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)

5-hydroxytryptamine (5-HT) hyperpolarizes hippocampal pyramidal cells in both areas CA1 and CA3 through an increase in potassium conductance. The receptor mediating the hyperpolarization in CA1 has been characterized as the 5-HT1A receptor, but has not been identified in area CA3. Intracellular recording techniques were used to record from CA1 and CA3 pyramidal cells in a hippocampal slice preparation. 5-HT agonists and antagonists were applied in known concentrations by bath perfusion. Antagonists were tested alone and for their ability to block the hyperpolarization elicited by 5-HT. The 5-HT1 agonist 5-carboxyamidotryptamine and 5-HT were full agonists and the 5-HT1A-selective ligand 8-hydroxydipropyl-aminotetralin hydrobromide was a partial agonist in both CA3 and CA1. The rank order potency was 5-carboxyamidotryptamine > 8-hydroxydipropyl-aminotetralin hydrobromide > 5-HT for both regions. The agonists were a half-log unit less potent and the maximum response elicited by 5-carboxyamidotryptamine and 5-HT was greater in area CA3 than in area CA1. The selective 5-HT1A antagonist BMY 7378 and the 5-HT1A/2 antagonist spiperone were competitive in area CA1, but insurmountable in area CA3. Other 5-HT antagonists that were not effective in blocking the 5-HT-mediated hyperpolarization included ketanserin, odansetron and BRL 24924. Based on these results, we conclude that the hyperpolarization elicited by 5-HT in areas CA1 and CA3 is mediated by the 5-HT1A receptor. However, there are significant differences in the nature of the 5-HT1A receptor-mediated hyperpolarization that may be attributed to differences in receptor-effector number, receptor-effector coupling and/or the structure of the recognition site.
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PMID:Comparison of 5-hydroxytryptamine1A-mediated hyperpolarization in CA1 and CA3 hippocampal pyramidal cells. 140 96

The effects of 5-hydroxytryptamine on the membrane potential and input resistance of 86 dorsal horn neurons were studied using intracellular recordings in isolated, hemisected spinal cords of adult frogs (Rana pipiens). Bath application of serotonin (5-100 microM) caused membrane depolarizations in 58 (67%) neurons, hyperpolarizations in 12 (14%) cells, biphasic responses in nine (11%) neurons, and no detectable change in seven (8%) cells. In some neurons depolarized by serotonin, the amine's responses could be mimicked by the selective 5-HT2 agonist (+/-)-1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride and the 5-HT1C/2 agonist alpha-methyl-5-hydroxytryptamine, and blocked by the 5-HT1C/2 antagonists ketanserin and mianserin. In other neurons depolarized by serotonin, the 5-HT3 agonist 2-methyl-5-hydroxytryptamine mimicked, and the 5-HT3 antagonist, 3-tropanyl-3,5-dichlorobenzoate, blocked the serotonin-induced responses. Depolarizing responses due to activation of 5-HT1C/2 receptors were generally accompanied by increases in the membrane input resistance, whereas depolarizations mediated by 5-HT3 receptors were associated with a decreased membrane input resistance. Superfusion with tetrodotoxin or low-Ca2+/high-Mg(2+)-containing media abolished about half of the depolarizing responses. Hyperpolarizations caused by serotonin were associated with a decrease in membrane input resistance, and might have been due to activation of a potassium conductance. These responses persisted in bathing solutions containing tetrodotoxin or low-Ca2+/high-Mg2+. The 5-HT1A agonist 8-hydroxy-2-(di-N-propylamine)tetralin hydrobromide mimicked, whereas the 5-HT1A antagonist spiroxatrine blocked, these hyperpolarizing responses. Other antagonists selective for 5-HT1C/2 or 5-HT3 receptors were without effect. Serotonin-produced biphasic responses consisted of either an initial depolarization followed by a hyperpolarization or the reverse. The selective 5-HT2 agonist (+/-)-1(2,5-dimethyoxy-4-iodophenyl)-2-aminopropane hydrochloride could only mimic the depolarizations, whereas the 5-HT1A agonist 8-hydroxy-2-(di-N-propylamine)tetralin hydrobromide produced only the hyperpolarizations. Spiroxatrine, a 5-HT1A antagonist, blocked only the hyperpolarizations without affecting the depolarizations, and methysergide, a non-specific 5-HT receptor antagonist, depressed both the depolarizations and hyperpolarizations. Serotonin also appeared to affect spinal dorsal horn neurons indirectly because it produced excitatory postsynaptic potentials, inhibitory postsynaptic potentials, and a mixture of both.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Diverse actions of 5-hydroxytryptamine on frog spinal dorsal horn neurons in vitro. 143 88

