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)

Previous reports based on studies with serotonin (5-HT) precursors or direct acting agonists have suggested that postsynaptic 5-HT1A and 5-HT2A/5-HT2C receptors may stimulate cortisol and prolactin (PRL) secretion in man. To further clarify the role of these receptors in the regulation of cortisol and PRL secretion in man, the effects of 6-chloro-2-(1-piperazinyl) pirazine (MK-212), a centrally acting direct 5-HT2A/5-HT2C agonist, on the above hormones were studied in 11 normal men with and without pretreatment with pindolol, a 5-HT1A partial agonist. MK-212 induced a significant increase in plasma concentrations of cortisol and PRL. The MK-212-induced response in plasma cortisol was not diminished by pindolol pretreatment, whereas the MK-212-induced PRL response was significantly inhibited by pindolol pretreatment. These data suggest that the MK-212-induced cortisol response may be mediated by 5-HT2A or 5-HT2C receptor activation, or both, despite 5-HT1A inhibition; however, PRL secretion by MK-212 requires 5-HT1A receptor availability as well as 5-HT2A/5-HT2C receptor activation, since blockade of the former appears to blunt the PRL responses to MK-212. These findings may be explained by postulating a cooperativity between 5-HT1A and 5-HT2A/5-HT2C receptors with regard to the 5-HT-dependent stimulation of PRL secretion.
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PMID:Effect of pindolol pretreatment on MK-212-induced plasma cortisol and prolactin responses in normal men. 749 25

Administration of various doses of DOI (a 5-HT2A/5-HT2C agonist) produced hyperthermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Similarly, administration of various doses of ipsapirone (a 5-HT1A agonist) produced hypothermia that was significantly less in the FH rat strain relative to the Wistar rat strain. Furthermore, m-CPP (a 5-HT agonist)-induced increases in growth hormone levels were also significantly less in the FH rat strain relative to the Wistar rat strain. There was no significant difference in the levels of either 5-HT or 5-HIAA between the two rat strains in the frontal cortex, hippocampus, hypothalamus, and striatum. In the brain stem, however, both 5-HT and 5-HIAA levels were significantly lower in the FH rat strain relative to the Wistar rat strain. On the other hand, 5-HT turnover rate was significantly higher in the hypothalamus and striatum and significantly lower in the hippocampus in the FH rat strain relative to the Wistar rat strain. These findings provide further evidence for altered serotonergic function in the FH rat strain and, in addition, suggest that the FH rat strain may prove to be a useful genetic model for some neuropsychiatric disorders with possible abnormalities in serotonergic function such as depression, obsessive-compulsive disorder, and the eating disorders.
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PMID:Functional and biochemical evidence for altered serotonergic function in the fawn-hooded rat strain. 753 10

Twenty five years ago, experimental procedures such as adrenalectomy and corticosteroid administration (to intact rats) allowed the recognition of direct and indirect controls of central 5-HT synthesis rate by corticosteroids. These effects indicated that the activity of the hypothalamo-pituitary-adrenal (HPA) axis, whether under basal conditions or during stress, is endowed with a modulatory action upon serotonergic neurons. Nowadays, in situ hybridisation, in vitro autoradiography, and radioligand binding on the one hand, and electrophysiological, behavioural, and neuroendocrinological responses on the other hand, are tools that allow the analysis of direct corticosteroid effects upon 5-HT receptors. Among the dozen of 5-HT receptors identified so far, four receptors (namely the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors)--and the 5-HT uptake system--have been the focus of studies aimed at detecting corticosteroid modulatory effects. The results that are reviewed herein indicate that hippocampal 5-HT1A receptors are under the tonic inhibitory control of corticosterone. This control is directly exerted at the level of the 5-HT1A receptor gene, essentially through mineralocorticoid receptors; as well, electrophysiological findings bring support for an additional modulation of hippocampal 5-HT1A receptor-mediated functions by indirect (ie 5-HT1A receptor gene-independent) genomic actions of corticosteroids. In keeping with the respective effects of stressful stimuli and psychotropic drugs upon the HPA axis and central serotonergic systems, it is likely that these corticosteroid-5-HT1A receptor interactions in the hippocampus have consequences in the pathophysiology of mood disorders. However, because the data regarding a corticosteroid control of other 5-HT receptors are either scarce and contradictory (eg 5-HT1B, 5-HT2A, 5-HT2C receptors and 5-HT uptake systems) or lacking, it is at the present time unknown whether corticosteroids exert other effects on 5-HT receptor-mediated functions, including those related to homeostasis.
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PMID:Regulation of 5-HT receptors by corticosteroids: where do we stand? 755 17

