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)

The aim of the present study was to examine the effects of N-(2-(4-2-methoxphenyl)-1-piperazinyl)ethyl)-N-(2-pyridnyl) cyclohexane carboxamide (WAY 100635) on 5-HT1A receptor-mediated responses in the dorsal raphe nucleus (DRN) and the CA1 hippocampal region. In DRN slices superfused with WAY 100635 (10 nM), the majority of putative 5-HT neurons increased their firing rate (13 +/- 2% of baseline rate). In addition, WAY 100635 completely prevented the decrease in firing rate produced by 5-HT (3-15 microM), 8-OH-DPAT (10 nM), 5-carboxamidotryptamine (20 nM) and lesopitron (100 nM). The antagonism exerted by WAY 100635 (IC50 = 0.95 +/- 0.12 nM against 15 microM 5-HT) was fully surmounted by increasing the concentration of 5-HT to 300 microM. In hippocampal slices, WAY 100635 (0.5-10 nM) did not alter the resting membrane potential or the membrane input resistance of intracellularly recorded CA1 pyramidal cells. However, WAY 100635 completely prevented (IC50 = 0.9-1.7 nM) the hyperpolarization and the decrease in membrane input resistance produced by 5-HT (15-30 microM) and by 5-carboxamidotryptamine (50-300 nM). In contrast, WAY 100635 affected neither the block of action potential frequency adaptation and slow afterhyperpolarization produced by 5-HT (15 microM) nor the hyperpolarization and decrease in membrane input resistance evoked by bath application of GABA(B) receptor agonist baclofen (10 microM). The cumulative concentration-hyperpolarization curve for 5-carboxamidotryptamine (3 nM-10 microM) was shifted to the right by WAY 100635 (apparent Kb = 0.23 +/- 0.07 nM), and the latter drug also reduced the maximal response to the agonist. These data show the WAY 100635 is a potent antagonist at 5-HT1A receptors, both in the DRN and in the CA1 region of the hippocampus. The antagonism is apparently competitive in the DRN and partly noncompetitive in the hippocampus. Kinetic characteristics of the antagonist-receptor interactions might account for these regional differences.
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PMID:Electrophysiological effects of N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) on dorsal raphe serotonergic neurons and CA1 hippocampal pyramidal cells in vitro. 876 19

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.
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PMID:Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells. 910 87

Several observations indicate that 5-HT1A receptors found on a long neuronal feedback loop, originating from the medial prefrontal cortex, regulate 5-HT neuronal firing. In the present study, the muscarinic (M) receptor antagonists atropine and scopolamine as well as the M2 receptor antagonist AF-DX 116, but not the preferential M1 receptor antagonist pirenzepine, reduced the suppressant effect of the 5-HT1A receptor agonist 8-OH-DPAT on the spontaneous firing activity of rat dorsal raphe 5-HT neurons. Moreover, AF-64A-induced lesions of cholinergic neurons directly in the medial prefrontal cortex and after its i.c.v. injection attenuated the effect of 8-OH-DPAT. Finally, the NMDA receptor antagonist (+)MK-801 and the GABA(B) receptor antagonist SCH-50911, but not the GABA(A) receptor antagonist (-)bicuculline, dampened the latter response. The present study unveiled a key role for the cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons.
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PMID:Role of cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons. 1105 9

