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)

Amperozide is an atypical antipsychotic drug with high affinity for the serotonin 5-HT2 receptor but with low affinity for the dopamine D1 and D2 receptors. Amperozide dose-dependently increased the level of plasma corticocorticosterone in the rat. The effect of amperozide on plasma corticosterone was not inhibited by pretreatment with the 5-HT1A receptor antagonist pindolol or the 5-HT2 receptor antagonist ritanserin. Nor was it inhibited by the dopamine D2 receptor antagonist haloperidol. In contrast to ritanserin, amperozide did not antagonize plasma corticosterone elevation elicited by the serotonin receptor agonist MK-212. Similar to the serotonin uptake inhibitor fluoxetine, amperozide (0.5 mg/kg) significantly (p < 0.05) blocked p-chloroamphetamine (PCA) induced corticosterone release 4 and 16 hrs after amperozide administration. However, amperozide significantly increased the plasma corticosterone concentration also in rats pretreated with parachlorophenylalanine (PCPA). These data suggest that other mechanisms than a 5-HT uptake inhibitory effect are involved in the acute stimulation of corticosterone by amperozide.
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PMID:The effect of amperozide, a new antipsychotic drug, on plasma corticosterone concentration in the rat. 135 66

1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.
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PMID:Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants. 142 68

Presentation of a nonstartling stimulus (prepulse) 100 msec before a startle-eliciting auditory stimulus (pulse) reduces startle reflex amplitude in mammals. Prepulse inhibition of acoustic startle reflex is smaller in schizophrenics than in nonschizophrenics, a phenomenon that has been hypothesized to reflect sensorimotor gating deficits underlying schizophrenic psychosis. Five 5-hydroxytryptamine1a (5-HT1a, serotonin) receptor agonists: 8-hydroxy-2-(di-n-propylamino) tetraline (8-OHDPAT), 5-methoxydimethyltryptamine, buspirone, gepirone and ipsapirone, were tested for effects on prepulse inhibition and startle reflex amplitude in rats. All five agents reduced prepulse inhibition at doses that had no effect on startle reflex amplitude or motor activity. Reduction of prepulse inhibition by 8-OHDPAT was antagonized by (-)propranolol, a 5-HT1a receptor antagonist, and partially by haloperidol, a dopamine D2 receptor antagonist, but not by ketanserin or methysergide, 5-HT2 receptor antagonists. 8-OHDPAT did not reduce prepulse inhibition in subjects pretreated with reserpine or tetrabenazine to deplete neuronal amines, but interpretation of this result is complicated because reserpine and tetrabenazine given alone reduced prepulse inhibition. The results indicate that 5-HT1a receptor agonists block prepulse inhibition of acoustic startle reflex, possibly via dopaminergic mechanisms.
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PMID:5-Hydroxytryptamine 1a receptor agonists block prepulse inhibition of acoustic startle reflex. 143 85

An experimental method to test the hypothesis that antipsychotic (neuroleptic) agents influence gene expression in the mouse brain has been developed using the cis and trans stereoisomers of flupenthixol. The cis form of the drug is known to be clinically effective against some of the psychotic symptoms of schizophrenia as opposed to the trans isomer which is relatively inactive. A 2- to 3-fold increase in the abundance of dopamine 2 receptor mRNA was observed in the cis treated mice after a period of ten weeks. No change was observed in the expression of the dopamine D2 receptor gene upon treatment with the trans isomer. No change in the amount of 5-HT1A, 5-HT1C, alpha 1 adrenergic, beta 1 and beta 2 adrenergic neuroreceptor mRNA was found in the mice treated with active drug. The results show a long-term adaptation to D2 antagonism at the level of gene expression which occurs over a similar time scale to that of the clinical response to neuroleptic treatment of schizophrenia.
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PMID:Stereospecific effect of flupenthixol on neuroreceptor gene expression. 164 66

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.
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PMID:Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy. 167 44

ACTH-(1-24) decreased the binding of the dopamine D2 receptor agonist, [3H]N-propylnorapomorphine ([3H]NPA), to rat striatal membranes in a concentration-dependent manner, with a Ki of 5 x 10(-7) M. Saturation curves for [3H]NPA binding in the presence of increasing concentrations of ACTH-(1-24) were performed. Scatchard analysis in the presence of ACTH-(1-24) revealed an increased dissociation constant (Kd), while the binding capacity (Bmax) was not affected by the peptide, suggesting an apparent competitive interaction between ACTH-(1-24) and [3H]NPA. ACTH-(1-24) also reduced the binding of the dopamine D2 receptor antagonist [3H]spiperone to striatal membranes, with a Ki of 10(-6) M. Much higher concentrations of ACTH-(1-24), up to 10(-4) M, were needed for the displacement of appropriate radiolabelled ligands from dopamine D1 receptors, serotonin 5-HT1A, serotonin 5-HT1B, muscarinic M1 acetylcholine and histamine H1 receptors. ACTH-(1-24) also inhibited the binding of [3H]spiperone to dopamine D2 receptors in membranes of the pituitary gland, the septum and the substantia nigra. ACTH-(1-39) and most ACTH fragments and analogs were less potent than ACTH-(1-24) in displacing [3H]NPA from the dopamine D2 receptor in striatal membranes. In general there was a relationship between displacing potency and chain length. ACTH-(7-16)-NH2 and benzyloxycarbonyl-ACTH-(8-16)-NH2, however, were more potent than ACTH-(1-24) in reducing the binding of [3H]NPA to dopamine D2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ACTH/MSH-like peptides inhibit the binding of dopaminergic ligands to the dopamine D2 receptor in vitro. 168 Jul 21

The three dimensional structure, electrostatic potentials and molecular dynamics of a series of tricyclic antipsychotic drugs and metabolites were examined by computer graphics and molecular modeling techniques. Three dimensional models of the 5-HT1A and 5-HT2 receptor and of the dopamine D2 receptor were constructed from the amino acid sequences. The receptor models have strongly negative electrostatic potentials around the synaptic domains and a postulated ligand binding site. This indicates that protonated ligands are attracted to these receptors by electrostatic forces. Pharmacologically inactive trans(E)-thioxanthenes and phenothiazine ring sulphoxides had strongly negative electrostatic potentials around a part of the ring system. This may weaken their electrostatic interactions with the D2 receptor, and be the reason for their lack of potency in D2 receptor binding and related pharmacological tests. Molecular dynamics simulations in aqueous solution demonstrated that both the side chains and the tricyclic ring systems of the drugs are highly flexible, and move between different conformations in picoseconds.
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PMID:Molecular modeling of antipsychotic drugs and G protein coupled receptors. 181 51

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.
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PMID:Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction. 252 57

Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic L-amino acid decarboxylase by means of NSD-1015, 100 mg kg-1 intraperitoneally. In animals treated with reserpine, 5 mg kg-1 subcutaneously -18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15-2.4 mumol kg-1, whereas the partial dopamine D2 receptor agonist (-)3-PPP, 2.5-10.0 mumol kg-1, or the full dopamine D2 receptor agonist quinpirole, 0.05-0.8 mumol kg-1, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mumol kg-1, but not by (-)pindolol, 8 mumol kg-1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (-)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for selective inhibition of limbic forebrain dopamine synthesis by 8-OH-DPAT in the rat. 257 Mar 61

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.
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PMID:Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. 756 37


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