Effects of various serotoninergic agonists and an antagonist on a nociceptive reaction in mice.
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Abstract:
Low doses of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine and cyproheptadine produced facilitation of jumping in mice using the hot plate method. Higher doses produced severe motor disturbances which precluded the assessment of effects on nociception. The observed hyperalgesia might be a consequence of diminution of serotoninergic tone resulting either from triggering of presynaptic serotoninergic receptors in the case of 5-MeODMT and quipazine or from the blockade of postsynaptic serotoninergic receptors in the case of cyproheptadine. The 5-MeODMT-induced hyperalgesia was not attenuated by buprenorphine, which under similar conditions antagonized completely the hyperalgesic effects of naloxone; thus, the hyperalgesic effects of 5-MeODMT do not seemingly involve opioidergic receptors.Keywords:
Cyproheptadine
Quipazine
Metergoline
Opioidergic
Methysergide
The serotonin (5-HT) receptor-related compounds metergoline, pirenperone, ketanserin, cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin were studied in pigeons trained to discriminate l-5-hydroxytryptophan (l-5-HTP) (18.0 mg/kg) from saline and in pigeons trained to discriminate quipazine (1.0 mg/kg) from saline. Metergoline did not generalize to either quipazine or l-5-HTP but did antagonize drug-appropriate responding in both groups. Ketanserin potently blocked the quipazine discriminative stimulus and neither generalized to nor attenuated the l-5-HTP discriminative stimulus. Pirenperone, cinanserin, cyproheptadine, methylsergide, pizotyline and mianserin attenuated the quipazine discriminative stimulus at low doses and, at higher doses, generalized to the l-5-HTP discriminative stimulus. No antagonism of the l-5-HTP-discriminative stimulus or generalization to the quipazine-discriminative stimulus were observed with these compounds. A correlation coefficient of 0.93 was calculated between the potencies of 5-HT compounds to generalize to the l-5-HTP stimulus and the binding affinities of these compounds for a 5-HT1 receptor in rat brain. In addition, a correlation coefficient of 0.78 was calculated between the potencies of 5-HT compounds to attenuate the quipazine stimulus and the binding affinities of these compounds for the 5-HT2 receptor in rat brain. These observations suggest cyproheptadine, pizotyline, methysergide, lysergic acid diethylamide, mianserin and cinanserin are agonists at the 5-HT1 receptor in the l-5-HTP discrimination and antagonists at a 5-HT2 receptor in the quipazine discrimination in pigeons.
Quipazine
Metergoline
Cyproheptadine
Methysergide
Ketanserin
Mianserin
Stimulus generalization
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Effects of the serotonin receptor antagonists ketanserin, metergoline, and methysergide on LH release were tested in ovariectomized (OVX) rats pretreated with estradiol benzoate (EB) (5 micrograms/100 g BW) on each of the 2 days preceding the experiment. LH concentration measured by RIA in plasma samples obtained at 10 min intervals was analyzed using the PULSAR computer program to identify and characterize pulses observed in the LH profile of each rat individually. Multiple pulses were identified in seven of seven OVX rats but in only two of eight OVX rats primed with EB. Multiple pulses were identified in OVX EB-primed rats pretreated with ketanserin (six of seven), metergoline (three of seven), and methysergide (six of eight). Administration of the serotonin (5HT) agonist quipazine (2 mg/kg iv) to OVX rats inhibited pulsatile LH release and depressed mean plasma concentrations for approximately 45 min. This inhibitory response was antagonized by pretreatment of the OVX animals with ketanserin. These results suggest that 1) quipazine inhibits pulsatile LH release in OVX rats by a serotonin2 receptor mechanism; and 2) the inhibitory effect of estrogen on pulsatile LH release may also be mediated, at least in part, via 5HT2 systems.
Quipazine
Methysergide
Metergoline
Ketanserin
Pulsatile flow
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The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.
