Targeted to medication-induced dyskinesia and tardive dyskinesia:A role of 5-HT_(1A) receptor

Objective To outline the recent progress in drug discovery for medication-induced dyskinesia(Parkinson disease,PD)and tardive diskinesia(schizophrenia)with emphasizing the role of 5-HT1A receptor.Methods Development of extrapyramidal syndrome(EPS)followed either chronic L-DOPA administration in PD(L-DOPA-induced dyskinesia,LID)or antipsychotic treatment in schizophrenia(Tardive dyskinesia,TD)remains a challenge in the clinical practice and drug discovery.In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD,recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD.Results l-Stepholidine(l-SPD),isolated from the Chinese herb Stephania,is known as a dual dopamine receptor agent(D1 receptor agonistic and D2 antagonistic activity).In addition,we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity.In LID rat model,l-SPD not only attenuated the development of L-DOPA-induced dyskinesia(LID),but also relived the established LID.The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist,indicating the role of 5-HT1A receptor.Furthermore,we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135,which also exhibits a significant relief on LID while elicits its antiparkinsonian action.Conclusions 5-HT1A receptor plys an important role in the development of LID,targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.     

(-)-Stepholodine induced enhancement of cardiac muscle contractions mediated by D1 receptors

Objective To investigate the effect of(-)-Stepholidine(SPD)on enhancing D1 receptor mediated contraction of cardiac muscle in isolated rat heart and to examine whether SPD has a direct effect on the heart dopamine D1 receptors.SPD an active ingredient of the Chinese herb Stephania intermedia,binds to dopamine D1 and D2 like receptors.Biochemical,electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D(1/5)agonist and a D(2/4)antagonist,which could indicate unique antipsychotic properties.Methods Normal adult rat working hearts were isolated by Langendorff technique.Results SPD significantly increased the cardiac muscle contraction in a dose-dependent manner.The selective D1 dopamine receptor antagonist SCH23390(1 μM)blocked the SPD induced heart contraction,however,neither the β-receptor antagonist propranolol(1 μM)nor the α1-receptor antagonist prazosin(1 μM)had any effect on blocking SPD induced heart contractions.Moreover,the L-type Ca2+ channel inhibitor nimodipine(1 μM)completely blocked the effect of SPD on cardiac muscle contraction.Conclusions SPD show the effect on enhancing contraction of isolated rat heart through activating L-type Ca2+ channel mediated by heart D1 receptors.     

Dopamine D2 receptors involved in Peony-Glycyrrhiza Decoction,an herbal preparation against antipsychotic-associated hyperprolactinemia

Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction(PGD) in alleviating antipsychotic-induced hyperprolactinemia(hyperPRL).In the present study,we further examined the pharmacological action of PGD on hyperPRL in in vitro and in vivo models,and associations with dopamine D2 receptors.Treatment with PGD at 1-5 g·L-1 significantly suppressed prolactin(PRL) secretion and synthesis in MMQ cells,a model of hyperPRL derived from pituitary adenoma cells.The suppressive effects were completely abolished by pretreatment with 10 μmol·L-1 haloperidol,a dopamine D2 receptor antagonist.Consistent with a D2-action,PGD did not affect PRL in rat pituitary somatolactotropic tumor-derived GH3 cells that lack the D2 receptor expression.In a rat model of hyper PRL,produced by repeated injection of metoclopramide(MCP),another dopamine D2 receptor antagonist,chronic PGD(2.5-10 g·kg-1 daily) significantly reduced elevated serum PRL.The reduction in magnitude was similar to that elicited by bromocriptine(BMT),a potent dopamine D2 receptor agonist currently used for treatment of hyperPRL.Neither PGD nor BMT altered serum estradiol,but PGD reversed decreased serum progesterone to control level,whereas BMT did not.These results indicate that the anti-hyperPRL effects of PGD are associated with the modulation of D2 receptors.The present study provides experimental evidence in support of clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL.     

Neuroprotection of putative PI-linked D1 dopamine receptor agonist SKF83959 is associated with its attenuation on L-DOPA-induced dyskinesia.