The present study assessed compounds displaying affinity for 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors for their ability to substitute for, enhance or antagonize the discriminative stimulus effects of cocaine (10 mg/kg) in rats. In substitution tests, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.2-1.6 mg/kg), the 5-HT1A/B receptor agonists RU 24969 (0.25-2 mg/kg) and CGS 12066B (2-16 mg/kg), the 5-HT1B/2C receptor agonists m-chlorophenylpiperazine (mCPP; 0.25-2 mg/kg) and m-trifluoromethylphenylpiperazine (TFMPP; 0.125-2 mg/kg), the 5-HT2A/2C receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane ([+/-]-DOB; 0.0625-0.5 mg/kg), the 5-HT2C receptor agonist MK 212 (0.25-1 mg/kg) and the nonselective 5-HT receptor agonist quipazine (1-8 mg/kg) engendered 30% to 70% cocaine-appropriate responding. The DA receptor antagonists SCH 23390 (0.025 or 0.05 mg/kg) and haloperidol (0.125 or 0.25 mg/kg) failed to block the partial substitution of RU 24969 (1 mg/kg) for cocaine. In combination tests, a fixed dose of either quipazine (4 mg/kg), RU 24969 (0.25, 0.5 or 1 mg/kg) or TFMPP (0.5 mg/kg) but not 8-OH-DPAT (0.4 mg/kg) or CGS 12066B (16 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.625-5 mg/kg). In contrast, coadministration of either mCPP (0.25-2 mg/kg) or MK 212 (0.125-2 mg/kg) plus a dose of cocaine (5 mg/kg) that produced > 85% cocaine-appropriate responding when given alone partially antagonized cocaine; mCPP (1 mg/kg) also produced a rightward shift in the cocaine dose-response curve. Neither 8-OH-DPAT (0.2-1.6 mg/kg), (+/-)-DOB (0.125-0.5 mg/kg) nor quipazine (2-8 mg/kg) blocked the cocaine stimulus. The 5-HT1A receptor antagonist NAN 190 (0.2-0.8 mg/kg), the 5-HT2A/2C receptor antagonist LY 53857 (0.5-4 mg/kg) and the 5-HT/DA receptor antagonist pirenperone (0.5-4 mg/kg) neither substituted for nor enhanced cocaine; however, pirenperone but not NAN 190 or LY 53857 partially blocked the cocaine (10 mg/kg) response. Although 5-HT receptor compounds do not substitute for cocaine, several 5-HT receptor agonists (i.e., the indole derivative RU 24969 and the arylpiperazines mCPP, MK 212, TFMPP and quipazine), but not antagonists, differentially modulate the stimulus effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of the discriminative stimulus properties of cocaine by 5-HT1B and 5-HT2C receptors. 756 16

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

5-Hydroxytryptamine (5-HT) is known to act in peripheral tissues to produce pain and inflammation, yet the mechanisms underlying 5-HT-induced inflammation have not been well studied. The present study uses a rat knee joint model of inflammation (synovial plasma extravasation) and molecular biological techniques to determine the site of action of 5-HT and the specific 5-HT receptor subtype mediating synovial 5-HT-induced plasma extravasation. 5-HT (1 microM) stimulates synovial plasma extravasation 7-fold above base-line levels. Surgical lumbar sympathectomy, but not C-fiber depletion by neonatal capsaicin, dramatically reduces 5-HT-induced synovial plasma extravasation (P < .001), indicating that sympathetic efferents mediate this effect. Polymerase chain reaction amplification of 5-HT receptor cDNA demonstrates that 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT3, but not the 5-HT2C, receptor subtypes are present in lumbar sympathetic ganglia. With selective ligands for these receptor subtypes, we demonstrate that 5-HT-induced synovial plasma extravasation is mediated via the 5-HT2A receptor. These findings suggest a role for 5-HT2A antagonists in various synovial inflammatory pain states.
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PMID:5-Hydroxytryptamine-induced synovial plasma extravasation is mediated via 5-hydroxytryptamine2A receptors on sympathetic efferent terminals. 756 92

