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 assess, using in vivo electrophysiological paradigms, the effect of sustained administration of the selective and reversible monoamine oxidase-A inhibitor beflotaxone on serotonin (5-hydroxytryptamine, 5-HT) neurotransmission. In male Sprague-Dawley rats with the osmotic minipumps in place, a treatment with befloxatone (0.75 mg/kg per day, s.c.) for 2 days decreased the spontaneous firing activity of dorsal raphe 5-HT neurons. The combination of befloxatone and the 5-HT1A/1B receptor antagonist (-)-pindolol (15 mg/kg per day, s.c.) for 2 days slightly increased the firing activity of 5-HT neurons, whereas a treatment with (-)-pindolol alone for 2 days did not modify this parameter. The suppressant effects on the firing activity of 5-HT neurons of the 5-HT autoreceptor agonist lysergic acid diethylamide (LSD), injected intravenously, and of both 5-HT and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), applied by microiontophoresis, were attenuated in rats treated with befloxatone for 2 days, suggesting an early desensitization of the somatodendritic 5-HT1A receptors. The firing activity of 5-HT neurons was back to normal after a treatment for 21 days with befloxatone but the suppressant effects of LSD, 5-HT or 8-OH-DPAT was the same as in controls. In contrast, the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of 5-HT neurons was significantly attenuated after the treatment with befloxatone for 21 days. At the postsynaptic level, the administration of the selective 5-HT1A receptor antagonist (N-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide trihydroxychloride (WAY 100635, 100 microg/kg, i.v.) did not modify the firing activity of quisqualate-activated dorsal hippocampus CA3 pyramidal neurons in control rats. In contrast, in rats treated with befloxatone in combination with (-)-pindolol for 2 days as well as with befloxatone alone for 21 days, WAY 100635 significantly increased the firing of CA3 pyramidal neurons. In conclusion, these data suggest that when the firing activity of 5-HT neurons is normal in the presence of befloxatone, either after a two-day treatment together with (-)-pindolol or alone for 21 days, the tonic activation of postsynaptic 5-HT1A receptors is enhanced.
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PMID:Effect of the reversible monoamine oxidase-A inhibitor befloxatone on the rat 5-hydroxytryptamine neurotransmission. 957 Apr 66

Flibanserin (BIMT 17) has been described as a 5-HT1A agonist with preferential affinity for postsynaptic 5-HT1A receptors and as a 5-HT2A antagonist. Indeed, using the forskolin-stimulated cAMP accumulation technique, flibanserin but not the 5-HT1A agonists buspirone and 8-OH-DPAT had agonistic activity at postsynaptic 5-HT1A receptors in the cerebral cortex. The present in vivo electrophysiological study investigated the agonistic properties of this novel compound in pre- and postsynaptic areas of the anesthetized rat brain using local microiontophoretic application and systemic administration. The inhibition induced by either local or intravenous administration of flibanserin was current- and dose-dependent. Based on the ability of 5-HT1A antagonists to block or reverse the inhibitory action of the compound, the effect of flibanserin was shown to be mediated via 5-HT1A receptors. In addition, as determined by the concurrent microiontophoretic application of flibanserin and 5-HT, flibanserin behaved as a full agonist in the dorsal raphe nucleus (DRN) and the medial prefrontal cortex (mPFC), but as a partial agonist in the CA3 region of the hippocampus. Based on neuronal responsiveness observed with the local microiontophoretic application of flibanserin, it was found that the agonist was most potent on 5-HT1A receptors in the hippocampus, followed by the mPFC and DRN (I.T50 values: 260, 1,260, and 1,365 nanocoulombs, respectively). However, based on the ED50 values obtained from intravenous administration of the drug, flibanserin was most potent in the DRN followed by the hippocampus and mPFC (ED50 values: 239, 1,414, and 2,984 micrograms/kg, respectively). Therefore, flibanserin presented a marked selectivity for postsynaptic 5-HT1A receptors when applied locally, but not when administered intravenously. It remains to be determined if flibanserin preferentially activates postsynaptic 5-HT1A receptors upon sustained systemic administration.
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PMID:In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT1A receptors in the rat brain. 966 Dec 57

Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.
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PMID:Effect of long-term administration of duloxetine on the function of serotonin and noradrenaline terminals in the rat brain. 968 35