SKF83959 is recently identified as a selective agonist for putative phosphoinositide-linked （PI-linked） D1 dopamine receptor （D1DR） and is found to elicit excellent anti-parkinsonism effects in monkeys and rodents We further demonstrated that chronic administration of SKF83959 significantly attenuated L-DOPA-induced dyskinesias （LID） in a unilateral 6-hydroxydopamine （6-OHDA） lesioned rat model of Parkinson＇s disease （PD） . Although delta FosB was reported to involve in the development of dyskinesias in a few studies, SKF83959-mediated attenuation of LID is independent of the delta FosB expression. In an effort to elucidate the signaling mechanism for the anti-dyskinesia effect of PI-linked receptor.[第一段]     

Role of hypothalamus nociceptin/orphanin FQ in pre-ovulatory luteinizing hormone surge of estrogen and progesterone-primed, ovariectomized rats

Aim： To investigate the role of hypothalamus nociceptin/orphanin FQ （OFQ） and its endogenous receptor, the opioid receptor-likel receptor （ORL1 receptor） in the estrus cycle of female rats. Method： Radioimmunoassay was used to detect the effect of the intracerebroventricular （icv） administration of OFQ and/or the ORL 1 receptor antagonist [Nphe^1]Nociceptin（1-13）NH2, that is, NC13 on luteinizing hormone （LH） levels of estrogen- and progesterone （EBP）-primed, ovariectomized （OVX） rats （EBP-primed OVX rats）. RT-PCR, Western blotting, and immunohis-tochemistry techniques were adopted to observe the changes of OFQ and the ORL 1 receptor in the pre-optic area （POA） and the medial basal hypothalamus （MBH） of the estrus cycle of female rat. Results： Pre-ovulatory LH surges in EBP- primed, OVX rats were significantly reduced by icv administration of 20 and 200 nmol OFQ （P〈0.05）, and the effect of 20 nmol OFQ could be abolished by pretreatment with 20 nmol NC 13. The OFQ mRNA level in the POA on pro-estrus was lowered markedly compared to diestrus and estrus （P〈0.05）, while the mRNA and protein levels of the ORL1 receptor showed no significant changes in the POA and MBH across the estrus cycle. Meanwhile, the number of OFQ-immunoreactive neurons in the medial POA, ventromedial hypothalamus, and the arcuate nucleus on pro-estrus was significantly decreased compared to diestrus and estrus （P〈0.05）. Conclusion： The inhibitory effect of OFQ on the LH surge of EBP- primed, OVX rats and its downregulation in POA and MBH on pro-estrus suggests that it might play a negative modulatory role in the estrus cycle.     

5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes

The effect of the selective r5-HT_1B agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo [3,2-b] pyril-5-one (CP93,129) on the K⁺-evoked overflow of [³H]dopamine was studied in rat striatal synaptosomes loaded with [³H]dopamine. The aim of the study was to investigate the participation of 5-HT_1B receptors in the serotonergic modulation of striatal dopaminergic transmission. The Ca²⁺-dependent, tetrodotoxin-resistant K⁺-evoked overflow of [³H]dopamine was inhibited by CP93,129 (0.01–100 μM) in a concentration-dependent manner (IC₅₀=1.8 μM; maximal inhibition by 35.5% of control). [±]8-OH-DPAT, a 5-HT_1A receptor agonist, [+/–]DOI, a 5-HT₂ receptor agonist, and 2-methyl-5-hydroxytryptamine, a 5-HT₃ receptor agonist, at concentrations ranging from 0.01 μM to 100 μM did not show any significant effect. Neither ketanserin (1 μM and 5 μM), a selective 5-HT₂/5-HT_1D receptor antagonist, nor ondansetron (1 μM), a 5-HT₃ receptor antagonist, changed the inhibitory effect of CP93,129. SB224289, GR55562, GR127935, isamoltane and metergoline, selective and non-selective 5-HT_1B receptor antagonists, in contrast, used at a concentration of 1 μM, antagonized the inhibitory effect of CP93,129 (3 μM and 10 μM). SB224289, a selective 5-HT_1B receptor antagonist, inhibited the effect of CP93,129 in a concentration-dependent manner; the calculated K _i value was 1.8 nM. Our results indicate that in rat striatal axon terminals the K⁺-evoked release of dopamine is regulated by the presynaptic 5-HT_1B heteroreceptors. Received: 7 September 1998 / Accepted: 2 November 1998     