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain in order to study serotonergic-GABAergic interaction. The slices were loaded with either [3H] serotonin or [3H]GABA, superfused and the electrically induced efflux of radioactivity was determined. The GABA(A) receptor agonist muscimol (3 to 30 microM) and the GABA(B) receptor agonist baclofen (30 and 100 microM) inhibited [3H]serotonin and [3H]GABA release. These effects of muscimol were reversed by the GABA(A) antagonists bicuculline (100 microM). The GABA(B) antagonist phaclofen (100 microM) also antagonized the baclofen-induced inhibition of [3H]serotonin and [3H]GABA release. Phaclofen by itself increased [3H]serotonin release but it did not alter [3H]GABA overflow. Muscimol (10 microM) and baclofen (100 microM) also inhibited [3H]serotonin release after depletion of GABAergic neurons by isoniazid pretreatment. These findings indicate the presence of postsynaptic GABA(A) and GABA(B) receptors located on serotonergic neurons. The 5-HT1A receptor agonist 8-OH-DPAT (0.01 to 1 microM) and the 5-HT1B receptor agonist CGS-12066A (0.01 to 1 microM) inhibited the electrically stimulated [3H]serotonin and [3H]GABA release. The 5-HT1A antagonist WAY-100135 (1 microM) was without effect on [3H]serotonin and [3H]GABA efflux by itself but it reversed the 8-OH-DPAT-induced transmitter release inhibition. During KCl (22 mM)-induced depolarization, tetrodotoxin (1 microM) did not alter the inhibitory effect of CGS-12066A (1 microM) on [3H]GABA release, it did blocked, however, the ability of 8-OH-DPAT (1 microM) to reduce [3H]GABA efflux. After depletion of raphe serotonin neurons by p-chlorophenylalanine pretreatment, CGS-12066A (1 microM) still inhibited [3H]GABA release whereas in serotonin-depleted slices, 8-OH-DPAT (1 microM) was without effect on the release. We conclude that reciprocal influence exists between serotonergic projection neurons and the GABAergic interneurons or afferents in the raphe nuclei and these interactions may be mediated by 5-HT1A/B and GABA(A/B) receptors. Both synaptic and non-synaptic neurotransmission may be operative in the 5-HTergic-GABAergic reciprocal interaction which may serve as a local tuning in the neural connection between cerebral cortex and midbrain raphe nuclei.
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PMID:Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. 1107 65

Effects of 5-hydroxytryptamine (5-HT) on EPSPs and EPSCs in the rat dorsolateral septal nucleus (DLSN) were examined in the presence of GABA(A) and GABA(B) receptor antagonists. Bath application of 5-HT (10 microm) for 5-10 min increased the amplitude of the EPSP and EPSC. (+/-)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (10 microm), an agonist for 5-HT1A and 5-HT7 receptors, did not facilitate the EPSP. alpha-Methyl-5-HT (10 microm), a 5-HT2 receptor agonist, increased the amplitude of the EPSC. Alpha-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (10 microm) and 6-chloro-2-(1-piperazinyl)pyrazine (10 microm), selective 5-HT2B and 5-HT2C receptor agonists, respectively, had no effect on the EPSP. The 5-HT-induced facilitation of the EPSP was blocked by ketanserin (10 microm), a 5-HT2A/2C receptor antagonist. However, N-desmethylclozapine (10 microm), a selective 5-HT2C receptor antagonist, did not block the facilitation of the EPSP induced by alpha-methyl-5-HT. The inward current evoked by exogenous glutamate was unaffected by 5-HT. 5-HT (10 microm) and alpha-methyl-5-HT (10 microm) increased the frequency of miniature EPSPs (mEPSPs) without changing the mEPSP amplitude. The ratio of the paired pulse facilitation was significantly decreased by 5-HT and alpha-methyl-5-HT. The 5-HT-induced facilitation of the EPSP was blocked by calphostin C (100 nm), a specific protein kinase C (PKC) inhibitor, but not by N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (10 microm), a protein kinase A inhibitor. Phorbol 12,13-dibutyrate (3 microm) mimicked the facilitatory effects of 5-HT. These results suggest that 5-HT enhances the EPSP by increasing the release of glutamate via presynaptic 5-HT2A receptors that link with PKC in rat DLSN neurons.
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PMID:Activation of presynaptic 5-hydroxytryptamine 2A receptors facilitates excitatory synaptic transmission via protein kinase C in the dorsolateral septal nucleus. 1219 74