Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The actions of 5-hydroxytryptamine (5-HT) on rat dentate gyrus neurones were measured with conventional intracellular recording techniques in brain slices maintained in vitro at 32 degrees C. 2. Bath application of 5-HT (0.3-100 microM) hyperpolarized the membrane potential and reduced the input resistance; these effects persisted in tetrodotoxin (1 microM) and were abolished by MDL 73,005EF, a 5-HT1A receptor antagonist. 3. Local application of 5-HT via a pressure pipette also elicited a hyperpolarization and a reduction in resistance, and evoked a transient 'burst' of spontaneous inhibitory postsynaptic potentials (IPSPs) which were blocked by tetrodotoxin or bicuculline. 4. The 'burst' of IPSPs was subject to desensitization. It was completely abolished in the presence of the 5-HT3 receptor antagonist dolasetron. 5. In some cells, a longer lasting increase in spontaneous IPSP frequency was observed during application of 5-HT; this effect was blocked by the 5-HT2 receptor antagonist MDL 100,907. 6. 5-HT (30 microM) shortened the decay time constants of the glutamatergic and GABAergic evoked EPSPs and IPSPs without changing their amplitudes. 7. It is concluded that 5-HT hyperpolarizes granule cells via postsynaptic 5-HT1A receptors and increases spontaneous GABA release from inhibitory interneurones via the activation of 5-HT3 receptors and/or 5-HT2 receptors.
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PMID:Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro. 770 31

1. We devised a new light/dark transition apparatus, recorded transitions, % time animals spent outside the dark chambers (% time) and locomotor activity, and evaluated this apparatus by testing anxiolytics, non-anxiolytic drugs and putative anxiogenic drugs in mice. 2. Diazepam and alprazolam significantly increased transitions, % time and locomotor activity. The effects of 1 mg/kg (i.p.) diazepam on these parameters in this modified test were blocked by flumazenil, a selective benzodiazepine antagonist. 3. Anxiogenic drugs such as beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) and picrotoxin significantly decreased all three parameters. Another anxiogenic drug, yohimbine, also significantly decreased transitions and locomotor activity, but it significantly increased % time at 5 mg/kg (i.p.). 4. Imipramine (5-10 mg/kg, i.p.), an antidepressant, sulpiride (10-25 mg/kg, i.p.), an antipsychotic drug, and scopolamine (0.1-1 mg/kg, i.p.), an anticholinergic drug, had no effect. 5. Buspirone, a partial 5-HT1A receptor agonist, produced parameter changes similar to those induced by anxiolytic benzodiazepines. 8-OH-DPAT, a full 5-HT1A receptor agonist, significantly increased transitions and locomotor activity but not % time. 5-HT3 receptor antagonists, ICS205-930 and MDL72222, did not have any effect on these parameters. 6. Methamphetamine (1-2 mg/kg, i.p.) increased all parameters, while caffeine increased only locomotor activity. 7. The present findings indicate that the modified light/dark transition test is very simple and easy to perform for testing the anxiolytic and anxiogenic effects of drugs.
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PMID:The modified light/dark transition test in mice: evaluation of classic and putative anxiolytic and anxiogenic drugs. 771 61

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, the alpha 2-adrenoceptor agonist clonidine and the alpha 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.
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PMID:Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs. 772

There was a significant increase in potassium-stimulated release of 3H-[5-HT] from hippocampal slices taken from rats withdrawn from chronic ethanol treatment, compared with control-treated rats. The anxiogenic behaviour observed 12 h after ethanol withdrawal was inhibited by the 5-HT1A partial agonist, buspirone (200 micrograms/kg s.c.), indicating that the increased 5-HT release might underlie the anxiogenic response. The ex-ethanol treated rats showed impaired habituation of motor activity in the holeboard and a reduced exploratory response. The latter, but not the former, were reversed by the 5-HT3 receptor antagonist, ondansetron (0.01 microgram/kg i.p.). Ondansetron was without effect on working memory errors, but significantly increased the number of reference memory errors made by the ex-ethanol group. It also had a significantly anxiogenic effect in this group. These results suggest that the chronic ethanol treatment changes the 5-HT system and has long-lasting effects on the function of 5-HT3 receptors.
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PMID:The role of 5-HT in the anxiogenic effects of acute ethanol withdrawal and in the long-lasting cognitive deficits. 774 45

