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)

'Giant' synaptosomes originating from mossy fibre terminals and having sedimentation properties different from those of standard synaptosomes were obtained from rat cerebellum. Exposure of superfused giant synaptosomes to 15 mM KCl caused the release of endogenous glutamate in a largely (about 80%) calcium-dependent manner. The K(+)-evoked overflow of glutamate was inhibited in a concentration-dependent manner by 5-hydroxytryptamine (5-HT) and by the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI), but not by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The effects of 5-HT and DOI were quite potent, already reaching significant inhibition (about 25%) at 10 nM. The 5-HT2 receptor antagonist ketanserin counteracted the inhibitory effect of 5-HT. In cerebellar slices, ketanserin increased on its own the calcium-dependent K(+)-evoked release of glutamate and this effect was not prevented by tetrodotoxin (TTX). The results support the idea that cerebellar mossy fibres use glutamate as a transmitter and show that the release of glutamate can be inhibited via presynaptic heteroreceptors of the 5-HT2 type probably localized on the mossy fibre terminals.
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PMID:5-HT2 presynaptic receptors mediate inhibition of glutamate release from cerebellar mossy fibre terminals. 183 84

The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.
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PMID:Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. 2654 64

In the present experiments we have investigated the possible coupling of 5-hydroxytryptamine (HT)3 receptors to the metabolism of phosphatidylinositol (PI) in the rat fronto-cingulate and entorhinal cortices, two brain regions with relatively high density of this receptor subtype. 5-HT dose-dependently increases PI turnover (20-80% increase above basal stimulation), with an EC50 of 0.5 and 0.3 microM for fronto-cingulate and entorhinal cortices, respectively. This effect was blocked by the selective 5-HT3 antagonists, BRL 43694 (granisetron), GR 38032F (ondansetron) and ICS 205-930. The selective 5-HT3 receptor agonists, 2-methyl-serotonin (2-Me-5-HT) and phenylbiguanide (PBG), mimicked the action of 5-HT and dose-dependently produced a significant increase in PI turnover (46-76% of the 5-HT response). The stimulatory action of 2-Me-5-HT and phenylbiguanide was blocked completely by granisetron, ondansetron and ICS 205-930 but not by other receptor antagonists such as (+/-)-pindolol (a beta, 5-HT1A and 5-HT1B receptor antagonist), methy-sergide (a 5-HT1 and 5-HT2 receptor antagonist), ritanserin (a 5-HT1C and 5-HT2 receptor antagonist), SR 95103 (gamma-aminobutyric acidA receptor antagonist), scopolamine (a muscarinic antagonist), (-)-eticlopride (a D2 receptor antagonist), SCH 23390 (a D1 5-HT2/1C receptor antagonist) and prazosin (an alpha-1 receptor antagonist). In addition, the stimulation of PI turnover by 2-Me-5-HT was antagonized stereospecifically by the 5-HT3 receptor blocker zacopride. Thus, only the active enantiomer (S)-zacopride, but not the less active enantiomer (R)-zacopride, was effective in blocking the 2-Me-5-HT-induced effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of 5-hydroxytryptamine3 receptor agonists on phosphoinositides hydrolysis in the rat fronto-cingulate and entorhinal cortices. 184 25

1. The effects of various 5-hydroxytryptamine (5-HT) receptor agonists were examined following unilateral infusion into the substantia nigra (SN) of the guinea-pig. 2. The 5-HT1 receptor agonists, 5-carboxamidotryptamine (5-CT) (2-25 micrograms), sumatriptan (10-25 micrograms) and RU24969 (25 micrograms) all induced a marked contralateral rotation. In contrast, the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT, 10-25 micrograms) produced only a very small response, whilst the selective 5-HT1C/5-HT2 receptor agonist (+-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+/-)-DOI) (25 micrograms) and the 5-HT3 receptor agonist, 2-methyl 5-HT (2-Me5-HT, 25 micrograms) were without effect. 3. The contralateral rotation induced by 5-CT (10 micrograms) was attenuated following pretreatment with the non-selective 5-HT1/5-HT2 receptor antagonists methiothepin (1 mg kg-1, s.c.) and metergoline (5-10 mg kg-1, s.c.) but not the 5-HT1C/5-HT2 antagonist ritanserin (1 mg kg-1, s.c.) or the 5-HT3 antagonist, ondansetron (0.5 mg kg-1, s.c.). An involvement of dopaminergic systems in the rotational response to 5-CT was implied by the antagonism of 5-CT-induced rotation by haloperidol (0.3 mg kg-1, s.c.). 4. At doses lower than those required to produce contralateral rotation, 5-CT (0.08-0.4 micrograms) and sumatriptan (2 micrograms) induced a small, but nonetheless consistent, ipsilateral rotation. 5. The data with agonists and antagonists taken together suggest that 5-CT-induced contralateral rotation may be mediated by 5-HTID receptor activation but definitive classification of the receptor will not be possible until selective 5-HTID-antagonists become available. This may therefore represent the first model to study this receptor subtype in vivo.
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PMID:Evidence that the unilateral activation of 5-HT1D receptors in the substantia nigra of the guinea-pig elicits contralateral rotation. 184 63

