Effects Of Serotonin Antagonists Research Articles

Inhibitory Effect of Serotonin Antagonist on Leukocyte-Endothelial Interactions In Vivo and In Vitro.

BackgroundAlthough 5-HT2A serotonergic antagonists have been used to treat vascular disease in patients with diabetes mellitus or obesity, their effects on leukocyte-endothelial interactions have not been fully investigated. In this study, we assessed the effects of sarpogrelate hydrochloride (SRPO), a 5-HT2A receptor inverse agonist, on leukocyte-endothelial cell interactions in obesity both in vivo and in vitro.Methods and FindingsIn the in vivo experiment, C57BL/6 mice were fed a high-fat high-fructose diet (HFFD), comprising 20% fat and 30% fructose, with or without intraperitoneal injection of 5 mg/kg/day SRPO for 4 weeks. The body weight, visceral fat weight, and serum monocyte chemoattractant protein-1 levels in the mice increased significantly with the HFFD, but these effects were prevented by chronic injections of SRPO. Intravital microscopy of the femoral artery detected significant leukocyte-endothelial interactions after treatment with HFFD, but these leukocyte-endothelial interactions were reduced in the mice injected with SRPO. In the in vitro experiment, pre-incubation of activated human umbilical vein endothelial cells (HUVECs) with platelet-rich plasma (PRP) induced THP-1 cell adhesion under physiological flow conditions, but the adhesion was reduced by pretreatment of PRP with SRPO. A fluorescent immunobinding assay showed that PRP induced significant upregulation of E-selectin in HUVECs, but this upregulation was reduced by pretreatment of PRP with SRPO. In other in vitro conditions, pre-incubation of THP-1 cells with phorbol 12-myristate 13-acetate increased the adhesion of THP-1 cells to activated HUVECs under rotational conditions, but this adhesion was reduced by pretreatment with SRPO. Western blotting analysis showed that protein kinase C α activation in THP-1 cells was inhibited by SRPO.ConclusionOur findings indicated that SRPO inhibits vascular inflammation in obesity via inactivation of platelets and leukocytes, and improvement of obese.

Cinanserin reduces plasma extravasation after burn plasma transfer in rats

BackgroundThermal injuries greater than 20% body surface area (BSA) lead to systemic edema and hypovolemic shock. Capillary leakage is induced by different immunomodulative cytokines. Serotonin (5-HT) plays an important role in inflammation, vasodilatation and vasoconstriction and many other pathways such as systemic inflammation in endotoxemia and burns. Cinanserin, a specific 5-HT2 receptor blocking agent was administered to observe whether burn induced systemic edema can be reduced. MethodsDonor animals underwent thermal injury (100°C water, 30% BSA, 12s) for positive controls and negative controls underwent a shamburn procedure (37°C water, 30% BSA, 12s). Donor rat-plasma was transferred to healthy individuals after bolus injection of Cinanserin (5mg/kg body weight) was performed in recipient animals. Intravital microscopy was performed in mesenteric venules (0/60/120min) to asses systemic edema by FITC-albumin extravasation. Additionally, leukocyte activation (cells/mm2) was observed. ResultsBurnplasma-transfer results in systemic capillary leakage that is not observed in sham burn controls. Intraveneous application of Cinanserin significantly reduces systemic burn edema to shamburn levels. Leukocyte-endothelial interactions are significantly reduced by administration of Cinanserin. ConclusionSpecific 5-HT2 antagonism reduces systemic burn edema and leukocyte activation after plasma transfer. Reduction of capillary leakage may be partially mediated by leukocyte dependent as well as independent mechanisms. Future studies need to evaluate specific 5-HT2 receptor subtypes to distinguish between local and systemic effects of serotonin antagonists.

Inhibitory effect of serotonin antagonists on JC virus propagation in a carrier culture of human neuroblastoma cells

Human polyomavirus, JCV, causes fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). It has been shown that 5HT(2A)R acts as a cellular receptor for JCV on human glial cells. In the current study, we examined the inhibitory effects of 5HT(2A)R antagonists, ketanserin and ritanserin, both on JCV infection and on propagation by using human neuroblastoma cells IMR-32 and JCI, which continuously produce JCV. Transcriptional analysis revealed that 5HT(2A)R was constitutively expressed in JCI cells. Treatments with 5HT(2A)R antagonists led to a significant reduction in the titers of progeny viruses and the population of infected JCI cells. In addition, the amount of JCV genomic DNA was decreased in JCI cells in the presence of 5HT(2A)R antagonists. These results indicate that 5HT(2A)R antagonists have an inhibitory effect on JCV infection and reproduction, and JCI cells are applicable to an experimental model for pharmacological evaluation of antiviral agents against JCV.