The extracellularly recorded firing rate of rat ventromedial hypothalamic neurones in vitro was inhibited by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, 2-methyl-5-HT was relatively ineffective. At 1 microM, spiperone and cyanopindolol antagonised the 5-CT induced inhibition, MDL 72222 (10 microM) and ketanserin (1 microM) did not. Intracellular recordings with voltage-clamp revealed that 5-HT and 5-CT evoked a tetrodotoxin-resistant outward current with a reversal potential of ca. -100 mV. 5-HT1A receptors likely activate a potassium conductance on these neurones.
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PMID:5-HT1A receptors activate a potassium conductance in rat ventromedial hypothalamic neurones. 160 Oct 58

1. The actions of serotonin (5-HT) and noradrenaline (NA) in the cat perigeniculate nucleus (PGN) and the guinea-pig nucleus reticularis thalami (NRT) were investigated with extracellular and intracellular recordings obtained from neurones in thalamic slices maintained in vitro. 2. Single, local application of either 5-HT or NA resulted in pronounced (5-50 Hz) and prolonged (2-10 min) excitation associated with the occurrence of single-spike activity. Serotoninergic excitation was specifically blocked by the 5-HT2/5-HT1C antagonists ketanserin and ritanserin, but not by the 5-HT1A antagonist pindolol or the 5-HT3 antagonist ICS 205-930. Furthermore, the 5-HT response was mimicked by alpha-methyl-5-HT, but not by the 5-HT1A agonist 8-hydroxydipropylaminotetralin (8-OHDPAT) or the 5-HT3 agonist 2-methyl-5-HT. Together, these results indicate that this excitatory response is mediated through 5-HT2 receptors with the possible involvement of 5-HT1C receptors. 3. Noradrenergic excitation was specifically blocked by the alpha 1-antagonist prazosin, but not by the beta-antagonist propranolol or the alpha 2-antagonist yohimbine. Similarly, the response was mimicked by the alpha-agonist phenylephrine, but not by the beta-agonist isoprenaline. These results indicate that the noradrenergic excitation is mediated by alpha 1-adrenoceptors. 4. Block of synaptic transmission either by lowering external calcium concentration ([Ca2+]o) to 0.5 mM and raising external magnesium concentration ([Mg2+]o) to 10 mM or by local application of tetrodotoxin failed to block the excitatory or depolarizing response to 5-HT or NA indicating that these responses are direct and not mediated through the release of other neurotransmitters. 5. Intracellular recordings revealed that the 5-HT- and NA-induced excitations are mediated by a pronounced slow depolarization associated with an apparent decrease in input conductance and an increase in the membrane time constant. Current versus voltage plots obtained under voltage clamp before and during the presence of 5-HT and NA revealed that these neurotransmitters induced an inward current which reversed to an outward current at -107 and -110 mV, respectively, in 2.5 mM external potassium concentration ([K+]o). This reversal potential was identical to that associated with an increase in potassium conductance activated by acetylcholine (-110 mV) in the same neurones. Plots of the amplitude of the 5-HT- or NA-induced current versus membrane potential revealed a linear relationship in the voltage range from -140 to -60 mV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. 166 58

The effects of carbamazepine (CBZ) on brain 5-hydroxytryptamine (5-HT) function were investigated in rodents pretreated with CBZ acutely or for 14 days. In behavioural experiments, mice pretreated with 14 days CBZ showed increased 5-HT2-mediated head twitch behaviour after injection of carbidopa (25 mg/kg) followed by 5-hydroxytryptophan (5-HTP, 100 mg/kg). However, no change in head twitches after 5-methoxy,N,N,-dimethyltryptamine (5MeODMT 5.0 mg/kg), a direct agonist, was observed. Chronic CBZ administration to rats did not alter either the behavioural syndrome induced by 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT, 1.0 mg/kg), an index of postsynaptic 5-HT1A responses, or hypothermia after 8-OH-DPAT (0.5 mg/kg) which is thought to reflect presynaptic 5-HT1A activity. Both hyperactivity and the behavioural syndrome seen after tranylcypromine (20 mg/kg) followed by L-tryptophan (100 mg/kg) were decreased by prior treatment with CBZ (14 days). Accumulation of 5-HTP after administration of the amino acid decarboxylase inhibitor NSD1015 (100 mg/kg) was decreased after acute CBZ (50 mg/kg) in hippocampus. However, after 14 days oral treatment no change in this measure of 5-HT synthesis was seen, in either hippocampus or frontal cortex. CBZ (50 microM) added to superfused brain slices did not affect potassium-stimulated [3H]-5-HT release. However, hippocampal slices from rats pretreated with CBZ (14 days) showed increased potassium-stimulated [3H]-5-HT release. CBZ (14 days) did not alter 5-HT2 binding in rat frontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of carbamazepine on 5-hydroxytryptamine function in rodents. 213 52

