclic voltammetry (FCV) was used to measure electrically stimulated monoamine efflux in the rat ventral lateral geniculate nucleus (vLGN). The electrochemical characteristics of the released species resembled 5-HT but not dopamine or noradrenaline. Amine efflux was abolished by the sodium channel blocker tetrodotoxin (0.1 microM), Ro 4-1284 (1.0 microM), the fast-acting reserpine analogue, and removal of Ca2+ from the superfusate. Amine efflux was unaffected by the monoamine oxidase inhibitor clorgyline (0.1 microM). Of paroxetine (0.1 microM), desipramine (50 nM) and vanoxerine (0.5 microM), selective blockers of 5-HT, noradrenaline and dopamine uptake respectively, only paroxetine increased monoamine efflux (to 194 +/- 25%, mean +/- SEM) and prolonged the removal half-life (to 638 +/- 105%). The non-specific 5-HT1 antagonist methiothepin (0.2 microM) increased 5-HT efflux on long (20 pulses at 20 Hz) but not short trains (20 pulses at 100 Hz). When tested on pseudo-one-pulse stimulations (5 pulses, 100 Hz), the selective 5-HT1A agonist 8-OHDPAT (1.0 microM) had no effect. CP 93129 (0.3 microM), the selective 5-HT1B agonist, decreased 5-HT efflux to 37 +/- 4% of control and was antagonised by the 5-HT1B blocker isamoltane (0.5 microM) and by the 5-HT1D/B antagonist GR 127935 (50 nM). The preferential 5-HT1D agonist sumatriptan (0.5 microM) also decreased 5-HT efflux, to 55 +/- 6% and was antagonised by GR 127935 (50 nM) but not isamoltane (0.5 microM). These results suggest that 5-HT released in the vLGN can be measured by FCV. Furthermore, released 5-HT is taken up by the 5-HT transporter and may be under the influence of 5-HT1B and 5-HT1D autoreceptors.
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PMID:Serotonin efflux in the rat ventral lateral geniculate nucleus assessed by fast cyclic voltammetry is modulated by 5-HT1B and 5-HT1D autoreceptors. 902 11

In the lamprey spinal cord, 5-hydroxytryptamine (5-HT) immunoreactivity (ir) is present in the ventromedial plexus originating from intraspinal neurons, ventrolateral column arising from the brainstem, and dorsal column. The latter 5-HT system originates from small dorsal root ganglion neurons. Combined Lucifer yellow intracellular labeling of the intraspinal sensory neurons, dorsal cells, and 5-HT immunohistochemistry showed close appositions between 5-HT-ir fibers and dorsal cell axons. Application of 5-HT depressed monosynaptic EPSPs evoked in giant interneurons by stimulation of single dorsal cells, dorsal roots, or dorsal column without any detectable change in the input resistance of postsynaptic neurons. Furthermore, the amplitude of AMPA-evoked depolarizations in giant interneurons was unaffected by 5-HT. The lack of postsynaptic effects of 5-HT indicates that the decrease of the amplitude of sensory monosynaptic EPSPs by 5-HT is mediated by presynaptic mechanisms. The inhibition of monosynaptic EPSPs by 5-HT was not counteracted by an antagonist of 5-HT1A receptors. 5-HT also reduced the amplitude of the calcium current recorded in isolated dorsal cells and slowed down its kinetics. The inhibition of calcium channels could represent the mechanism mediating the depression of synaptic transmission at the axonal level. These results show that activation of 5-HT receptors on dorsal cell axons as well as on other sensory neurons mediates inhibition of sensory synaptic transmission to giant interneurons. In intact animals, 5-HT could be released from small 5-HT neurons in dorsal root ganglia, which thus may underlie direct sensory-sensory interactions.
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PMID:5-HT inhibits calcium current and synaptic transmission from sensory neurons in lamprey. 903 Jun 37


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