Antagonism of amphetamine-induced disruption of latent inhibition in rats by haloperidol and ondansetron: Implications for a possible antipsychotic action of ondansetron

Latent inhibition (LI) is a behavioural phenomenon whereby preexposure to a stimulus without reinforcement interferes with the formation of subsequent associations to that stimulus. Using preexposure to a tone stimulus which subsequently serves as a conditioned stimulus for suppression of licking, we have confirmed that LI is disrupted by a low dose of amphetamine. Haloperidol was able to prevent this effect of amphetamine. Ondansetron, a selective and potent 5HT₃ receptor antagonist, was also shown to be effective at blocking the amphetamine-induced disruption of LI at a dose of 0.01 mg/kg, but not at 0.1 mg/kg. In addition, it was demonstrated that ondansetron could enhance LI; using only ten preexposures, no LI was obtained in the saline group, but was apparent in animals given ondansetron, an effect which has been previously shown with haloperidol. Haloperidol, at the higher dose used, reduced suppression of licking, however, ondansetron at the effective dose had no such effect. It is concluded that ondansetron is able to attenuate increases in dopamine activity, produced pharmacologically with amphetamine without affecting baseline dopamine activity. The implications of these findings for a possible antipsychotic action of ondansetron are discussed.     

Temperature,food intake,and locomotor activity effects of a 5-HT3 receptor agonist and two 5-HT3 receptor antagonists in rats

This study investigated three physiologic functions known to be modulated by serotonin — temperature, food intake and locomotor activity — using the 5-HT₃ receptor agonist,m-chlorophenylbiguanide (m-CPBG), and two 5-HT₃ antagonists, MDL-72222 and ondansetron. m-CPBG produced dose-dependent elevations in rectal temperature. MDL-72222, which had no effects on temperature when given alone, significantly attenuated m-CPBG-induced hyperthermia. Food intake in food-deprived rats was reduced during the first hour by the highest dose of m-CPBG. Food intake was also dose-dependently reduced by MDL-72222; m-CPBG plus MDL-72222 led to greater reductions in food intake. Food intake in freely fed rats was unaffected by m-CPBG or MDL-72222. Locomotor activity was unaffected by m-CPBG, but was dose-dependently reduced by MDL-72222, an effect which may have contributed to its hypophagic effects. Ondansetron, used in ten-fold lower doses than MDL-72222, was inactive in all of these paradigms. These data: (1) provide some evidence for 5-HT₃ receptor-mediated changes in temperature; (2) are in agreement with two prior studies which reported locomotor activity reductions following 5-HT₃ antagonists; but (3) do not support an important role for 5-HT₃ receptors in the regulation of food intake in rats.     

格拉司琼和恩丹西酮预防顺铂所致消化道反应的随机对照研究

目的 观察并比较格拉司琼与恩丹西酮在预防顺铂所致的消化道反应的疗效和毒性反应。方法 采用随机自身前后对照试验设计，将37例接受顺铂联合化疗的肺癌患者，分为AB和BA两组，AB组第1周期用A方案（盐酸格位司琼3mg静注）每日1次，连用5d，第2周期用B方案（盐酸恩丹西酮8mg静注）每12h 1次，连用5d;BA组第1周期用B方案，第2周期用A方案，前后两周期化疗方案完全相同。结果 A，B方案均有良好的止吐疗效，在呕吐控制率，平均呕吐次数，恶心控制率及食欲影响方面两方案无统计学差异（P＞0．05）。两方案毒副反应均较小，可以耐受。结论 格拉司琼与恩丹西酮预防顺铂所致的消化道反应均有较好的疗效，毒副反应低。格拉司琼价格较低廉，更适合临床应用。     

昂丹司琼预防术后舒芬太尼硬膜外自控镇痛引起恶心呕吐的临床研究

目的观察昂丹司琼预防舒术后舒芬太尼硬膜外自控镇痛(PCEA)引起恶心呕吐的效果观察。方法选择在腰麻与硬膜外联合麻醉下行开腹妇科手术患者120例,随机分为两组:每组60例。A组:昂丹司琼4mg,B组为生理盐水4ml,分别加入PCEA药盒注入硬膜外间隙。术后舒芬太尼PCEA镇痛,PCEA药液为舒芬太尼100ug,罗派卡因75mg,加生理盐水至100ml,观察两组术后48h内的镇痛效果及恶心呕吐的发生率。结果两组患者术后镇痛效果比较差异无统计学意义(P>0.05)两组患者术后48h内恶心呕吐发生率A组显著低于B组。恶心8例(13.3%)B组16例(26.7%);呕吐:A组3例(5.0%)B组18例(30.0%)(P〈0.05或P〈0.01),差异有统计学意义。结论昂丹司琼能够安全有效地减少硬膜外舒芬太尼术后镇痛引起的恶心呕吐。     