The present studies evaluated the effects of acute and long-term administration of the 5-HT1A agonist BAY x 3702 on the responsiveness of dorsal raphe 5-HT neurons and of dorsal hippocampus CA3 pyramidal neurons. BAY x 3702 potently reduced the firing activity of 5-HT neurons and of CA3 pyramidal neurons when applied by microiontophoresis and this inhibitory effect of BAY x 3702 was fully antagonized by low intravenous doses of the 5-HT1A antagonist WAY 100635. Concurrent microiontophoretic application of BAY x 3702 did not antagonize the suppressant effect of 5-HT on firing activity of 5-HT and CA3 pyramidal neurons. Sustained administration of BAY x 3702 for 2 days (1 and 1.25 mg/kg/day using osmotic minipumps implanted subcutaneously) markedly decreased the firing rate of dorsal raphe 5-HT neurons. This was followed by a full recovery to normal after only 7 days of treatment. The postsynaptic 5-HT1A receptors in the hippocampus, contrary to the presynaptic 5-HT1A receptors, were not desensitized after a 14-day treatment. In conclusion, BAY x 3702 acted as a full and potent agonist both at somatodendritic 5-HT1A autoreceptors and at postsynaptic 5-HT1A receptors. Long-term administration of BAY x 3702 resulted in a desensitization of the somatodendritic 5-HT1A autoreceptors, but in an unaltered responsiveness of 5-HT1A receptors on pyramidal neurons. These results suggest that sustained administration of BAY x 3702 enhances neurotransmission at postsynaptic 5-HT1A receptors.
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PMID:Full agonistic properties of BAY x 3702 on presynaptic and postsynaptic 5-HT1A receptors electrophysiological studies in the rat hippocampus and dorsal raphe. 973 84

The present studies have examined whether the neuropeptide galanin can modulate brain serotoninergic (5-HT) neurotransmission in vivo and, particularly, 5-HT1A receptor-mediated transmission. For that purpose, we studied the ability of galanin (given bilaterally into the lateral ventricle, i.c.v.) to modify the impairment of passive avoidance retention induced by the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propyloamino)tetralin (8-OH-DPAT) when injected prior to training. This impairment appears to be mainly related to activation of 5-HT1A receptors in the CNS. Galanin dose-dependently (significant at 3.0 nmol/rat) attenuated the passive avoidance impairment (examined 24 h after training) induced by the 0.2 mg/kg dose of 8-OH-DPAT. This 8-OH-DPAT dose produced signs of the 5-HT syndrome indicating a postsynaptic 5-HT1A receptor activation. Furthermore, both the impairment of passive avoidance and the 5-HT syndrome were completely blocked by the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg). Galanin (0.3 or 3.0 nmol) or WAY 100635 (0.1 mg/kg) failed by themselves to affect passive avoidance retention. 8-OH-DPAT given at a low dose 0.03 mg/kg, which presumably stimulates somatodendritic 5-HT1A autoreceptors in vivo, did not alter passive avoidance retention or induce any visually detectable signs of the 5-HT syndrome. Galanin (0.3 or 3.0 nmol) given i.c.v. in combination with the 0.03 mg/kg dose of 8-OH-DPAT, did not modify passive avoidance. The immunohistochemical study of the distribution of i.c.v. administered galanin (10 min after infusion) showed a strong diffuse labelling in the periventricular zone (100-200 microm) of the lateral ventricle. Furthermore, in the dorsal and ventral hippocampus galanin-immunoreactive nerve cells appeared both in the dentate gyrus and the CA1, CA2 and CA3 layers of the hippocampus. In the septum only endogenous fibres could be seen while in the caudal amygdala also galanin-immunoreactive nerve cells were visualized far away from the labelled periventricular zone. At the level of the dorsal raphe nucleus a thin periventricular zone of galanin immunoreactivity was seen but no labelling of cells. These results suggest that galanin can modulate postsynaptic 5-HT1A receptor transmission in vivo in discrete cell populations in forebrain regions such as the dorsal and ventral hippocampus and parts of the amygdala. The indication that galanin administered intracerebroventrically may be taken up in certain populations of nerve terminals in the periventricular zone for retrograde transport suggests that this peptide may also affect intracellular events.
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PMID:Intraventricular galanin modulates a 5-HT1A receptor-mediated behavioural response in the rat. 974 77

