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)

Ditolyguanidine (DTG) induced a dose-dependent emetic response in pigeons, with 100% of the birds vomiting after 5.6 mg/kg. Retching and vomiting originally induced by DTG could be conditioned to the test situation. Both the unconditioned and conditioned emetic responses were dose-dependently blocked by 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) and LY228729, agonists at the 5-HT1A subtype of serotonin receptor, but not by the 5-HT3, antagonist tropisetron. Higher doses (0.25-0.5 mg/kg) of tropisetron exhibited intrinsic emetic activity which could also be prevented by 8-OH-DPAT. NAN-190, a putative 5-HT1A partial agonist, produced both an antiemetic response when administered before DTG and also attenuated the antiemetic effects of 8-OH-DPAT. Pentobarbital blocked the conditioned, but not the unconditioned DTG-induced emesis. These results support the possibility that 5-HT1A agonists exhibit antiemetic activity against a broad range of emetic stimuli, including conditioned vomiting which is usually resistant to pharmacological attenuation.
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PMID:Antiemetic effects of 5-HT1A agonists in the pigeon. 782 54

5-Hydroxytryptamine (5-HT)-induced increase of intracellular Ca2+ concentration ([Ca2+]i) was monitored in cultured canine tracheal smooth muscle cells (TSMCs) using a fluorescent Ca2+ indicator Fura-2. Stimulation of TSMCs by 5-HT produced an initial transient peak followed by a sustained, concentration-dependent elevation of [Ca2+]i. The log (EC50) values of 5-HT for the peak and sustained plateau responses were -7.43 and -7.60 M, respectively. 5-HT1A and 5-HT3 receptor antagonists, NAN-190 and metoclopramide, inhibited the 5-HT-stimulated increase in [Ca2+]i with pKB values of 6.3 and 6.2, respectively, indicating that the 5-HT receptors mediating Ca2+ signal had low affinity for these receptor antagonists. In contrast, 5-HT2A receptor antagonists, ketanserin and mianserin, had high affinity in antagonizing the changes in [Ca2+]i response to 5-HT with pKB values of 8.3 and 8.3, respectively. The sustained elevation of [Ca2+]i was dependent on the presence of extracellular Ca2+. Removal of extracellular Ca2+ by addition of 2 mM EGTA during the sustained phase caused a rapid decline in [Ca2+]i to the resting level. In the absence of extracellular Ca2+, only an initial peak was observed which then declined to the resting level; the sustained elevation of [Ca2+]i could then be evoked by addition of 1.8 mM Ca2+ in the continued presence of 5-HT. Ca2+ influx was required for the changes of [Ca2+]i, since the Ca(2+)-channel blockers, diltiazem, verapamil, and Ni2+, decreased both the initial and sustained elevation of [Ca2+]i in response to 5-HT. These Ca(2+)-channel blockers also decreased the sustained elevation of [Ca2+]i when applied during the plateau phase. In conclusion, these findings indicate that the initial increase in [Ca2+]i stimulated by 5-HT acting on 5-HT2A receptors is due to the release of Ca2+ from internal stores, followed by the influx of external Ca2+ into the cells. The influx of extracellular Ca2+ partially involves a diltiazem and verapamil sensitive Ca2+ channel.
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PMID:5-Hydroxytryptamine-stimulated calcium mobilization in cultured canine tracheal smooth muscle cells. 782 73

8-OH-DPAT, a selective 5-HT1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after initial testing, they did not differ in the hypothermic responses induced by 8-OH-DPAT. Mice treated with aldosterone (50 mg/kg), dexamethasone (50 mg/kg) and the specific type 2 corticosteroid receptor agonist, 11b,17b-dihydroxy-21-methyl-17a-pregna-1,4,6-trien-20-yn+ ++-3-one (RU26988, 30 mg/kg) for 10 days, did not differ from vehicle treated controls in the hypothermic response to 8-OH-DPAT. Mice administered corticosterone-21-acetate (30 mg/kg, daily) for 10 days displayed a motor behavioural syndrome, which was not seen in controls, when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg) 15 min after the injection of carbidopa (25 mg/kg). This was significantly decreased by pretreatment with the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, 30 min prior to administration of carbidopa). Taken together, this evidence is compatible with a specific corticosterone induced facilitation of 5-HT release due to attenuation of inhibitory 5-HT1A autoreceptor function.
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PMID:Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse. 783 29