Metergoline
Methysergide
Cyproheptadine
Lisuride
Idazoxan
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Cyproheptadine
Metergoline
Lisuride
Methysergide
Apomorphine
Mianserin
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Using animals with large electrolytic lesions of the median eminence-mediobasal hypothalamus, we confirmed earlier findings that metergoline (ME) and methysergide (MS) inhibit PRL secretion through activation of the dopamine receptors of the pituitary lactotrophs and established, in a quantitative manner, that their dopaminergic potencies are comparable to the potency of the dopamine receptor agonist, piribedil, with ED50 in the order of 0.35 to 0.22 mg/kg. Cyproheptadine (CYP), acting by an unknown mechanism, had only a weak inhibiting effect (ED50 greater than 20.0 mg/kg) in these experimental conditions. In the second part of the study, the PRL-inhibiting actions of ME, MS, CYP, and piribedil, respectively, were tested against the PRL release-stimulating effect of activation of the central serotonergic system that was induced by administration of a large dose of L-5-hydroxytryptophan (5HTP; 100 mg/kg), a small dose of 5HTP (15 mg/kg) in rats pretreated with fluoxetine, or by the serotonin receptor agonist quipazine (10.0 mg/kg, ip). The inhibiting potencies of ME (ED50 0.019, 0.014, and 0.048 mg/kg, respectively) against these three stimuli were much larger than in the lesioned animals or than the corresponding potencies of piribedil (ED50 2.2, 0.24, and 0.41 mg/kg, respectively). It is assumed that in these experimental conditions ME inhibited PRL release by blockade of the central serotonin receptors in addition to its dopaminergic effect and that at low doses (0.1 mg/kg or less) the entire inhibiting effect of ME was probably due to its antiserotonergic activity. With MS, which is a weaker serotonin receptor blocker than ME (ED50 0.178, 0.075, and 0.55 mg/kg, respectively, for the three serotonergic stimuli of PRL release), the antiserotonergic component in its PRL-inhibiting effect was evident but less clearly separable from the dopaminergic component in experiments with 5HTP and with fluoxetine plus 5HTP, whereas in experiments with quipazine the entire action could be accounted for by its dopaminergic activity. CYP was the least potent among the three blockers (ED50 0.6, 0.4, and 1.37 mg/kg, respectively, for the three serotonergic stimuli of PRL release), but appropriate tests indicated that it acted only as a serotonin receptor blocker and not by virtue of its antihistaminic, anticholinergic properties or by a direct action on the pituitary lactotrophs. SQ 10,631, another serotonin receptor blocker that was also tested, had no PRL-inhibiting activity. Because of the dual nature of the PRL-inhibiting mechanism of ME and MS and the low effectiveness of CYP, combined possibly with other actions, the serotonin receptor blockers have limited value in studies concerning the role of the central serotonergic system in the regulation of PRL secretion.
Metergoline
Cyproheptadine
Quipazine
Methysergide
ED50
Serotonin Agonist
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Cyproheptadine
Methysergide
Quipazine
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Metergoline
Cyproheptadine
Methysergide
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The nature, development, and specificity of serotonergic involvement in the control of suckling behavior in rat pups from 10 to 35 days of age were studied. During development, suckling normally declines after 10 days and is abandoned after 30 days. It was found that (a) methysergide, a serotonin (5-HT) receptor blocker, reinstated suckling behavior in pups 15 days of age and older but had no effect on the suckling of 10-day old pups, (b) quipazine, a 5-HT receptor agonist, inhibited suckling of pups 10 days of age and older, (c) methysergide pretreatment blocked the quipazine inhibition of suckling, and (d) metergoline, another 5-HT blocker, also stimulated suckling, and fenfluramine, a 5-HT releaser, blocked suckling in deprived pups. Together, these data support the hypothesis that a serotonergic inhibitory mechanism modulates the suckling of weaning-age rats. These pharmacological manipulations of 5-HT appear to alter specific components of suckling behavior involved in its initiation and maintenance but do not appear to alter a general hunger system.
Methysergide
Metergoline
Quipazine
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Ritanserin
Metergoline
Methysergide
Cyproheptadine
Dexfenfluramine
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Cyproheptadine
Methysergide
Quipazine
Mianserin
Mescaline
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