Impulse activity of midbrain dopamine neurons modulates drug-seeking behavior

Rationale Withdrawal from non-contingent exposure to psychostimulants increases the activity of midbrain dopamine cells and impairs the function of impulse-regulating dopamine autoreceptors. It is unclear whether these neuroadaptations play an important role in withdrawal-associated drug seeking. Objectives We determined whether cocaine self-administration modifies the impulse activity of midbrain dopamine neurons and dopamine autoreceptor function, and whether experimentally induced reduction in dopamine cell activity (by autoreceptor activation) could influence drug-seeking behavior. Methods Animals were trained to self-administer saline or cocaine (500 μg/kg per infusion) for 7 days. At different withdrawal periods, we used single-unit extracellular recordings to measure impulse activity of dopamine cells and administered the D2/D3 dopamine receptor agonist quinpirole to determine autoreceptor sensitivity. In a separate set of experiments, we determined the effects of autoreceptor-selective doses of quinpirole on drug-seeking behavior (non-reinforced responding in the absence of cocaine) during an extinction/reinstatement task. Results Cocaine self-administration induced a short-lived increase in the mean firing rate and bursting activity of midbrain dopamine cells. This effect was greatest at early withdrawal and was paralleled by decreased ability of quinpirole to inhibit dopamine cell firing rate and drug-seeking behavior. Changes in dopamine cell activity dissipated over time; at late withdrawal, when both impulse activity and autoreceptor sensitivity returned to control values, quinpirole dramatically decreased drug-seeking behavior. Conclusions These results show that inhibiting dopamine cell impulse activity, by activation of dopamine autoreceptors, reduces drug-seeking behavior. This suggests that the impulse activity of midbrain dopamine cells could be an important factor contributing to relapse. An erratum to this article can be found at     

Potent, stereoselective, and brain region selective modulation of second messengers in the rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist

LY354740 is a highly potent and selective agonist for recombinant Group II mGlu receptors (mGlu2 and mGlu3), which has anxiolytic and drug withdrawal alleviating properties when administered systemically in rats and mice. The modulation of second messengers by LY354740 in rat brain tissues was investigated to understand the cellular basis for the pharmacological and potential therapeutic actions of LY354740. LY354740 potently decreased forskolin-stimulated cAMP formation in slices of the adult rat hippocampus (EC₅₀=22±3 nM) in a stereoselective manner. LY354740 (at 1 μM) greatly (>90%) suppressed forskolin-stimulated cAMP in the cerebral cortex, hippocampus, and striatum, while producing only partial suppression (about 50%) in midbrain regions and olfactory bulb, and no significant cAMP alterations in the cerebellum and brainstem regions. Inhibition of forskolin-stimulated cAMP formation was antagonized by (+)-α-methyl-4-carboxyphenylglycine [(+)MCPG], a competitive mGlu receptor antagonist. LY354740 did not alter phosphoinositide hydrolysis in the rat hippocampus per se, but potentiated stimulation of phophoinositide hydrolysis by the Group I mGlu receptor selective agonist 3,5-dihydroxyphenylglycine (DHPG) or stimulation of cAMP formation by the adenosine receptor agonist 5’-N-ethylcarboxamideoadenosine (NECA). These data indicate that LY354740 is a highly potent, efficacious, and selective Group II mGlu receptor (mGlu 2/3) agonist in the rat brain. The potent, stereoselective, and brain region selective actions of LY354740 on mGlu receptor linked second messenger systems likely underlie the in vivo potency and stereoselectivity of this compound in animal models. Received: 25 February 1998 / Accepted: 18 April 1998     

Studies on the antinociception effect of melatonin and its mechanism in the rat

The antinociception effect of melatonin（Mel） and its mechanisms were studied on the trauma- pain model in the rat. A trauma - pain model was established in Wistar rats by combining right - hind limb amputation with 50℃ tail - flick test. The effects of Mel on central sensitization were studied through measuring the changes of the expression of c - fos （ an indicator of nociceptive transmission at the spinal level ） , subtance P（SP） and brain - derived neurotrophic factor （BDNF） in the spinal cord using immunohistochemistry. In addition, the contents of nitric oxide （NO） in brain and spinal tissues were also observed. The results showed that the immunoreactivity of BDNF and c - fos in spinal dorsal horn in injuried rats began to increase at the first day,     

Alteration of airway responsiveness mediated by receptors in ovalbumin-induced asthmatic E3 rats