Serotonin (5-HT) nerve terminals innervate sympathetic preganglionic neurons of the intermediolateral cell column (IML); however, neither the depolarization-induced release of 5-HT nor the presence of presynaptic modulatory autoreceptors have been directly studied in this system. We used in vitro superfusion of the microdissected intermediate area (including the intermediolateral cell column, intercalated nucleus, and central autonomic nucleus) of the rat thoracic spinal cord to measure basal and stimulated release of preloaded [3H]5-HT. Elevated K+ evoked a concentration- and Ca(2+)-dependent release of [3H]5-HT. Exogenous 5-HT and the 5-HT1B agonist, CGS-12066B, both decreased the K(+)-stimulated release of [3H]5-HT. A 5-HT1B antagonist (methiothepin) blocked the 5-HT- and the CGS-12066B-induced inhibition of K(+)-evoked release of [3H]5-HT. A 5-HT1A antagonist (NAN-190) did not alter the inhibitory actions of exogenous 5-HT. Moreover, a 5-HT1A agonist (8-OH-DPAT), a 5-HT2A/2C agonist [(+/-)-DOI hydrochloride), and a 5-HT3 agonist (2-methyl-5-HT) did not alter the K(+)-evoked release of [3H]5-HT. These data demonstrate that 5-HT is released from the intermediate area of the rat thoracic spinal cord. The 5-HT receptor subtype involved in the inhibition of the evoked release of [3H]5-HT is of the 5-HT1B subtype. These findings may help clarify the complex role of 5-HT in spinal regulation of the sympathetic nervous system.
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PMID:Release of [3H]5-hydroxytryptamine from the intermediate area of rat thoracic spinal cord is modulated by presynaptic autoreceptors. 785 32

A series of experiments examined the effects of 5-HT1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task. 786 42

The role of serotonergic (5-HT) receptor subtypes in mediation of aggressive behaviour in isolated male mice has been studied. Increase of attack latency was used as a simple measure of antiaggressive behaviour. 5-HT1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities. Also the putative antagonists spiroxatrine and NAN 190 as well as the non-selective 5-HT1 agonists RU 24969, TFMPP, mCPP and eltoprazine have an antiaggressive effect. The mixed 5-HT1A and beta-adrenoceptor antagonists (-)-alprenolol and pindolol are ineffective and do not inhibit the effect of 8-OHDPAT. Neither does the non-selective 5-HT antagonist metergoline. The antiaggressive effect correlates with 5-HT1A receptor affinity in vitro and with generalization to the 8-OHDPAT-induced discriminative stimulus. The selective 5-HT uptake inhibitor citalopram does not inhibit aggressive behaviour. The 5-HT2 agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT2 antagonist ritanserin and the 5-HT3 antagonist ondansetron are ineffective. Prazosin (alpha 1-adrenoceptor antagonist), clonidine (alpha 2-adrenoceptor agonist), clenbuterol (beta-adrenoceptor agonist), ketanserin (5-HT2 receptor and alpha 1-adrenoceptor antagonist), clozapine and (-)-octoclothepin (dopamine (DA), 5-HT2 receptor and alpha 1-adrenoceptor antagonist) all show an antiaggressive effect. SCH 23390 (DA D1 receptor antagonist) and emonapride (DA D2 receptor antagonist) are ineffective. In conclusion, 5-HT1A receptors are involved in mediation of isolation-induced aggressive behaviour in mice. The involvement of other 5-HT receptor subtypes needs further clarification. The adrenergic system may also be involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice. 787 Aug 99

Using the conflict drinking test as a model, we studied in rats the effect of the nonselective beta-adrenoceptor blockers pindolol and cyanopindolol which bind to 5-HT1A and 5-HT1B receptors, and of the selective beta 1- and beta 2-adrenoceptor antagonists betaxolol and ICI 118,551, respectively, which have a negligible affinity for 5-HT receptors. Both pindolol (2.0-8.0 mg/kg) and cyanopindolol (0.5-2.0 mg/kg) showed an anticonflict effect, having dose dependently increased the number of punished licks. On the other hand, neither betaxolol nor ICI 118,551--administered separately or in combination--affected the punished responding. The anticonflict effects of pindolol and cyanopindolol were completely abolished by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phtalimmido)butyl]piperazine (NAN-190), but were not modified by the selective alpha 1(-)-adrenoceptor antagonist prazosin. The effects of pindolol and cyanopindolol were also not modified in animals with lesions of 5-HT neurons, produced by p-chloroamphetamine (PCA). Moreover, it was also found that the anticonflict effects of pindolol and cyanopindolol in PCA-pretreated rats were antagonized by NAN-190 but not prazosin. Our results indicate that the anticonflict effects of pindolol and cyanopindolol depend on their agonist action on postsynaptic 5-HT1A receptors.
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PMID:The role of 5-hydroxytryptamine1A (5-HT1A) receptors in the anticonflict activity of beta-adrenoceptor antagonists. 791 23

