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)

PD 118717 (7-[3-[4-(2-pyrimidinyl)-1-piperazinyl]-propoxy]-2H-1- benzopyran-2-one sulfate) proved to be a dopamine (DA) D-2 autoreceptor agonist in biochemical and electrophysiological studies in rats and to exhibit an antipsychotic-like profile in behavioral tests in rodents and monkeys. In vitro binding studies indicated that PD 118717 bound selectively to DA D-2 vs. D-1 receptors and exhibited agonist binding properties (biphasic inhibitory curves and GTP shift) similar to DA. It also had significant affinity for serotonin-(5-HT)1A but not 5-HT1B and 5-HT2 receptors. PD 118717 was active in antagonizing the tau-butyrolactone-induced accumulation of dopa in rat striatum and mesolimbic regions. PD 118717 also depressed the firing of DA neurons in substantia nigra pars compacta of rats. In both of the latter tests the effects of PD 118717 were reversed by haloperidol. PD 118717 decreased brain DA metabolism, decreased DA utilization, decreased accumulation of dopa after inhibition of L-aromatic amino acid decarboxylase, stimulated serum corticosterone and inhibited stimulated serum prolactin levels. PD 118717 did not alter striatal acetylcholine levels; nor did it induce locomotor stimulation or stereotypy in normal animals, suggesting a lack of postsynaptic DA stimulation of normosensitive DA receptors. In tests designed to reveal even weak postsynaptic DA agonist effects, PD 118717 stimulated locomotor activity in 6-hydroxydopamine-lesioned animals and relatively higher doses induced a low degree of stereotyped behavior when combined with the DA D-1 agonist SKF 38393. PD 118717 decreased the accumulation of 5-hydroxytryptophan in brain, an effect probably due to an agonist action at 5-HT1A receptors. PD 118717 decreased spontaneous locomotor activity in rodents, antagonized amphetamine-stimulated hyperactivity in mice and inhibited Sidman avoidance in monkeys, effects seen with antipsychotic agents. Unlike DA antagonist antipsychotics, PD 118717 did not induce extrapyramidal dysfunction in monkeys. PD 118717 displayed behavioral activity after p.o. dosing and its effects did not show tolerance on repeated dosing. In conclusion, PD 118717 has the profile of a DA autoreceptor agonist in neurochemical and neurophysiological tests and produces effects suggestive of antipsychotic efficacy without neurological side effect liability in preclinical behavioral tests.
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PMID:Pharmacological characterization of PD 118717, a putative piperazinyl benzopyranone dopamine autoreceptor agonist. 136 70

The effects of repeated treatment of rats with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT. 169 32

The concentrations and synthesis of monoamines in various hypothalamic nuclei and the influence of monoaminergic drugs on food intake were studied in two rat lines produced by selective outbreeding for voluntary high and low alcohol drinking. The hypothalamic nuclei of the alcohol-preferring AA rats contained slightly more serotonin than those of the alcohol-avoiding ANA rats, but the accumulation of 5-hydroxytryptophan after inhibition of aromatic amino acid decarboxylase was the same in both lines. There was no significant difference in the basal concentrations of catecholamines between the lines, but the accumulation of L-DOPA was significantly greater in the ANA than the AA rats, suggesting differences in catecholamine turnover. This difference was significant in the paraventricular nucleus, which is involved in the regulation of food intake. Clonidine (an alpha 2-agonist) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A agonist) induced hyperphagia and 1-(3-trifluoromethylphenyl)piperazine (TFMPP, a 5-HT1B agonist) induced hypophagia dose-dependently in both rat lines. Clonidine tended to be more potent in the ANA than the AA rats. Food intake following a 20-h fast was significantly lower in the ANA than AA rats. These results suggest that the alcohol-avoiding ANA and alcohol-preferring AA rats have different hypothalamic monoamine mechanisms controlling food intake, which could also partially account for their differential alcohol acceptance.
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PMID:Hypothalamic monoamines and food intake in alcohol-preferring AA and alcohol-avoiding ANA rats. 182 11

Measurements of tissue levels of monoamines and their metabolites, and of the rates of 5-hydroxytryptophan and dihydroxy-phenylalanine accumulation after blockade of aromatic amino acid decarboxylase by benserazid indicated that ipsapirone (1-10 mg/kg i.p.) decreased 5-hydroxytryptamine (5-HT) turnover and accelerated dopamine (DA) turnover in various brain regions. The reduced 5-HT turnover probably resulted from the stimulation of 5-HT1A autoreceptors within the anterior raphe nuclei as in vitro tests [( 3H]-8-hydroxy-2-[di-n-propylamino]tetralin binding and adenylate cyclase assays) demonstrated that ipsapirone was a 5-HT1A agonist almost as potent as 8-OH-DPAT, and the same decrease in 5-hydroxytryptophan accumulation could be induced by the i.p. (5 mg/kg) or intraraphe (1 microgram) injection of ipsapirone. Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT. These results demonstrate that ipsapirone-induced acceleration of DA turnover did not result from the stimulation of 5-HT1A (auto)receptors, but involved additional target(s) of the drug. The possible participation of dopaminergic systems in the "anxiolytic" properties of ipsapirone should deserve further investigations.
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PMID:Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1A agonists with potential anxiolytic properties. 245 83