The release of serotonin (5-HT) from the terminals of serotonergic (raphe) neurons is under inhibitory feed-back control. 5-HT, acting on raphe cell body autoreceptors, also mediates inhibitory postsynaptic potentials as a result of release from collaterals from neighboring raphe neurons. This may involve a ligand (5-HT)-gated increase in the membrane potassium conductance, leading to a decrease in action potential frequency, which could indirectly reduce calcium influx into nerve terminals. In this report we demonstrate that 5-HT can also directly reduce calcium influx at potentials including and bracketing the peak of calcium current activation. Using acutely isolated, patch-clamped dorsal raphe neurons, we found that low concentrations of 5-HT and the 5-HT1A-selective agonist 8-OH-DPAT reversibly decrease whole-cell calcium current. This effect is antagonized by the putative 5-HT1A-selective antagonist NAN 190. Hence, the inhibition of calcium current may serve a physiological role in these cells and elsewhere in the brain.
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PMID:Serotonin receptor activation reduces calcium current in an acutely dissociated adult central neuron. 214 May 14

1. Intracellular recordings were made from neurones of the nucleus prepositus hypoglossi (PH) in slices of guinea-pig brain. Focal stimulation evoked an inhibitory postsynaptic potential (IPSP) that was typically 10-25 mV in amplitude and 1 s in duration. The IPSP reversal potential showed a Nernstian dependence on the external potassium concentration ([K+]o). 2. Spiperone blocked the IPSP with an IC50 of 40 nM, while ketanserin and (-)sulpiride had no effect. Cocaine (1 microM) prolonged the IPSP half-duration by 157%, and increased the amplitude by 28%. 3. 5-Hydroxytryptamine (5-HT, serotonin) hyperpolarized PH cells with an EC50 of 8.5 microM in control, and 135 nM in cocaine (10 microM). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) also hyperpolarized PH cells with an EC50 of 16 nM, although the maximal effect was only 81% of the maximum 5-HT hyperpolarization. Spiperone produced a parallel, right shift of the 5-HT concentration-response curve; Schild analysis gave a Kd of 10 nM. Application of 5-HT to neurones voltage-clamped near their resting potential (about -55 mV) caused an outward current and an increase in membrane conductance. 4. The amplitude of the IPSP was reversibly decreased by non-hyperpolarizing concentrations of 5-HT and by the 5-HT1 receptor agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP). The IC50 values for the latter two compounds were 50 nM and 1.5 microM, respectively; the maximal effect was a 90% inhibition. Neither compound affected the membrane potential nor changed the hyperpolarization induced by 5-HT. Quipizine competitively antagonized TFMPP with an estimated Kd of 165 nM. 5. When trains of stimuli were applied, an inhibition of the IPSP was observed following the first stimulus. At a frequency of 1 Hz, the inhibition was approximately 75%. This frequency-dependent 'run-down' of the IPSP was markedly attenuated by pre-treatment with TFMPP (1 microM). 6. It is concluded that the IPSP in PH cells is caused by 5-HT acting on 5-HT1A receptors to activate a potassium conductance. The release of 5-HT can be inhibited by activation of a presynaptic 5-HT1D receptor. This presynaptic receptor appears to be at least partly responsible for the run-down phenomenon, and may be involved in the physiological regulation of 5-HT synaptic transmission.
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PMID:Serotonin-mediated inhibitory postsynaptic potential in guinea-pig prepositus hypoglossi and feedback inhibition by serotonin. 214 Oct 79