Aim： Airway hyperresponsiveness is a constant feature of asthma. The aim of the present study was to investigate airway hyperreactivity mediated by contractile and dilative receptors in an ovalbumin （OVA）-induced model of rat asthma.
Methods： Asthmatic E3 rats were prepared by intraperitoneal injection with OVA/aluminum hydroxide and then challenged with intranasal instillation of OVA-PBS two weeks later. The myograph method was used to measure the responses of constriction and dilatation in the trachea, main bronchi and lobar bronchi.
Results： In asthmatic E3 rats, 132 adrenoceptor-mediated relaxation of airway smooth muscle pre-contracted with 5-HT was inhibited, and there were no obvious difference in relaxation compared with normal E3 rats. Contraction of lobar bronchi mediated by 5-HT and sarafotoxin 6c was more potent than in the trachea or main bronchi. Airway contractions mediated by the endothelin （ET）A receptor, ETB receptor and M3 muscarinic receptor were augmented, and the augmented contraction was most obvious in lobar bronchi. The order of efficacy of contraction for lobar bronchi induced by agonists was ET-1, sarafotoxin 6c〉ACh〉5-HT. OX8 （an antibody against CD8^＋ T cells） strongly shifted and OX35 （an antibody against CD4^＋ T cells） modestly shifted isoprenaline-induced concentration-relaxation curves in a nonparallel fashion to the left with an increased Rmax in asthmatic rats and sarafotoxin 6c-induced concentration-contractile curves to the right with a decreased Emax.
Conclusion： The inhibition of airway relaxation and the augmentation of contraction mediated by receptors contribute to airway hyperresponsiveness and involve CD8^＋ and CD4^＋ T cells.     

姜辣素在2种呕吐动物模型中止呕作用机制的探讨

目的开发姜的止呕制剂,弥补临床上5-羟色胺Ⅲ亚型受体(5-hydroxytryptamine-3 receptor,5-HT3)及神经激肽Ⅰ亚型受体(neurokinin-1 receptor,NK1)拮抗剂靶点单一、价格昂贵、毒性及不良反应大等缺点。方法用特异性5-HT3受体激动剂1-phenylbiguanide hydrochloride(PBG)和多巴胺受体激动剂阿朴吗啡(apomorphine)建立新型水貂呕吐模型和经典大鼠异嗜模型,观察姜辣素对水貂呕吐行为和大鼠异嗜高岭土行为的抑制作用。结果姜辣素对水貂呕吐行为和大鼠异嗜高岭土行为均表现出显著的抑制作用(P<0.05),并呈现一定的量效关系。结论姜辣素有止呕作用,其止呕机制可能涉及到5-羟色胺和多巴胺受体系统;姜辣素在研究天然多靶点新型止呕药方面具有潜在的应用价值。     

Gingerol inhibits cisplatin-induced acute and delayed emesis in rats and minks by regulating the central and peripheral 5-HT,SP, and DA systems

Gingerol, a biologically active component in ginger, has shown antiemetic properties. Our study aimed to explore the underlying mechanisms of gingerol on protecting rats and minks from chemotherapy-induced nausea and vomiting. The preventive impact of gingerol was evaluated in the pica model of rats and the vomiting model of minks induced by cisplatin at every 6 h continuously for a duration of 72 h. Animals were arbitrarily separated into blank control group, simple gingerol control group, cisplatin control group, cisplatin + metoclopramide group, cisplatin + three different doses gingerol group (low-dose; middle-dose; high-dose). The area postrema as well as ileum damage were assessed using H&E stain. The levels of 5-TH, 5-HT3 receptor, TPH, SERT, SP, NK1 receptor, PPT, NEP, DA, D2R, TH, and DAT were determined using immunohistochemistry or qRT-PCR in rats and minks. All indicators were measured in the area postrema along with ileum. The kaolin intake by rats and the incidence of CINV of minks were significantly decreased after pretreatment with gingerol in a dosage-dependent way for the duration of 0–24-h and 24–72-h. Gingerol markedly decreased the levels of 5-TH, 5-HT3 receptor, TPH, SP, NK1 receptor, PPT, DA, D2R, TH, alleviated area postrema as well as ileum damage, and increased the accumulation of SERT, NEP, DAT in the area postrema along with ileum of rats and minks. Gingerol alleviates cisplatin-induced kaolin intake of rats and emesis of minks possibly by regulating central and peripheral 5-HT system, SP system and DA system.     