VA21B7 (3-[2-(4'-piperonylpiperazinyl) indolyl] carboxaldehyde) was synthesized as a potential 5-HT3 receptor antagonist. Even though VA21B7 showed a higher affinity towards 5-HT3 receptors as compared to other receptors studied, it was not a potent 5-HT3 receptor antagonist either in the periphery or in the brain. In a simple animal model of anxiety such as the two-compartment box in mice, a remarkable anxiolytic-like effect was found at doses of 2-500 micrograms/kg IP and also at low oral doses, in the microgram range. These drug doses did not produce any significant effect on spontaneous motor activity of mice. The anxiolytic profile of VA21B7 was further explored using other models of anxiety in rats such as the elevated plus-maze and punished-drinking. VA21B7 was compared with standard 5-HT3 receptor antagonists such as ondansetron, tropisetron and granisetron, with the 5-HT1A agent buspirone and with diazepam. In the plus-maze, VA21B7 showed an anxiolytic-like profile after doses of 0.25-0.5 mg/kg IP or 2-4 mg/kg PO which did not modify the number of total entries into the open and closed arms of the maze. Diazepam, granisetron and tropisetron were also effective in this test but not ondansetron and buspirone. VA21B7 was also able to release suppressed behaviour in the punished-drinking test. The dose-response curve was bell-shaped with a peak at 2-4 mg/kg. At variance with other studies, 5-HT3 receptor antagonists also increased the number of shocks taken in this test and the dose-response curve was also bell-shaped. VA21B7 was not anticonvulsant like diazepam, its anxiolytic action in the light/dark test was not flumazenil-sensitive and there was no rebound anxiogenic effect on withdrawal from chronic VA21B7 treatment for 15 consecutive days. Moreover, VA21B7 was not amnesic like the benzodiazepines but low doses of 2-4 mg/kg reduced the memory deficits induced in rats by scopolamine. Much higher doses were necessary to decrease spontaneous motor activity in rats. Since VA21B7 appears to be well tolerated in rodents at high doses, we think that it is of potential interest as an anxiolytic in humans.
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PMID:The pharmacology of VA21B7: an atypical 5-HT3 receptor antagonist with anxiolytic-like properties in animal models. 775 59

The hypothesis that a dysfunction of serotonergic neurotransmission is implicated in depression is supported by the clinical efficiency of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) in the treatment of depressive disorders. These drugs, such as fluoxetine and paroxetine, exert their antidepressant activity by increasing 5-HT concentration in the synaptic cleft and thus enhancing serotonergic neurotransmission. However, two to three weeks of treatment are necessary to see the first signs of clinical efficiency. Several hypothetical mechanisms have been put forward to account for this delay, taking into account pharmacokinetic considerations, neurotransmitter metabolism, and/or adaptive regulation of pre and/or post-synaptic receptors. The aim of this study was to look for such adaptive changes in the course of a 3-week treatment with fluoxetine (5 mg/kg/day, i.p.) or paroxetine (5 mg/kg/day, i.p.) in adult rats. In vitro binding and quantitative autoradiographic studies showed that neither 5-HT1A, 5-HT1B, 5-HT2A, nor 5-HT3 receptor binding sites in various brain areas were affected by these treatments. Furthermore, comparison of the specific binding of [3H]8-OH-DPAT to 5-HT1A receptors functionally coupled to G proteins with that of [3H]WAY 100635 to all 5-HT1A receptor binding sites (i.e. coupled and uncoupled with regard to G proteins) revealed no significant change in rats treated with either SSRI. Accordingly, the proportion of functional 5-HT1A receptors (i.e. those physically coupled to G proteins) appeared to remain unaltered all along a 3-week treatment with either fluoxetine or paroxetine. Nevertheless, in vitro electrophysiological recordings of serotonergic neurons in the dorsal raphe nucleus allowed the demonstration of a clearcut functional desensitization of somatodendritic 5-HT1A autoreceptors. Thus, the potency of the 5-HT1A autoreceptor agonist, 8-OH-DPAT, to depress the firing of serotonergic neurons in brain stem slices was significantly reduced as soon as after a 3-day treatment with either SSRI. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT1A autoreceptors then increased along the treatment, and was generally larger with fluoxetine than with paroxetine. As 5-HT1A autoreceptor desensitization can contribute to facilitate serotoninergic neurotransmission, the remarkable efficiency of fluoxetine to trigger this adaptive regulatory mechanism might account, at least partly, for its potent antidepressant activity.
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PMID:[Central serotonin receptors and chronic treatment with selective serotonin reuptake inhibitors in the rat: comparative effects of fluoxetine and paroxetine]. 778 83