Agonist occupancy of the cloned human serotonin (5-HT)1A receptor expressed in HeLa cells stimulates Na+/K+ ATPase activity as assessed by rubidium uptake. The purpose of the study was to determine which of the receptor-associated signaling mechanisms was responsible for this effect. 5-HT stimulated Na+/K+ ATPase 38% at 2 mM extracellular potassium, an effect characterized by a decrease in apparent K0.5 from 2.8 +/- 0.3 to 1.8 +/- 0.3 mM potassium without a significant change in apparent Vmax. The EC50 for the transport effect was approximately 3 microM 5-HT. The response was pertussis toxin-sensitive but did not involve inhibition of adenylate cyclase, as stimulation of Na+/K+ ATPase by 5-HT was observed in the presence of excess dibutyryl cAMP. Protein kinase C was not required for the response since short-term incubation with the phorbol esters phorbol 12 myristate, 13 acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) did not mimic the 5-HT effect. Moreover, 5-HT increased Na+/K+ ATPase activity after inactivation of protein kinase C by overnight incubation with PMA. 5-HT and the sesquiterpene lactone thapsigargin increased cytosolic calcium in this cell model, and the EC50 for 5-HT corresponded with that for stimulation of Na+/K+ ATPase. Both thapsigargin and A23187, a calcium ionophore, also increased Na+/K+ ATPase activity in a dose-responsive fashion. The response to 5-HT, thapsigargin, and A23187 was blocked by conditions that removed the cytosolic calcium response. By two-dimensional gel electrophoresis, we established evidence for a calcium-sensitive but protein kinase C-independent signaling pathway. We conclude that the 5-HT1A receptor, which we have previously shown to stimulate phosphate uptake via protein kinase C, stimulates Na+/K+ ATPase via a calcium-dependent mechanism. This provides evidence for regulation of two separate transport processes by a single receptor subtype via different signaling mechanisms.
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PMID:Short-term regulation of Na+/K+ adenosine triphosphatase by recombinant human serotonin 5-HT1A receptor expressed in HeLa cells. 217 7

In vivo dialysis coupled to high-performance liquid chromatography with electrochemical detection (HPLC-EC) was used for measurement of extracellular serotonin (5-HT) in the hypothalamus of unanesthetized, unrestrained rats. A series of experiments was carried out to determine if 5-HT in the dialysis solution was released from nerve terminals. Fenfluramine, a 5-HT-releasing drug and fluoxetine, a 5-HT-reuptake inhibitor, both significantly increased extracellular 5-HT. Elevating potassium concentration in the dialysis solution also significantly increased 5-HT. Reciprocally, 5-HT was significantly reduced to about half of control levels with either local administration of tetrodotoxin, zero calcium dialysis solution, or systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A agonist that suppresses 5-HT neuronal activity via activation of the somatodendritic autoreceptor. In addition, 5-HT levels were elevated during the dark portion of the light-dark cycle, a period when rats are more active. Changes in extracellular 5-hydroxyindoleacetic acid (5-HIAA) rarely followed changes in 5-HT. The results indicate that 5-HT in the dialysis solution, but not 5-HIAA, was a reliable measure of depolarization-induced release of 5-HT from nerve terminals. This is the first report establishing the reliability of in vivo dialysis coupled to HPLC-EC for measurement of synaptically released 5-HT.
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PMID:Extracellular serotonin and 5-hydroxyindoleacetic acid in hypothalamus of the unanesthetized rat measured by in vivo dialysis coupled to high-performance liquid chromatography with electrochemical detection: dialysate serotonin reflects neuronal release. 247 59

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and flesinoxan, agents which show high affinity and selectivity for 5-HT1A receptors, were administered intravenously in doses of 0.003 to 0.1 and 0.01 to 0.3 mg kg-1 respectively to 5 rabbits each. Their effects were compared with those of the centrally acting agent and alpha 2-adrenoceptor agonist, guanfacine, 0.01-0.3 mg kg-1, administered to a group of 5 rabbits. Five further rabbits were used as controls and treated with the vehicle of the active agents. 2. Both flesinoxan and 8-OH-DPAT induced similar systemic and regional haemodynamic changes. Both lowered mean arterial pressure and heart rate. The principal blood pressure lowering mechanism was vasodilatation; cardiac output changed minimally despite the falls in heart rate and myocardial contractile force. 3. With guanfacine the maximal fall of blood pressure was comparable to that obtained with the 5-HT1A receptor ligands; however, in contrast to the latter, the dose-response curve was U-shaped, the highest dose eliciting a pressor effect with reversal of the vasodilatation. 4. Widespread peripheral vasodilatation was found with all the agents in the splanchnic circulation and also in the brain and skeletal muscle. A weak tendency towards vasodilatation was found in the kidneys where the dose-response curve was bell-shaped for guanfacine. 5. This spectrum of activity is different from that of peripheral vasodilators, such as calcium antagonists, potassium channel activating agents or hydralazine; it is, however, consistent with the putative mechanism of action of these compounds to reduce peripheral sympathetic tone by a central mechanism of action.
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PMID:8-OH-DPAT, flesinoxan and guanfacine: systemic and regional haemodynamic effects of centrally acting antihypertensive agents in anaesthetized rabbits. 256 44


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