Serotonergic neurons from the midbrain raphe nuclei innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, which functions as the dominant pacemaker for mammalian circadian rhythms. We investigated the effects of serotonin (5-HT) on firing rates of light-activated SCN cells in urethane-anesthetized hamsters. Micro-iontophoretic application of 5-HT or 5-HT1A agonists (8-OH-DPAT and 5-CT) caused a dose-dependent inhibition of spontaneous activity and photic responses in the majority of SCN cells tested. Application of metergoline alone, a non-selective 5-HT antagonist, slightly increased firing rates during darkness and light exposure, suggesting a tonic serotonergic suppression of SCN activity. Metergoline also effectively attenuated suppression induced by the three 5-HT agonists. In addition, the effects of 8-OH-DPAT were blocked by a 5-HT1A antagonist, SDZ 216-525. However, other putative 5-HT antagonists were weak (propranolol and NAN-190) or ineffective (ketanserin) in blocking the action of 8-OH-DPAT. These results indicate that serotonin has a potent role in reducing photic effects on retinally activated SCN cells in hamsters, and that these effects are mediated by a receptor with properties similar to those of the 5-HT1A subtype.
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PMID:Effects of serotonergic agonists on firing rates of photically responsive cells in the hamster suprachiasmatic nucleus. 792 88

Recent evidence from our laboratory has demonstrated that blockade of somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors by systemic administration of spiperone increases the firing rate of central serotonergic neurons in awake cats. The present study examines the effects of three other putative 5-HT1A antagonists (BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5]decane-7,9-dione), NAN 190 [1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine) and (-)-propranolol) on the single-unit activity of serotonergic neurons recorded in the dorsal raphe nucleus of free-moving cats. Systemic administration of the phenylpiperazine derivatives BMY 7378 (5-100 micrograms/kg i.v.) and NAN 190 (5-250 micrograms/kg i.v.) produced a rapid, dose-dependent inhibition of neuronal activity with BMY 7378 being approximately twice as potent as NAN 190 (ED50 = 15.3 micrograms/kg vs. 34.2 micrograms/kg). The suppression of neuronal activity produced by both compounds was greatly attenuated by spiperone (1 mg/kg i.v.). Systemic administration of (-)-propranolol (2 and 4 mg/kg i.v.) produced a modest suppression of serotonergic neuronal activity which did not appear to be dose-related. The ability of BMY 7378, NAN 190 and (-)-propranolol to block the suppression of neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist, was also examined. Pretreatment with these compounds had no significant effect on the inhibitory response of serotonergic neurons to 8-OH-DPAT challenge. These results indicate that BMY 7378 and NAN 190 act as agonists rather than antagonists at the somatodendritic 5-HT1A autoreceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the putative 5-hydroxytryptamine1A antagonists BMY 7378, NAN 190 and (-)-propranolol on serotonergic dorsal raphe unit activity in behaving cats. 793 90

The aim of the present work was to know whether the excitatory modulation of the central respiratory rhythm generator by serotonin (5-HT) previously found to occur in the newborn rat, is already functional during the fetal life. Experiments were performed at embryonic day 18 (D18) and 20-21 (D20-21; full-term day 21) on the fetal rat brainstem-spinal cord preparation in which the ability to generate central respiratory activity in vitro persists. Replacing the normal medium which bathed the preparation by a medium containing 5-HT increased the respiratory frequency (RF) within 2-3 min in a dose-dependent manner in both D18 and D20-21 fetuses but the effect was particularly drastic at D18. Applying a medium containing the 5-HT antagonist, methysergide, to block the effect of endogenous 5-HT, if any, reduced the RF within 2-3 min and the reduction was especially drastic at D18 where respiratory arrests occurred for several minutes in most of the experiments. Applying a medium containing either the 5-HT reuptake inhibitor fluoxetine to potentiate the effect of endogenous 5-HT or the 5-HT precursor, L-tryptophan, to activate 5-HT biosynthesis mechanisms, increased the RF. To define the type of 5-HT receptors involved in the modulation of the RF, experiments were conducted with specific 5-HT agonists and antagonists. Both 5-HT1 (8-OH-DPAT, buspirone) and 5-HT2 agonists (DOI, alpha-methyl-5-HT) increased the RF but only the 5-HT1A agonist 8-OH-DPAT was efficient at submicromolar concentrations. Applying the 5-HT1A antagonist NAN-190 alone decreased the RF and even elicited respiratory arrests while the 5-HT2 antagonist ketanserin was inefficient. NAN-190 pre-treatment blocked the increase in the RF due to 8-OH-DPAT and 5-HT. Taken as a whole these results clearly indicate that endogenous 5-HT exerts an excitatory modulation on the respiratory rhythm generator via activation of medullary 5-HT1A receptors well before birth, as soon as D18 where the modulation is particularly potent.
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PMID:Endogenous serotonin modulates the fetal respiratory rhythm: an in vitro study in the rat. 795 47


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