To elucidate the mechanism of antinociceptive effects of calcitonin, we investigated whether receptor antagonists for various neurotransmitter receptors alter the inhibitory effect of calcitonin on intrathecally injected N-methyl-D-aspartate-induced aversive behavior in mice. Neither naloxone, an opioid receptor antagonist, phentolamine and benextramine, alpha-adrenoceptor antagonists, nor ritanserin, a 5-HT2A receptor antagonist, inhibited the calcitonin-induced anti-aversive effects. Pindolol and (--)-propranolol, non-selective antagonists of beta-adrenoceptors and 5-HT1 receptors, 1-(2-methoxyphenyl)-4-[4-(2-phethalimido) butyl]-piperazine hydrobromide (NAN-190), a 5-HT1A receptor antagonist, 3-tropanyl-3,5-dichlorobenzoate (MDL72222) and metoclopramide, 5-HT3 receptor antagonists, significantly inhibited the calcitonin-induced anti-aversive effects. (--)-Bicuculline, a GABAA receptor antagonist, phaclofen and 5-aminovaleric acid, GABAB receptor antagonists, also attenuated the calcitonin-induced anti-aversive effects. These results suggest that beta-adrenoceptor, 5-HT1A, 5-HT3, GABAA and GABAB receptors, but not alpha-adrenoceptor, opioid nor 5-HT2A receptors, are involved in the inhibitory effect of calcitonin on intrathecally injected N-methyl-D-aspartate-induced aversive behavior in mice.
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PMID:Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-aspartate-induced aversive behavior. 779 51

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.
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PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

5-Hydroxytryptamine (5-HT) contracts and relaxes isolated stomach preparations. This study attempts to characterise receptors involved in the contractile response using electrically stimulated circular muscle strips from guinea pig stomach. Electrically induced contractions were abolished by atropine and tetrodotoxin. 5-HT enhanced contractions in corpus and fundus strips with pEC50% values (-log10 of the concentrations causing a 50% increase in twitch height) of 9.6 and 9.1, respectively. 5-Carboxamidotryptamine and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), 5-HT1A receptor agonists, and alpha-methyl-5-HT, an agonist at 5-HT2 receptors, reduced contractions. The 5-HT3 receptor agonist, 2-methyl-5-HT, increased contractions. The effect of 2-methyl-5-HT but not of 5-HT was antagonized by the 5-HT3 receptor antagonist, tropisetron (10(-7) M). The 5-HT3 receptor antagonists, tropisetron, MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), grainsetron and ondansetron, did not modify twitch responses at concentrations below 10(-7) M. Renzapride and metoclopramide, agonists at 5-HT4 receptors, increased contractions and this effect was inhibited by the 5-HT4 receptor antagonist SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) with a pA2 of 7.4. The effect of 5-HT at a submaximal concentration of 10(-8) M was blocked by SDZ 205-557 (10(-6) M). It is concluded that electrically induced contractions in guinea pig stomach strips are enhanced by activation of 5-HT3- and 5-HT4 receptors and are diminished by 5-HT1 receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulant effects of 5-hydroxytryptamine on guinea pig stomach preparations in vitro. 781 82

In previous studies, we showed that localized perfusion of the SCN region with serotonin (5-HT) or the non-selective serotonergic, quipazine, using the microdialysis technique significantly reduced the extracellular concentration of the excitatory amino acid (EAA), glutamate. The present investigation was undertaken to extend these findings by characterizing the effects of various classes of 5-HT receptor ligands on the extracellular glutamate concentration in the SCN. Localized SCN application or i.p. injection of the 5-HT1A receptor agonist, 8-OH-DPAT, during the dark phase (6 h after lights-off) significantly reduced the extracellular glutamate concentration in the SCN region from baseline levels (38.7 +/- 8.7 and 53.4 +/- 11.2%, respectively, of pretreatment values; P < 0.05). The effect of systemically applied 8-OH-DPAT was abolished by i.p. injection of the 5-HT1A receptor antagonist, NAN-190, administered 20 min before the 8-OH-DPAT. Localized perfusion of the SCN with the 5-HT1B receptor agonist, TMFPP, also reduced extracellular glutamate but to a lesser degree than 8-OH-DPAT (80.1 +/- 3.9% of pretreatment levels; P < 0.05). This effect was prevented by i.p. injection of the non-selective 5-HT receptor antagonist, metergoline 20 min before TFMPP perfusion. Localized perfusion of the SCN region with the 5-HT2 and 5-HT3 receptor agonists, alpha-methyl 5-HT and 1-phenylbiguanide, respectively, had little effect on extracellular glutamate (both P > 0.1 vs. baseline). Systemic treatment with NAN-190 alone had little effect on extracellular glutamate, however, similar treatments with metergoline or the 5-HT2 receptor antagonist, ritanserin, induced significant increases extracellular glutamate levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serotonergic inhibition of extracellular glutamate in the suprachiasmatic nuclear region assessed using in vivo brain microdialysis. 782 May 91


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