Effects of serotonin antagonists in sexually impotent men.

Thirty-one men affected with sexual impotence were studied. Since sexual function in the male seems to be controlled by both dopaminergic stimulatory and serotoninergic inhibitory mechanisms, the patients were treated with serotonin antagonists. In basal conditions mean serum LH, FSH, PRL and testosterone did not significantly differ from those found in normal subjects; no significant variations, except for PRL reduction, were observed after treatment. Both methysergide, in association with bromocriptine or mesterolone, and metergoline, either alone or in association with mesterolone, were ineffective in significantly improving sexual activity.

The effects of serotonin antagonists in an animal model of sleep-disordered breathing.

Recent studies have shown excitatory effects of serotonin on upper airway motoneurons. This excitatory effect is normally present and arises from cells in the caudal raphe nuclei. The firing of these serotonergic neurons is reduced during sleep. To determine the importance of serotonin in the maintenance of patient airways and normal respiration in waking in obstructive sleep apnea, we studied the effects of two serotonin antagonists on upper airway dilator muscle activity, diaphragm activity, Sao2, and upper airway cross-sectional area in an animal model of sleep-disordered breathing, the English bulldog. Systemic administration of both antagonists resulted in significant reductions in the peak amplitudes of upper airway muscle respiratory bursts (range, 39 to 62% suppression; p < 0.05). Lesser reductions in diaphragm activity were noted (range, 10 to 33% suppression; p < 0.05). Oxyhemoglobin saturations also fell (p < 0.05), coinciding with suppressions in upper airway muscle activity. With reductions in dilator muscle activity, upper airway cross-sectional areas, as measured with cine CT, showed significant inspiratory collapse. These results support the hypothesis that serotonin is important in the maintenance of patent upper airways in obstructive sleep apnea.

暑熱ならびに快適環境に馴化したラットの摂食に対するセロトニン阻害薬シプロヘプタジンおよびセロトニン合成阻害薬 &lt;i&gt;p&lt;/i&gt;-クロロフェニルアラニンの影響

暑熱ならびに快適環境に馴化したラットの摂食に対するセロトニン阻害薬シプロヘプタジンおよびセロトニン合成阻害薬 &lt;i&gt;p&lt;/i&gt;-クロロフェニルアラニンの影響

Inhibiting effects of serotonin antagonists on the proliferation of mercuric chloride stimulated human peripheral blood T lymphocytes.

The serotonin antagonists ketanserin and methiotepine were tested for a modulating effect on the proliferative response of human peripheral blood T lymphocytes to mercuric chloride. This response was inhibited by ketanserin at 8 x 10(-5) mol/l and by methiotepine at 8.0 x 10(-6) mol/l. There were no additive effects at these concentrations of antagonists and at 10(-5) mol/l of serotonin. Low concentrations of ketanserin eliminated the inhibiting effect of serotonin on mercuric chloride induced proliferation of T lymphocytes. It thus seems as if the inhibiting effect of serotonin on T lymphocytes is mediated by 5-HT1c or 5-HT2 receptors, while the mechanism for the intrinsic inhibiting effect of the antagonists at present is unknown.

Visual recognition memory in squirrel monkeys: Effects of serotonin antagonists on baseline and hypoxia-induced performance deficits

Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Preclinical anxiolytic versus antipsychotic profiles of the 5‐HT3 antagonists ondansetron, zacopride, 3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester, and 1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate

AbstractIn preclinical studies, the behavioral effects of serotonin antagonists at 5‐HT3 receptor sites suggest potential efficacy in the treatment of anxiety and schizophrenia. The present study shows that 5‐HT3 antagonists were effective in disinhibiting behavior in non‐conditioned rodent models which elicit a behavioral state presumed to be analogous to anxiety, but were generally not effective in conditioned rodent anxiety models or in assays that are traditionally predictive of antipsychotic agents. Ondansetron (0.01–0.1 mg/kg), zacopride (0.1–1.0 mg/kg), ICS 205–930 (3α‐tropanyl‐1H‐indole‐3‐carboxylic acid ester; 0.5 and 1.0 mg/kg), and MDL 72222 (1αH, 3α, 5αH‐tropan‐3‐yl‐3,5‐dichlorobenzoate; 10.0 and 20.0 mg/kg) demonstrated anxiolytic effects in the social interaction and elevated plus maze procedures, while having little or no effect in a modified Cook and Davidson conflict procedure. Ondansetron, zacopride, and ICS 205–930 had no effect in neuroleptic screening procedures, such as the apomorphine climbing mouse assay (CMA), the pole climb avoidance (PCA) procedure, and the intracranial self‐stimulation of the medial forebrain bundle (ICSS‐MFB) assay. MDL 72222 had no effect on CMA but dose‐dependently antagonized PCA (ED50 = 10.9 mg/kg) and ICSS‐MFB (ED50 = 8.8 mg/kg). The results of the present study suggest that MDL 72222 possesses a profile of activity that is different from the other 5‐HT3 antagonists tested and that, in general, 5‐HT3 antagonists may prove to be efficacious in the treatment of certain forms of anxiety in man.

Effects of serotonin antagonists on motion sickness and its suppression by 8-OH-DPAT in cats

This investigation evaluated the antagonist properties of (-)propranolol, (+)propranolol, metergoline and BMY 7378 on the known effect of 8-OH-DPAT (DPAT) to decrease motion sickness in cats. (-)Propranolol produced a greater decrease in the antiemetic effect of DPAT than did (+)propranolol. Although metergoline produced a decrease in the antiemetic effect of DPAT, the decrease could not be clearly attributed to interactions with 5-HT 1A receptors because metergoline alone slightly enhanced motion sickness. Depletion of 5-HT with PCPA produced a weaker, nonsignificant enhancement of motion sickness, while mesulergine had no effect. As neither nonspecific 5-HT receptor blockade with metergoline nor depletion of 5-HT mimicked the antiemetic effect of DPAT, it was concluded that DPAT acts on postsynaptic 5-HT 1A receptors to prevent emesis. BMY 7378 alone decreased the incidence of motion sickness. A dose just below this agonist range did not decrease the effects of DPAT.

Effects of serotonin antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects

The serotonin (5HT) agonist, m-chlorophenylpiperazine (MCPP), has been used as a challenge agent to assess central 5HT receptor sensitivity in normal subjects and patients with panic disorder, obsessive-compulsive disorder, and major depression. Adrenocorticotropin, cortisol, and prolactin responses to MCPP were among the variables measured. MCPP's usefulness as a probe of 5HT receptors, however, hinges on its 5HT selectivity. To address MCPP's selectivity for 5HT, this study tested whether two different 5HT antagonists, methysergide (4 mg p.o.) and metergoline (4 mg p.o.), could block the hormonal and behavioral effects of MCPP (0.5 mg/kg p.o.) in 10 normal male subjects in comparison to placebo. Both 5HT antagonists abolished the prolactin release to MCPP. Metergoline, the antagonist with the more potent 5HT binding affinity, significantly blocked MCPP's effect on cortisol release as compared to placebo, and methysergide showed a nonsignificant trend to that effect. MCPP alone did not have a significant effect on behavioral variables, perhaps explaining why neither 5HT antagonist affected these measures. The findings from this study suggest that both MCPP-induced prolactin release and cortisol release are indeed 5HT-mediated effects.

抗悪性腫よう薬によって惹起されるｆｅｒｒｅｔのおう吐に及ぼすセロトニンきっ抗薬とドパミンきっ抗薬の影響

抗悪性腫よう薬によって惹起されるｆｅｒｒｅｔのおう吐に及ぼすセロトニンきっ抗薬とドパミンきっ抗薬の影響

Suppression of food intake in rats by fluoxetine: Comparison of enantiomers and effects of serotonin antagonists

R- and S-enantiomers of fluoxetine lowered food intake in meal-fed rats and in 2-deoxyglucose-induced hyperphagic rats. In both feeding paradigms, the S-enantiomer was slightly more potent. The potency of the two enantiomers of fluoxetine in producing anorectic effects paralleled their potency as inhibitors of 5-hydroxytryptamine (5HT) uptake in vivo. Both enantiomers were selective inhibitors of 5HT uptake in vitro and showed only weak affinity for 5HT-1, 5HT-1A and 5HT-2 receptors or for other receptors in rat brain. The anorectic effect of fluoxetine in meal-fed rats was not reversed by either centrally or peripherally acting 5HT-2 receptor antagonists (ritanserin, LY53857, xylamidine, BW 501C67) or a nonspecific 5HT receptor antagonist, metergoline. However, the serotonergic mechanism involved in the anorexic effect of fluoxetine is discussed.