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.
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PMID:Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163. 295 21

The two diphenylbutylpiperazinepyridinyl derivatives, FG5865 and FG5893, have a unique receptor binding profile in that they show very high and essentially equipotent affinities for both 5-HT1A and 5-HT2 receptors. The present report describes the acute effects of FG5865 and FG5893 on presynaptic 5-hydroxytryptamine (5-HT) neuronal function in the rat CNS, using established ex vivo and in vivo neurochemical techniques. Post-mortem measurements of tissue levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and of the formation of 5-hydroxytryptophan (5-HTP; after inhibition of aromatic amino acid decarboxylase by NSD 1015) showed that FG5865 (0.1-20 mg/kg, s.c.) and FG5893 (0.1-20 mg/kg, s.c.) dose dependently decreased the synthesis and the metabolism/turnover of 5-HT--this to an extent comparable to the reference 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Reserpine (5 mg/kg, s.c.) pretreatment did not prevent the FG5893-induced decrease of 5-HT synthesis rate. In contrast, about 25-50 times higher doses of FG5865 were required to produce a comparable decrease in brain 5-HT synthesis in reserpinized vs. non-pretreated rats. In in vivo microdialysis experiments, both FG5865 (0.1-3.0 mg/kg, s.c.) and FG5893 (0.03-1.0 mg/kg, s.c.) caused a marked and dose-dependent decrease of 5-HT release in the ventral hippocampus. Pretreatment with the 5-HT1A receptor antagonist, (+/-)-pindolol (8 mg/kg, s.c.), abolished the FG5865 (0.3 mg/kg, s.c.)-induced reduction of 5-HT release, and (-)-pindolol (8 mg/kg, s.c.) similarly reversed the FG5893 (0.3 mg/kg, s.c.)-induced decrease. Local infusion of FG5865 into the ventral hippocampus (10 microM, 20-min pulse) resulted in a rapid and transient elevation of the 5-HT output, an effect that was independent of extracellular Ca2+. FG5893, on the other hand, did not affect the 5-HT release upon local administration. The results demonstrate that FG5865 and FG5893 potently affect a range of neurochemical indices of rat brain 5-HT neuronal activity in vivo, in a way consistent with indirect (FG5865) and direct (FG5865 and FG5893) stimulation of the 5-HT1A autoreceptors in the raphe nuclei.
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PMID:5-HT1A autoreceptor-mediated effects of the amperozide congeners, FG5865 and FG5893, on rat brain 5-hydroxytryptamine neurochemistry in vivo. 769 22

The role of serotonin (5-HT)1A heteroreceptors as modulators of dopamine synthesis was investigated by using in vitro and in vivo methods. In vitro studies were conducted utilizing either synaptosome-rich preparations of rat striatal tyrosine hydroxylase or soluble preparations of rat striatal tyrosine hydroxylase enzyme. 5-HT1A receptor modulation of tyrosine hydroxylation in vitro was estimated by using a radiometric, coupled enzyme assay. For in vivo investigations of the modulation of tyrosine hydroxylation, striatal dopa accumulation was measured (high-performance liquid chromatography-electrochemical detection) after administration of the aromatic amino acid decarboxylase inhibitor NSD-1015 (3-hydroxybenzylhydrazine). Both serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, were moderately potent, receptor-mediated inhibitors of tyrosine hydroxylation in synaptosomes, with EC50 values of 8.4 and 7.0 microM, respectively. The inhibitory activity of 8-OH-DPAT was attenuated by 5-HT1A-selective antagonists [10 microM propranolol, 10 microM (-)-alprenolol, 10 microM NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl] piperazine hydrobromide) and 10 microM pindolol] but not by a beta adrenoceptor antagonist devoid of activity at the 5-HT1A receptor (10 microM atenolol) or by a D2-dopamine-selective receptor antagonist [10 microM (-)-sulpiride]. In vivo 8-OH-DPAT exhibited a biphasic dose-response curve for inhibition of tyrosine hydroxylation, significant inhibition (30%, P < .05) occurred at a dose of 0.3 mg/kg s.c. In vivo, the 5-HT1A-selective antagonist NAN-190 (1 or 3 mg/kg s.c.) caused dramatic 2- to 2.5-fold elevations of dopa accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum. 810 Dec 15

Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administrative of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1A agonists, (+/-) 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1A/B agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo[1,2-a]-quinox ali ne (CGS 12066B), the 5-HT1A/B ligands and beta-adrenoceptor antagonists, (+/-) pindolol and (+/-) alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1A/5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1A antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (+/-)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1A or 5-HT2 receptors and that other receptors may be involved.
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PMID:Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis. 920 78

Hippocampal serotonin (5-hydroxytryptamine, 5-HT) synthesis, as determined by the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of L-aromatic amino acid decarboxylase with NSD 1015, was inhibited by systemic administration of the selective serotonin reuptake inhibitors fluoxetine (10 mg/kg i.p.) and paroxetine (3 mg/kg i.p.). Pretreatment of rats with the selective 5-HT1A receptor antagonist WAY 100635 for a period of 7 days using subcutaneously implanted osmotic minipumps (1 mg/kg/day) was sufficient to block the inhibition of 5-HT synthesis following the 5-HT 1A receptor agonist 8-OH-DPAT (0.3 mg/kg s.c.), but failed to inhibit the decrease of hippocampal 5-HT synthesis by fluoxetine (10 mg/kg i.p.) or paroxetine (3 mg/kg i.p.). Similarly, pretreatment of rats with GR 127935 (5 mg/kg i.p.), an antagonist with high affinity for 5-HT1B/D receptors, blocked the reduction of hippocampal 5-HT synthesis following the 5-HT receptor agonist TFMPP (3 mg/kg s.c.) without affecting the reduction of hippocampal 5-HT synthesis by either fluoxetine or paroxetine. In contrast, pretreatment with WAY 100635 (1 mg/kg/day, for 7 days s.c. in osmotic minipumps) in combination with GR 127935 (5 mg/kg i.p.) significantly attenuated the decrease of hippocampal 5-HT synthesis by both fluoxetine and paroxetine. These results indicate that both 5-HT1A and 5-HT1B/1D receptors, which function in the rat as inhibitory somatodendritic and nerve terminal autoreceptors, independently regulate hippocampal 5-HT synthesis and must be simultaneously blocked to prevent the inhibition of 5-HT synthesis by selective serotonin reuptake inhibitors which increase 5-HT availability at both nerve terminals in hippocampus and 5-HT cell bodies in the raphe nuclei.
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PMID:Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: evidence for the involvement of both 5-HT1A and 5-HT1B/D autoreceptors. 1002 79

In male rats, the effects of the administration of the novel serotonergic agent flibanserin on the synthesis of 5-HT were evaluated in the frontal cortex (FC), hippocampus (Hip) and brainstem (Br). The selective serotonergic uptake blocker, fluoxetine, and two serotonin1A (5-HT1A) agonists, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) and buspirone, were used as reference compounds. The synthesis of 5-HT was assessed by measuring the accumulation of 5-hydroxytryptophan (5-HTP) after blockade of aromatic amino acid decarboxylase induced by m-hydroxybenzylhydrazine (NSD-1015), at 100 mg/kg i.p., 30 min before sacrifice. Flibanserin, 8-OH-DPAT and buspirone were given 15 min before NSD-1015, while fluoxetine 120 min before NSD-1015. In our experimental conditions, a different efficacy, expressed as percentage of maximal inhibition (Max) of 5-HTP accumulation, and a different potency, expressed in terms of minimal effective dose (MED), were observed in different brain areas with tested compounds. Flibanserin (1-32 mg/kg) decreased 5-HT synthesis with preferential activity in the FC, compared to the Hip and Br, both in terms of potency (MED=2 mg/kg in FC, 16 mg/kg in Hip and Br) and efficacy (Max=65% in FC, 44% in Hip and 29% in Br). Fluoxetine (1-30 mg/kg) decreased 5-HT synthesis with preferential activity in FC than in Hip and Br, only in terms of potency (MED=3 mg/kg in FC, 10 mg/kg in Hip and Br), this result being similar to that observed for flibanserin. In contrast, it showed greater efficacy both in FC and Hip (Max about 60%), than in Br (Max=49%). On the contrary, 8-OH-DPAT (0.3-3 mg/kg) decreased 5-HT synthesis with the same potency in all brain regions (MED=3 mg/kg) and showed the greatest efficacy in FC than in Hip and Br (Max=56% in FC, 49% in Hip and 40% in Br). Furthermore, buspirone (3-30 mg/kg), while inhibiting 5-HTP accumulation in all areas with the same efficacy (Max about 30%), seemed to have higher potency in Br than in FC and Hip (MED=3 mg/kg in Br, 10 mg/kg in FC and Hip). The results in terms of regional differences are discussed.
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PMID:Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain. 1064 99


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