Anti-idiotypic antibodies were generated by immunizing rabbits with affinity-purified antibodies to serotonin (5-hydroxytryptamine; 5-HT). Anti-5-HT activity was removed from the resulting antisera by chromatography through a 5-HT affinity column. The anti-idiotypic antibodies were demonstrated by enzyme-linked immunosorbent assay to bind to affinity-purified whole anti-5-HT antibodies and their Fab fragments. Anti-idiotypic antibodies, purified by affinity chromatography on columns to which antibodies to 5-HT were coupled, competed with 5-HT (covalently bound to protein) for the binding sites on anti-5-HT antibodies and serotonin binding protein. The anti-idiotypic antibodies antagonized the binding of [3H]5-HT to membranes isolated from the cerebral cortex, striatum, and raphe area more than to membranes from hippocampus or cerebellum. The anti-idiotypic antibodies also blocked the binding of the 5-HT1B-selective ligand (-)-[125I]iodocyanopindolol (in the presence of 30 microM isoproterenol) to cortical membranes. In contrast, anti-idiotypic antibodies failed to inhibit binding of the 5-HT1A-selective ligand 8-hydroxy-2-(di-n-[3H]propylamino)-tetralin [( 3H]8-OH-DPAT) to raphe area membranes or hippocampal membranes. These observations suggested that the anti-idiotypic antibodies may recognize some 5-HT receptor subtypes but not others. This hypothesis was tested by ascertaining the ability of anti-idiotypic antibodies to immunostain cells transfected in vitro with cDNA encoding the 5-HT1C or 5-HT2 receptor or with a genomic clone encoding the 5-HT1A receptor. Punctate sites of immunofluorescence were found on the surfaces of fibroblasts that expressed 5-HT1C and 5-HT2 receptors, but not on the surfaces of HeLa cells that expressed 5-HT1A receptors. Immunostaining of cells by the anti-idiotypic antibodies was inhibited by appropriate pharmacological agents: immunostaining of cells expressing 5-HT1C receptors was blocked by mesulergine (but not ketanserin, 8-OH-DPAT, or spiperone), whereas that of cells expressing 5-HT2 receptors was blocked by ketanserin or spiperone (but not mesulergine or 8-OH-DPAT). The anti-idiotypic antibodies failed to inhibit the uptake of [3H]5-HT by serotonergic neurons. It is concluded that the anti-idiotypic antibodies generated with anti-5-HT serum recognize the 5-HT1B, 5-HT1C, and 5-HT2 receptor subtypes; however, neither 5-HT1A receptors nor 5-HT uptake sites appear to react with these antibodies.
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PMID:Identification of serotonin receptors recognized by anti-idiotypic antibodies. 186 Nov 58

The effect of tandospirone, a 5-hydroxytryptamine (5-HT)1A agonist/anxiolytic, injected directly into dorsal hippocampus, on Vogel-type conflict behavior in rats was investigated and the findings were compared with the effects of diazepam and zopiclone. Tandospirone (30 micrograms/2 microliters and 60 micrograms/2 microliters) and diazepam (40 micrograms/2 microliters) but not zopiclone (20 micrograms/2 microliters), produced a potent anticonflict action in rats. The anticonflict action of tandospirone (30 micrograms/2 microliters), injected into the dorsal hippocampus, was significantly blocked by (-)-propranolol (5 mg/kg i.p.). The present findings provide evidence that suggests that tandospirone has an antianxiety action, presumably by stimulating 5-HT1A receptors in the dorsal hippocampus.
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PMID:Involvement of the dorsal hippocampus in mediation of the antianxiety action of tandospirone, a 5-hydroxytryptamine1A agonistic anxiolytic. 186 94

The actions of 5-hydroxytryptamine (5-HT) and the 5-HT1A receptor ligand MDL 73005EF on neuronal activity in the CA1 region of rat hippocampal slices in vitro were recorded using intra- and extracellular recording techniques. 5-HT (1-30 microM) hyperpolarised the pyramidal neurones in a concentration-dependent manner and reduced membrane resistance and action potential after-hyperpolarisations (AHPs). MDL 73005EF (1-30 microM) had no clear effects on membrane potential, membrane resistance or AHPs. However, prior application of 3 microM MDL 73005EF to the slices for 10-60 min antagonised the hyperpolarisation induced by 30 microM 5-HT but not the reduction in spike AHP or the hyperpolarisation induced by the GABAB receptor agonist baclofen. MDL 73005EF and the 5-HT1A/2 receptor antagonist spiperone (both 3 microM) reduced the frequency and amplitude of spontaneous inhibitory (bicuculline-sensitive) postsynaptic potentials. Extracellular recordings of population action potentials revealed that MDL 73005EF did not prevent the induction or maintenance of hippocampal long-term potentiation or exhibit local anaesthetic properties. It is concluded that MDL 73005EF is an antagonist at 5-HT1A receptors on hippocampal CA1 pyramidal neurones.
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PMID:Electrophysiology of the 5-HT1A ligand MDL 73005EF in the rat hippocampal slice. 189 14

