Agonist and antagonist properties of serotonergic compounds in pigeons trained to discriminate either quipazine or L-5-hydroxytryptophan.
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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.Keywords:
Quipazine
Metergoline
Cyproheptadine
Methysergide
Ketanserin
Mianserin
Stimulus generalization
This study investigates the possibility that mianserin, a serotonin-2 (5HT2) receptor antagonist, produces a prolonged antagonism of quipazine discrimination, consistent with its prolonged biochemical effects. Rats were trained on a saline-quipazine (1.5 mg/kg) discrimination; following acquisition, the animals were assigned to groups and given injections of 2.0 mg/kg mianserin. Individual groups were tested at 45 min and successive 12-hr intervals for their ability to discriminate 0.75 mg/kg of quipazine, a dose that elicited 75% responding on the quipazine lever. Blockade of the quipazine cue persisted for 48 hr following mianserin administration. The above procedure was replicated using lower doses of mianserin (0.25, 0.10 and 0.05 mg/kg) and two other 5HT2 antagonists, pizotifen and metergoline (2.0 mg/kg), both of which showed similar profiles of extended antagonism. Changes in both receptor density and receptor sensitivity were investigated as possible mechanisms of mianserin's prolonged activity. Analysis of [3H]ketanserin binding revealed that a single 2.0-mg/kg dose of mianserin produced a significant decrease in the number of receptor sites (44%) 24 hr after treatment; however, this loss of sites recovered by 36 hr post-injection and could therefore not account for mianserin's continued antagonism at this and later times. 5HT-mediated phosphoinositide hydrolysis in cerebral cortex slices was used as a measure of 5HT2 receptor sensitivity. Treatment of rats with 2 mg/kg of mianserin caused a marked reduction in the maximum phosphoinositide response to 5HT that persisted for up to 36 hr. Hence, the time course for recovery of 5HT2 receptor sensitivity corresponded more closely to behavioral recovery than did 5HT2 receptor binding.
Quipazine
Mianserin
5-HT2 receptor
Ketanserin
Metergoline
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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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Abstract Selective serotonin reuptake inhibitors (SSRIs) can mimic the physiological actions of serotonin, and in bivalve molluscs they induce zebra mussel spawning and fingernail clam parturition. We have elucidated further the pharmacology of SSRI‐induced spawning and part‐urition by blocking these reproductive processes with two mammalian 5‐HT 2 receptor antagonists, cyproheptadine and mianserin. These two antagonists were potent inhibitors of both spawning and parturition induced by the SSRIs fluvoxamine, fluoxetine, and zimelidine. In zebra mussels, both cyproheptadine and mianserin significantly blocked spawning induced by fluvoxamine and by zimelidine. In the fingernail clams Sphaerium spp., both cyproheptadine and mianserin blocked fluvoxamine‐induced parturition. A possible mechanism of action for SSRI‐induced spawning and parturition in bivalves is suggested. J. Exp. Zool. 298A:67–72, 2003 . © 2003 Wiley‐Liss, Inc.
Cyproheptadine
Fluvoxamine
Mianserin
Metergoline
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Cyproheptadine
Methysergide
Ketanserin
Mianserin
Ritanserin
Serotonin Antagonists
Quipazine
Trazodone
Metergoline
Serotonin Agonist
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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
Mianserin
Methysergide
Metergoline
Ketanserin
Phenoxybenzamine
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Metergoline
Quipazine
Anorectic
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Cyproheptadine
Mianserin
Oxotremorine
Quipazine
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Quipazine
Metergoline
Locomotor activity
Serotonin Agonist
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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 sero-toninergic 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 bupre-norphine, which under similar conditions antagonized completely the hyperalgesic effects of naloxone; thus, the hyperalgesic effects of 5-MeODMT do not seemingly involve opioidergic receptors.
Cyproheptadine
Metergoline
Quipazine
Opioidergic
Methysergide
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