Effect of serotonin antagonists on prolactin and progesterone secretion in rats: evidence that the stimulatory and inhibitory actions of serotonin on prolactin release may be mediated through different receptors.

The serotoninergic regulation of prolactin release was studied in female rats in different reproductive states using ketanserin, a specific S2 receptor blocker, ICS 205-930 ((3 alpha-tropanyl)1H-indol-3-carboxylic acid ester), a specific S3 receptor blocker and p-chlorophenylalanine (pCPA), a serotonin synthesis inhibitor. Administration of ketanserin to pro-oestrous rats inhibited the afternoon prolactin surge; this inhibition was prevented by progesterone. On day 3 of pregnancy, pCPA or ketanserin blocked the afternoon prolactin surge, and administration of oestrogen (on day 2) and progesterone (on day 3) in combination, but not alone, prevented this effect. On day 9 of pregnancy, treatment with oestrogen (on day 8) and progesterone (on day 9) induced an afternoon surge of prolactin which was prevented by administration of ketanserin or pCPA. On days 9 and 16, pCPA induced a slight increase in serum prolactin in rats not treated with steroids, but ketanserin had no effect. On day 13, ketanserin and pCPA had no effect on serum prolactin levels, but after increasing serotoninergic transmission by injecting fluoxetine and 5-hydroxytryptophan, serum prolactin levels were decreased. On day 19, ketanserin produced a transient increase in the serum concentration of prolactin, probably produced by the marked decrease in the serum concentration of progesterone induced by the S2 receptor blocker. Administration of ICS 205-930 to pro-oestrous rats or rats on day 19 of pregnancy had no effect on serum concentrations of prolactin and progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amine dependence of proliferative activity in two transplantable lines of mouse colonic carcinoma.

Serotonin, histamine and their antagonists have previously been shown to influence both the cell proliferation rate and the volumetric growth rate of colonic tumours. Of these earlier studies, those on cell proliferation could not distinguish between direct effects on tumour cells and indirect effects on the host, whereas those on the volumetric growth rate of tumours, whilst suggesting an outcome related to the individual properties of the tumour rather than the host, could not distinguish between influences on cell gain, cell loss or stromal changes. In an attempt to distinguish between these possibilities the current experiments on the mitotic rate in two lines of transplantable mouse colonic carcinoma were undertaken. One line of tumour proved to be sensitive to inhibition by a histamine H2 receptor antagonist and a dopamine D2 antagonist but resistant to serotonin antagonists; the inhibition by histamine antagonists was surmountable by co-administration of histamine. The other line proved to be highly sensitive to the inhibitory effects of serotonin antagonist and less so to antagonists of the other two amines and in this case the effect of serotonin antagonists was surmountable by serotonin. These results suggest that the variations between different colonic tumours in the response to amine antagonists is due to differences in the extent of inhibition of cell proliferation rather than differences in cell loss or stromal effects. Thus it appears likely that amine antagonists are able to directly interfere with the proliferation of some colonic tumour cells.

Effects of serotonin antagonists on the performance of a simple food acquisition task in rats treated with fenfluramine isomers

The effect of fenfluramine on food-rewarded runway behaviour was studied in rats that had reached stable performance levels in a three-trials test procedure. d-Fenfluramine was about twice as potent as 1-fenfluramine in its influence on all aspects of runway behaviour: starting speed, running speed and the number of pellets eaten in each trial. Blockade of peripheral serotonin receptor sites by pretreatment with xylamidine, at a dose (2 mg/kg) blocking serotonin-induced inhibition of food intake, was unable to counteract the decrease in runway performance that resulted from treatment with either 2.5 mg/kg d-fenfluramine or 5.0 mg/kgl-fenfluramine. However pretreatment with metergoline (2 mg/kg), an antagonist that affects both central and peripheral receptor sites, improved the performance of rats given these doses of d- and 1-fenfluramine. It is concluded that both isomers of fenfluramine affect food-rewarded runway behaviour through a mechanism that involves the stimulation of central but not peripheral serotoninergic pathways.