1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg-1.5. In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-depend entinhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50= 81.3 microg kg-1, i.p. and 1.1 mg kg-1,p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg-1.6. In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose ratios to 5-HT at 0.1 mg kg-1, i.v., 1 mg kg-1, i.v. and 10 mg kg-1, i.duod. were 4.6, 30.7 and 10.8,respectively. SB 204070 behaved as an unsurmountable antagonist in this assay.7. In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg-1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg-1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model.8. The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.
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PMID:RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist. 758 7

5-HT receptors represent a superfamily of receptors with the largest known number of receptor subtypes. At present 15 receptor subtypes of three groups has been recognized. The 5-HT1 subfamily of receptors contains subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F; activation of all of them results in the inhibition of adenylylcyclase. The subfamily of 5-HT2 contains subtypes 5-HT2A, 5-HT2B, and 5-HT2C; their activation leads to the stimulation of PLC. Finally, subfamily of miscellaneous 5-HT receptors contains subtypes 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7; some of them has been cloned, however, our knowledge on their function is still minimal. 5-HT receptors participate in many physiological functions and a disturbance in serotonergic neurotransmission might cause several types of disease. 5-HT plays an important role in depression; to cure this disease, drugs which increase levels of this neurotransmitter are used. A new drug group called Selective Serotonin Reuptake Inhibitors (SSRI) has been recently discovered. These drugs block the reuptake of 5-HT into nerve endings. There is an intensive search for new selective agonists as well as antagonists which could be use not only in the classification of receptor subtypes but which also possess certain therapeutic potential.
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PMID:[5-hydroxytryptamine (serotonin) receptors--nomenclature and classification of types and subtypes]. 758 16

An overview of the behavioral data arising from the vast literature concerning the involvement of 5-hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating 5-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals' emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT1A, 5-HT2A or 5-HT2C receptor subtypes; (3) anxiolytic-like effects of 5-HT3 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes, are involved in the genesis of anxiety.
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PMID:5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. 764 67

In this study, the involvement of serotonergic and dopaminergic receptors in the modulation of the head-twitch (HTW) response to the 5-hydroxytryptamine (5-HT)2A/5-HT2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, was characterized in rats using novel and selective ligands at 5-HT2A, 5-HT2C, D1, D2 and 5-HT1A receptors. HTW were dose-dependently inhibited by the 5-HT2A/2C antagonists, ritanserin, metergoline, mesulergine, mianserin, ICI 169,369 and LY 58,537, by the preferential 5-HT2A antagonist, ketanserin and by the novel, selective 5-HT2A antagonist, SR 46349B. A further selective 5-HT2A antagonist, MDL 100,907, very potently abolished HTW (ED50 = 0.005 mg/kg). The order of relative potency correlated highly with their affinity at 5-HT2A (r = 0.83) but not 5-HT2C receptors (r = 0.06). In addition, the novel, selective 5-HT2C antagonist, SB 200,646A, failed to abolish HTW and the 5-HT2C agonists/5-HT2A antagonists, 1-(3-chlorophenyl)piperazine and 1-(3-trifluoromethylphenyl)piperazine, blocked, rather than elicited, HTW. The D1 antagonists, SCH 23390, NNC 112, NNC 756, SCH 39166 and A 69024, in this order of relative potency that correlated with their affinity at D1 receptors (r = 0.98), blocked HTW. The D2 antagonists, raclopride, eticlopride and haloperidol also blocked HTW. The 5-HT1A agonists, S 14671, S 14506, 8-hydroxy-2-(di-n-propylamino)tetralin, buspirone, ipsapirone and (+)-flesinoxan, abolished HTW. The action of 8-hydroxy-2-(di-n-propylamino)tetralin was blocked by (-)-tertatolol (ID50 = 4.5 mg/kg), a novel 5-HT1A receptor antagonist. Similarly, (-)-tertatolol attenuated the action of S 14506 and abolished that of S 14671, buspirone and ipsapirone. A role of postsynaptic 5-HT1A receptors in the action of 5-HT1A agonists was suggested by the finding that parachlorophenylalanine (3 x 300 mg/kg, i.p.), which depleted cerebral pools of 5-HT, did not modify the activity of ipsapirone. The present data demonstrate that 5-HT2A receptors mediate HTW in rats and that both D1 and D2 receptors as well as (postsynaptic) 5-HT1A receptors play a role in their expression.
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PMID:(1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. 771 55


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