辣椒的止呕作用研究

目的:研究辣椒的止呕作用及其机制。方法:复制新型水貂呕吐模型,观察辣椒(主要成分辣椒素)对顺铂、阿朴吗啡导致的水貂呕吐行为的抑制作用,并通过免疫组化法和特异性5-羟色胺3(5-HT3)受体激动药盐酸苯甲双胍(PBG)的应用,对其机制进行初步探讨。结果:辣椒对顺铂、阿朴吗啡引起的水貂的呕吐行为有抑制作用(P<0.05);对PBG导致的水貂的呕吐行为有抑制作用(P<0.05);对水貂胃窦组织P物质的释放有抑制作用。结论:辣椒在新型水貂呕吐模型上表现出止呕作用,其机制可能与外周组织5-HT、P物质的释放及其相应受体有关。     

Gingerol inhibits cisplatin-induced vomiting by down regulating 5-hydroxytryptamine,dopamine and substance P expression in minks

Objective  To investigate the antiemetic effect of gingerol and its multi-targets effective mechanism on 5-hydroxytryptamine (5-HT), dopamine (DA) and substance P (SP). The antiemetic effect of gingerol was investigated on a vomiting model of mink induced by cisplatin (7.5 mg · kg⁻¹, i.p.) in 6 h observation. The levels of 5-HT, DA and distribution of substance P in the area postrema and ileum were measured by high performance liquid chromatography (HPLC) and immunohistochemistry respectively. The frequency of cisplatin induced retching and vomiting was significantly reduced by pretreatment with gingerol in a dose-dependent manner (P<0.05). Cisplatin produced a significant increase in 5-HT and DA levels in the area postrema and ileum of minks (P<0.05), and this increase was significantly inhibited by gingerol in a dose-dependent manner (P<0.05). Substance P-immunoreactive was mainly situated in the mucosa and submucosa of ileum as well as in the neurons of area postrema, and gingerol markedly suppressed the increase immunoreactivity of substance P induced by cisplatin in a dose-dependent manner (P<0.05). Gingerol has good activity against cisplatin-induced emesis in minks possibly by inhibiting central or peripheral increase of 5-HT, DA and substance P.     

姜辣素对顺铂致大鼠异嗜模型行为的作用

目的研究姜辣素对顺铂所致大鼠异嗜高岭土模型的影响并观察外周和中枢c-fos蛋白的表达。方法大鼠随机分成正常对照组、模型组、昂丹司琼+地塞米松组、阿瑞吡坦+地塞米松组、姜辣素组及姜辣素+地塞米松组,24 h及72 h记录各组摄食量及食高岭土量。免疫组化方法观察脑和回肠中c-fos蛋白的表达。结果 24 h内,姜辣素组、姜辣素+地塞米松组摄食量增加,啃食高岭土量减少,姜辣素组与姜辣素+地塞米松组相比摄食量增加(P<0.05);48～72h内,姜辣素组食高岭土量减少(P<0.05)。姜辣素组、姜辣素+地塞米松组c-fos阳性表达颗粒的灰度值明显高于模型组(P<0.05)。结论姜辣素可促进摄食并可抑制顺铂所致的大鼠异嗜高岭土行为,地塞米松对姜辣素无辅助作用。     

生姜的丙酮提取物对大鼠异嗜高岭土模型的止呕作用

目的研究生姜丙酮提取物(EG)对大鼠的止呕作用。方法大鼠分别给予不同剂量的顺铂、阿朴吗啡及接受旋转刺激,建立大鼠异嗜高岭土的3种呕吐模型。观察EG预防给药对3种模型大鼠的止呕作用。结果顺铂(3mg/kg,ip)、阿朴吗啡(3.2mg/kg,sc)以及旋转刺激(100 r/min,1h)均能引起大鼠的异嗜行为,可作为建立大鼠异嗜高岭土模型的最适剂量。EG600、300、150mg/kg三个剂量组可抑制顺铂、阿朴吗啡、旋转所致的大鼠异嗜高岭土的量(P<0.05 P<0.01),并呈现一定的量效关系。结论EG在大鼠异嗜呕吐模型上具有止呕作用,其机制可能与P物质、5-HT及抑制呕吐中枢有关。     

Anti-emetic mechanisms of Xiaobanxia Tang decoction on the chemotherapy-induced pica model in rats