The effects of serotonin antagonists in a behavioral despair procedure in mice

Six serotonin antagonists (pizotifen, mianserin, cyproheptadine, ketanserin, trazodone and methysergide) were tested in mice in a behavioral despair procedure. The behavioral despair procedure detects most antidepressant compounds. Pizotifen, mianserin and cyproheptadine were found to be active and the others were inactive. The serotonin binding potency at serotonin 1 or serotonin 2 receptors, or the ratio of potency at these receptors did not correlate with activity in the behavioral despair procedure. However, the serotonin antagonists that were active in the behavioral despair procedure were all found to be potent antagonists at histamine 1 receptors. It is suggested that the activity of some serotonin antagonists in the behavioral despair procedure is best explained by their antihistaminergic potency.

Effect of serotonin antagonists on the dextran-induced anaphylactoid reaction in the rat.

Dextran injected intravenously into rats causes a rapid lowering of the extent of activation of factor XII and of the plasma levels of prekallikrein and plasminogen, and at the same time a profound fall in blood pressure. The effects on these dextran-induced reactions of three serotonin antagonistic lysergic acid derivatives were studied in the rat: bromolysergic acid diethylamide (BOL 148), methysergide, and ergotamine. BOL 148 was found to be the only effective inhibitor of the blood pressure fall, possessing an inhibitory effect over the dose range 1.0-4.0 mg/kg intravenously. The finding supports the assumption that part of the dextran-induced blood pressure fall is mediated by serotonin through D-receptors. All three serotonin antagonists showed a serotonin-like lowering effect on the activation of factor XII and on the level of prekallikrein in plasma (BOL 148 1.0-4.0 mg/kg; methysergide 0.10-0.60 mg/kg; ergotamine 0.10-0.60 mg/kg). The results with the serotonin antagonist alone and in combination with dextran provided evidence that the serotonin-mediated part of the blood pressure fall can not be secondary to the effect of dextran on the plasma parameters assayed.

Effects of serotonin antagonists on the development of inherited muscular dystrophy in the chicken

The antiserotoninergic drugs methysergide and cyproheptadine were investigated for their therapeutic effects on an hereditary strain of dystrophic chickens (New Hampshire, line 304). The drugs, given intraperitoneally either alone or in combination, significantly delayed the onset of dystrophic symptoms, as quantitated by a “flip test” for muscular disability. Untreated dystrophic chickens reached a maximum flip-test average at approximately day 23 ex ovo, and subsequently declined in this ability to flip upright when overturned. Concomitant with this decline, there was a marked rise in the activity of plasma creatine phosphokinase, reaching values of 8500 mU/ml plasma, as compared to approximately 350 mU/ml plasma found constantly in nondystrophic chickens. At day 60 ex ovo, 80% of the methysergide-treated chickens retained the unimpaired ability to rise from the supine, as compared to only 6% of the untreated dystrophics at that age. The other drug treatments gave rather similar results. The plasma creatine phosphokinase was found to be significantly lower in the treated dystrophic chickens, about two-thirds of its rise (at about day 60) being prevented in the drug-treated birds now passing the flip test. The negative correlation between the flip-test ability of the treated and untreated dystrophic chickens and their plasma creatine phosphokinase, is illustrated. Determinations of plasma alkaline phosphatase, lactate dehydrogenase, and glutamic oxaloacetate transaminase in these cases are also presented. Blood serotonin was significantly higher in the untreated dystrophic chickens (2.03 μg/ml blood) compared to the concentrations found in normal, nondystrophic animals (1.55 μg/ml blood). The drug treatments were found to reduce the serotonin in dystrophic animals. The use of antiserotoninergic drug therapy is discussed in light of the vascular hypothesis for muscular dystrophy etiology.

Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors.

The pathogenesis of flushing attacks in patients with malignant carcinoid tumors is attributed to the direct pharmacologic effect of excessive amounts of circulating serotonin. It was hoped that potent serotonin antagonists might relieve symptoms of the carcinoid syndrome in the inoperable patient. The nature of flushing attacks was studied in carcinoid patients and the influence thereon of 3 serotonin antagonists, a benzyl analog of serotonin, bromo-lysergic acid diethylamide, and chlorpromazine. The systemic, subjective, and vascular effects of these antagonists in normal subjects were also investigated.