甲氧氯普胺与恩丹西酮对化疗或术后恶心呕吐的疗效和安全性荟萃分析

目的　对甲氧氯普胺与恩丹西酮预防化疗 /术后恶心、呕吐的有效性和安全性进行系统性评价。方法　系统检索Medline 196 6～ 2 0 0 2年数据库和中国生物医学文献光盘数据库 (CBMdisc) 1978～ 2 0 0 2年文献。根据纳入标准和排除标准筛选文献 ,由 2名评价者各自独立地对入选文献中有关试验设计、研究对象的特征、研究结果等内容进行摘录和质量评价 ,并对各研究结果进行异质性检验和数据合并。结果　共收集 33篇合格随机临床对照试验报告 ,评分在 6 5～ 95分之间 ,其中优质文献 (≥ 85分 )19篇。甲氧氯普胺治疗恶心、呕吐的近期 (用药时程为 1d和 3d)有效率明显不如恩丹西酮 ,差异有显著性 (P <0 .0 1) ,远期 (用药时程为 3d以上 )有效率差别不大。甲氧氯普胺引起锥体外系症状和腹痛、腹泻不良反应明显多于恩丹西酮 ,差异均有显著性 (P <0 .0 1)。而引起便秘不良反应明显少于恩丹西酮 ,差异有显著性 (P <0 .0 1)。引起头痛不良反应与恩丹西酮相仿 ,差异无显著性 (P =0 .4 1)。当甲氧氯普胺的日均剂量小于 2 0mg时 ,未见锥体外系症状发生 ;当日均剂量超过 10 0mg时 ,其锥体外系症状发生率为 17.4 %。结论　甲氧氯普胺治疗恶心、呕吐的疗效较恩丹西酮差 ,但远期疗效比较接近。甲氧氯普胺引起锥体外系症状和腹     

PRESSOR RESPONSES TO SEROTONIN INJECTED INTO THE NUCLEUS TRACTUS SOLITARIUS OF SPRAGUE-DAWLEY RATS AND SPONTANEOUSLY HYPERTENSIVE RATS

Previous studies in rats have shown that injection of nanomoles of serotonin (5-hydroxytryptamine; 5HT) into the nucleus tractus solitarius (NTS) acts on 5HT3 receptors to increase arterial pressure (AP). We investigated the effect of 5HT in Sprague-Dawley (SD) rats and in spontaneously hypertensive rats (SHR). Injection of nanomoles of 5HT into the NTS of chloralose-anesthetized SD rats increased AP. This effect was inhibited by prior injection of 5HT3 receptor antagonist ondansetron. The GABA_A receptor antagonist bicuculline did not inhibit the effect of 5HT. Bilateral injection of 5HT or ondansetron did not affect the baroreflex sensitivity. Bilateral injection of ondansetron did not alter AP. The pressor effect of 5HT was exaggerated in SHR. These results suggest that stimulation of 5HT3 receptors in the NTS increases AP independently of activation of GABAA receptors and the baroreflex sensitivity. Furthermore, this serotonergic system is supersensitive in the NTS of SHR.     

盐酸昂丹司琼口腔崩解片预防胃癌辅助同步放化疗所致恶心呕吐疗效观察

目的：评价盐酸昂丹司琼口腔崩解片预防胃癌辅助同步放化疗致恶心呕吐的疗效和安全性.方法：将接受辅助同步放化疗的52例胃癌患者分为实验组（盐酸昂丹司琼口腔崩解片组,26例）和对照组（甲氧氯普胺组,26例）,观察2组恶心呕吐的发生率、不良反应和生活质量.结果：实验组的总体恶心呕吐的发生率明显低于对照组（46.2％ vs 88.5％,P＜0.05）,其中实验组和对照组3～4级以上恶心呕吐的发生率分别为15.4％和34.6％（P＜0.05）.结论：盐酸昂丹司琼口腔崩解片预防胃癌放化疗所致恶心呕吐疗效确切,安全性良好.     

Non-reversal of scopolamine- or age-related EEG changes by ondansetron,methysergide or alaproclate

The present studies investigates the effects of a 5HT3-antagonist (ondansetron: 0.01, 0.1, 1, 10 µg), a 5HT2-antagonist (methysergide: 2, 10, 20 mg/kg) and a serotonin uptake inhibitor (alaproclate: 2, 10, 20 mg/kg) on the neocortical electrical activity of young scopolamine-treated and aged rats. The scopolamine (0.2 and 0.8 mg/kg)-induced increase in EEG spectral components was not reversed by ondansetron, methysergide or alaproclate. The scopolamine (0.8 mg/kg)-induced EEG amplitude increase reversing potency of a subthreshold dose of the muscarinic agonist pilocarpine (2 mg/kg) was not potentiated by ondansetron, methysergide or alaproclate. A higher dose of pilocarpine (10 mg/kg) reversed scopolamine-induced EEG slowing. Age-related increase in high voltage spindles (HVS) was not alleviated by either ondansetron, methysergide or alaproclate. The HVS activity stabilizing effect of pilocarpine (2 mg/kg) was not enhanced by ondansetron, methysergide or alaproclate. These results suggest that the serotonergic agents investigated could not alleviate cortical cholinergic activation deficit and once again implicate the role of cholinergic system in both the neocortical electrical activation and age-related cortical electrical arousal deficit.     

5-HT3 receptors which modulate [3H]5-HT release in the guinea pig hypothalamus are not autoreceptors

The 5-HT₃ agonist 2-methyl-5-HT had previously been shown to enhance the electrically evoked release of [³H]5-HT from preloaded slices of the guinea pig brain. In the present study, 2-methyl-5-HT (1 μM) was also found to increase the K⁺ evoked release of [³H]5-HT from preloaded slices of the guinea pig hypothalamus and this effect was blocked by the selective 5-HT₃ antagonist ondansetron. In the presence of tetrodotoxin, the enhancement of the K⁺-evoked release of [³H]5-HT by 2-methyl-5-HT in hypothalamus slices was blocked, thus suggesting that the 5-HT₃ receptors mediating this effect are not located directly on 5-HT terminals. In agreement with this, 2-methyl5-HT did not alter the K⁺-evoked release of [³H]5-HT in a synaptosomal preparation of the same brain structure, even at a concentration 10-fold greater than that used in the slices. Taken together, these data indicate that these facilitatory 5-HT₃ receptors are not located on 5-HT terminals in the guinea pig hypothalamus and therefore are not autoreceptors. © 1993 Wiley-Liss, Inc.