In the rat dorsal hippocampus and dorsal raphe nucleus, the microiontophoretic application of ergotamine and 5-HT suppressed the firing activity of CA3 pyramidal neurons and 5-HT neurons, an effect antagonized by selective 5-HT1A receptor antagonists. Co-application of ergotamine prevented the inhibitory action of 5-HT on the firing activity of CA3 pyramidal neurons but not of 5-HT neurons, indicating that ergotamine acted as a partial 5-HT1A receptor agonist in the dorsal hippocampus and as a full agonist at 5-HT1A autoreceptors. Ergotamine decreased, in a concentration-dependent manner, the electrically evoked release of [3H]5-HT in preloaded rat and guinea pig hypothalamus slices; this effect was prevented by the nonselective 5-HT receptor antagonist methiothepin but not by the selective 5-HT1B/1D receptor antagonist GR 127935 or the alpha 2-adrenoceptor antagonist idazoxan. Although body temperature in humans remained unchanged following inhaled ergotamine, in the rat, subcutaneously injected ergotamine produced a hypothermia that was prevented by a pretreatment with the 5-HT1A/1B receptor/beta-adrenoceptor antagonist pindolol. Finally in humans, ergotamine did not alter prolactin or adrenocorticotropic hormone levels, but increased growth hormone level, which was prevented by pindolol. Cortisol level was increased in humans by ergotamine, but this enhancement was unaltered by pindolol. In conclusion, the present results suggest that ergotamine acted in the rat brain as a 5-HT1A receptor agonist and as an agonist of terminal 5-HT autoreceptor of a yet undefined subtype. In humans, ergotamine also displayed some 5-HT1A receptor activity but, probably because of lack of receptor selectivity, it did not present the same profile as other 5-HT1A receptor agonists.
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PMID:Effect of ergotamine on serotonin-mediated responses in the rodent and human brain. 977 59

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.
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PMID:Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. 982 68

5-HT1A receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5-HT1A receptor agonism. Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT2A receptors. This reduction in the effect of locally-applied DOI was no longer present following 7-day flibanserin administration. Two-day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administration, 5-HT neuronal firing activity had returned to normal and the somatodendritic 5-HT1A autoreceptors were desensitized. The responsiveness of postsynaptic 5-HT1A receptors located on CA3 hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically-applied 5-HT and gepirone, was unchanged following a 7-day flibanserin treatment. As demonstrated by the ability of the 5-HT1A receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2- and 7-day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5-HT1A receptors in this brain region. The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action.
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PMID:Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain. 1018 73

The effects of neuroleptics have been attributed to dopamine (DA) receptor blockade; however, other neurotransmitters, in particular serotonin (5-HT), have also been implicated. In this study, we examined the effects of clozapine and haloperidol on the distribution of DA and 5-HT transporters, on endogenous DA, 5-HT and their major metabolites, and on 5-HT1A receptors. Adult male Sprague-Dawley rats were treated with either haloperidol (1 mg/kg/day, i.p.), clozapine (20 mg/kg/day, i.p.) or saline for 21 days, and following 3 days of withdrawal, the brains were removed. Tissue levels of DA and 5-HT and their metabolites were measured by high-performance liquid chromatography in 16 brain regions, while quantitative autoradiography with [125I]RTI-121, [3H]citalopram and [3H]8-OH-DPAT was employed to label DA transporters, 5-HT transporters and 5-HT1A receptors, respectively. After haloperidol, densities of 5-HT transporters were increased in the dorsal insular cortex and in the ventral half of caudal neostriatum, while 5-HT1A receptors augmented in cingulate cortex but decreased in the entorhinal area. After clozapine, [3H]citalopram labelling was increased in ventral hippocampus, ventral caudal neostriatum and nucleus raphe dorsalis, but decreased in medio-dorsal and latero-dorsal neostriatum as well as in substantia nigra. Binding of [3H]8-OH-DPAT following clozapine was decreased in frontal, parietal, temporal and entorhinal cortices but increased in the CA3 division of Ammon's horn. The changes in 5-HT transporters in nucleus raphe dorsalis and substantia nigra, as well as the 5-HT1A receptor down-regulations caused by clozapine but not by haloperidol, may explain effects obtained with clozapine and other atypical neuroleptics. There were no modifications in densities of DA transporters, nor of tissue DA levels, after the chronic neuroleptic treatments. The results are in line with previous suggestions that a certain degree of tolerance to neuroleptics develops, in spite of profound D1 and D2 receptor changes that persist during the entire chronic treatment with these psychotropic agents.
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PMID:Effects of antipsychotic drugs on dopamine and serotonin contents and metabolites, dopamine and serotonin transporters, and serotonin1A receptors. 1019 36

Mirtazapine (ORG 3770, Remeron) is a new alpha 2-adrenoceptor antagonist which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha 2-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of alpha 2-adrenergic autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of alpha 2-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3 pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine.
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PMID:Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission. 1033 81


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