OBJECTIVE To investigate the mechanisms of Xiaobanxia Tang(XBXT)in the prevention and treatment of chemotherapy-induced nausea and vomiting.METHODS The chemotherapy-induced rat pica model was established by intraperitoneal injection of cisplatin 6mg·kg-1.Kaolin consumption was used as an indicator of nausea and vomiting.Wistar male rats were randomly divided into normal control,XBXT normal control,model,ondansetron treating,XBXT decoction high and low dose groups.The rats in ondansetron group,XBXT normal control group,XBXT high and low dose groups were gavaged ondansetron 2.6mg·kg-1·d-1,XBXT 1.6,3.2and 1.6g·kg-1·d-1,respectively 1hbefore cisplatin injection,and the administration were given every 12 h.Kaolin consumptions were weighed every 12 h.After 24 hand 72hof cisplatin injection,animals were sacrificed respectively.The contents of 5-HT,5-HIAA,dopamine(DA),DOPAC,substance P(SP),TPH,MAO and TH were measured by ELISA.The mRNA expression of 5-HT transporter(SERT),5-HT3 Areceptor,SP precursor(PPTA),NK1 and D2receptors in rat ileum and medulla oblongata were measured by RT-PCR,the protein expression were measured by Western blotting.RESULTS The high and low dosages of XBXT could significantly inhibit kaolin consumptions in cisplatin-treated rats,and reduce5-HT,increase 5-HIAA contents and reduce 5-HT3 Areceptor mRNA and protein expression,above effects are related to the reduction of TPH and the enhancement of MAOA levels.The two dosages of XBXT could significantly reduce SP and NK1 mRNA and protein expression,which was related to the reduction of PPTA mRNA expression.XBXT could also significantly reduce DA contents and D2 receptor mRNA and protein expression,which was related to the reduction of TH.CONCLUSION XBXT has significant antiemetic effect in chemotherapy-induced nausea and vomiting,the underlying mechanisms are related to the inhibition of 5-HT and5-HT3 Areceptor,SP and NK1 receptor,DA and D2 receptor.     

Pharmacological characterization of cyclosporine A-induced kaolin intake in rats.

Kaolin intake behavior of rats is known to be one of the useful animal models to evaluate the emetic and antiemetic actions of drugs. The present study was aimed at elucidating the pharmacological characterization of cyclosporine A (CsA)-induced kaolin intake in rats. Subchronic treatment (once a day for 3 days) with CsA produced a dose- and time-dependent increase in kaolin intake. Scopolamine (muscarinic antagonist), mepyramine (selective histamine H(1) antagonist) and diphenhydramine (H(1) and muscarinic antagonist) but neither domperidone (dopamine D(2) antagonist) nor ondansetron (serotonin 5-HT(3) antagonist) significantly inhibited CsA-induced kaolin intake. These findings suggest that an activation of central muscarinic and H(1) receptor is closely associated with CsA-induced kaolin intake in rats. Use of scopolamine and/or diphenhydramine may be possible regimens to alleviate and avoid nausea and vomiting in patients with CsA therapy.     

Pica in mice as a new model for the study of emesis

In general, rats and mice have not been used in research on emesis because they do not vomit. However, emetogenic stimuli such as anticancer drugs, apomorphine, copper sulfate and rotation induced pica, a behavior characterized by eating nonfood substances such as kaolin, in rats. We also found that cisplatin induced pica in mice, but it was rather difficult to determine the exact kaolin consumption in this species. In this study, we prepared kaolin pellets mixed with carmine, a dye not absorbed in the gastrointestinal tract, and estimated kaolin consumption by determination of carmine excreted in feces. Cisplatin (5 mg/kg) caused a significant increase in kaolin consumption (saline: 0.15 +/- 0.08 g vs. cisplatin: 0.45 +/- 0.16 g) and pretreatment with the 5-HT3 receptor antagonist, ondansetron (2 mg/kg), suppressed the increased consumption (vehicle: 0.33 +/- 0.05 g vs. ondansetron: 0.13 +/- 0.04 g). These findings suggested that the exact kaolin consumption could be quantified by the determination of carmine in feces and that mice could be useful for studying emesis.     

Cisplatin-induced pica behaviour in rats is prevented by antioxidants with antiemetic activity

Pica, eating of non-nutritive substances such as kaolin in rats has been suggested as an illness response behaviour, analogous to vomiting in species that have developed emetic reflex. We have recently demonstrated that antioxidants-glutathione, N-(2- mercaptopropionyl)glycine (tiopronin), vitamin C and vitamin E-exert antiemetic effect against cisplatin-induced emesis in dogs. In the present study, the effect of these antioxidants was investigated against pica model in rats. Pretreatment with these agents significantly inhibited the cisplatin induced enhanced kaolin intake. However, these agents failed to exert any significant improvement in the decreased food intake by cisplatin. The findings confirm the potential of these antioxidants as antiemetics against cancer chemotherapy induced vomiting, though they may not improve the anorexia. The experiments further support that pica in rats can be used as a good alternative rodent model to dogs and cats particularly for preliminary and rapid screening of antiemetic agents.