1. 1-3(Chlorophenyl)piperazine (mCPP) (5 mg kg-1, i.p.) inhibited 2 h food intake in rats previously deprived of food for one day. Ten 5-hydroxytryptamine (5-HT) antagonists given s.c. opposed this hypophagic response. Calculated ID50 values correlated significantly with reported affinities (r = 0.81, n = 10, P less than 0.01) for 5-HT1C but not for 5-HT2, 5-HT1A, 5-HT1B or 5-HT1D receptors. 2. ID50 values of the ten antagonists against 5-hydroxytryptophan (5-HTP) + carbidopa-induced head shakes (a 5-HT2-mediated response) correlated significantly (r = 0.81, n = 10, P less than 0.01) with their affinities for 5-HT2 but not for 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptors. 3. ID50 values for inhibition of hypophagia and head shakes did not correlate significantly with each other. 4. Ratios of ID50 values against hypophagia and 5-HT2-mediated head shakes gave indices of relative in vivo potencies independent of differences in drug metabolism and disposition. These ratios correlated highly significantly (r = 0.91, n = 10, P less than 0.001) with the ratios of the affinities of the drugs for 5-HT1C (but not for 5-HT1A, 5-HT1B or 5-HT1B or 5-HT1D receptors) and with their affinities for 5-HT2 receptors. These results strongly support the hypothesis that mediation of mCPP-induced hypophagia is by stimulation of 5-HT1C receptors and the mediation of 5-HTP-induced head twitches by 5-HT2 receptors.
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PMID:Potencies of antagonists indicate that 5-HT1C receptors mediate 1-3(chlorophenyl)piperazine-induced hypophagia. 191 90

Systemic, intra-raphe and microiontophoretic administration of the 5-hydroxytryptamine (5-HT)1C/5-HT2 agonist (1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (DOI) inhibited the firing of 5-HT neurones in the dorsal raphe. DOI administered systemically and directly into the raphe also decreased the extracellular concentration of 5-hydroxytryptamine (5-HT) in the frontal cortex. In contrast, the administration of DOI directly into the frontal cortex did not significantly alter the concentration of frontal cortical extracellular 5-HT. The reduction of the firing rate of 5-HT neurons in the dorsal raphe and extracellular 5-HT concentration in the frontal cortex induced by systemic administration of DOI could not be blocked by the 5-HT2 antagonist ketanserin, ritanserin (5-HT2/5-HT1C antagonist) or the putative 5-HT1A antagonist, pindolol. These results suggest that the inhibition of 5-HT neuronal firing seen with administration of DOI is mediated via an action within the dorsal raphe and at least in close proximity to the 5-HT neurone cell bodies. The decrease in frontal cortical extracellular concentration of 5-HT release was not due to a direct action in the frontal cortex itself and may possibly be as a result of the decrease in the firing rate of the 5-HT neurones in the dorsal raphe. The mechanism of action of DOI to produce these effects is, however, unclear and warrants further investigation.
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PMID:Inhibition of 5-hydroxytryptamine neuronal activity by the 5-HT agonist, DOI. 191 82

1. With radioligand binding techniques, MDL 73005 EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-az aspiro[4, 5]decane-7,9-dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (greater than 100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5-hydroxytryptamine (5-HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2. In rats pretreated with reserpine, 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8-OH-DPAT. 3. In rats trained to discriminate 8-OH-DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose-dependently and completely to the 8-OH-DPAT cue. 4. To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus-maze test and in the water-lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water-lick conflict test but opposite effects in the elevated plus-maze. 8-OH-DPAT also had opposite effects in the elevated plus-maze test to MDL 73005EF and diazepam. 5. The anti-conflict effects of MDL 73005EF were reversed by low doses of the 5-HT1A receptor agonist, 8-OH-DPAT; those of buspirone were neither antagonised nor mimicked by 8-OH-DPAT. 6. These results suggest that an interaction with 5-HTIA receptors is the basis of the anxiolytic-like activity of MDL 73005EF. However, its mechanism of action is clearly different from that of buspirone, possibly reflecting a greater selectivity for the 5-HTlA receptors located presynaptically on central 5- hydroxytryptaminergic neurones.
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PMID:Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam. 197 Feb 69


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