Evaluation of acute bis(7)-tacrine treatment on behavioral functions in 17-day-old and 30-day-old mice, with attention to drug toxicity

Bis(7)-tacrine was evaluated for efficacy on memory retention in mice 17 days of age and 30 days of age. The tests used were a passive-avoidance response test and a measure of spontaneous motor activity. Also, possible drug-induced hepatotoxicity and acute drug toxicity were evaluated. Behavioral studies were performed using a step-through task and an open-field test with a 24-h interval between training and evaluation tests. Bis(7)-tacrine (0.06-20 micromol/kg) was subcutaneously injected 30 min prior to the first session of both test types. During the training session of the step-through task, bis(7)-tacrine treatment reduced (by 46%, P<0.01) the number of avoidable electric shocks (footshocks) only at a high dose of 20 micromol/kg in mice 17 days of age, but dose-dependently decreased the number of footshocks (10-56%, P<0.001) in mice 30 days of age. Bis(7)-tacrine treatment at all doses tested did not produce any detectable changes in retention latency in mice 17 days of age, but the drug significantly prolonged retention latency at low doses (1.25 and 2.50 micromol/kg), and not high doses (5-20 micromol/kg), in mice 30 days of age. In the open-field test, bis(7)-tacrine decreased spontaneous motor activity in the acquisition session only at a high dose of 20 micromol/kg in mice 17 days of age and 30 days of age (by 28 and 45%, respectively), but did not affect spontaneous motor activity in the recall session. Bis(7)-tacrine treatment at a dose of 20 micromol/kg produced a more potent hepatotoxic effect in mice 30 days of age than in mice 17 days of age, (P<0.05), and the drug caused acute toxicity with comparable potencies in mice of both age groups. In conclusion, mice 30 days of age seemed to be more sensitive than mice 17 days of age to bis(7)-tacrine-induced cognitive function enhancement and hepatotoxicity. Bis(7)-tacrine appears to be more potent and more selective as a cognitive function-enhancing agent than tacrine.     

莨菪类生物碱对18,28及38日龄小鼠的行为和记忆障碍作用

比较阿托品（Ａｔｒ），东莨菪碱（Ｓｃｏ），樟柳碱（ＡＴ３）和山莨菪碱（Ａｎｉ）对小鼠行为及记忆损伤作用。方法：行为和记忆实验用开阔和回避反应法。脑Ｍ受体用［＾３Ｈ］ＱＮＢ测定。结果：Ａｔｒ，Ｓｃｏ和ＡＴ３增加小鼠走动行为２６％－４２％，降低站忆。４个药物均能妨碍回避反应。小鼠１８日龄额叶皮层和海马［＾３Ｈ］ＱＮＢ结合位点数少于３８日龄７％－２３％。结论：１）莨菪类生物碱对小鼠行为和记忆障碍的作用随     

臭氧对小鼠开阔行为、被动回避反应、脑区M受体和LPO的影响

幼年小鼠吸入臭氧（０．９ＰＰｍ）１２ｈ·ｄ－１连续３０ｄ后体重减轻。并减弱了东莨菪碱（Ｓｃｏｐ）对行为的作用，但增加了小鼠对Ｓｃｏｐ致记忆障碍的敏感性。受体结合实验显示、吸臭氧小鼠的额叶皮层和海马Ｍ受体数增加，纹状体Ｍ受体数减少。全脑过氧化脂质（ＬＰＯ）减少４７％，皮层ＬＰＯ减少４６％。     

Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model

Rationale  

P-glycoprotein (P-gp) plays an important role in the efflux of drugs from the brain back into the bloodstream and can influence the pharmacokinetics and pharmacodynamics of drug molecules. To our knowledge, no studies have reported pharmacodynamic effects of any antidepressant drug in the P-gp knockout mice model.     

Effects of chlordane on conditioned avoidance response, brain seizure threshold and open-field performance of prenatally-treated mice

1. Three groups of six pregnant albino mice at the third stage of gestation were given chlordane 1 or 2.5 mg/kg body weight or olive oil 10 ml/kg. They were dosed orally for seven consecutive days.2. Ten young mice, regardless of sex, were randomly selected from the progeny of each group of treated mothers and tested for conditioned avoidance response, electroshock seizure threshold, and open-field performance.3. Offspring of chlordane-treated mice made fewer conditioned avoidance responses than the controls on each day of training.4. Electroshock seizure threshold was raised.5. In the open-field test, progeny of mothers receiving the larger dose were more active than controls. A dose x days interaction indicated a complex response of the chlordane-treated mice to experience in the open-field.6. The significance of these findings is discussed.     

Influence of clonidine, methyldopa and propranolol on acute toxicity of fenitrothion in mice

The effect of pretreatment with clonidine, methyldopa and propranolol, and of atropine was studied in mice on acute toxicity of fenitrothion, the active ingredient of TIK-20. Atropine significantly decreased and propranolol somewhat decreased the fenitrothion induced death in mice. Clonidine and methyldopa somewhat increased the percentage mortality due to fenitrothion.     

百草枯对小鼠的急性毒性试验

目的 观察百草枯(Paraquat,PQ)对小鼠的急性毒性,计算其半数致死量(LD50).方法 给小鼠灌服不同浓度的PQ溶液,通过观察小鼠的活动和毒性反应,记录小鼠的死亡数,用概率单位法计算LD50.结果 给药后不同时间内,小鼠出现自由活动减少,濒死时呼吸频率加快、张口呼吸、鼻翼扇动等中毒症状,死亡高峰在2 h内,死亡原因为多脏器损伤.♂小鼠LD50=106.99 mg·kg-1,95%可信限范围为97.01～118.03 mg·kg-1;♀小鼠LD50=86.40 mg·kg-1,95%可信限范围74.54～100.14 mg·kg-1.结论 PQ属于中等毒农药,♀小鼠更敏感.     

Evaluation of dimethoate toxicity on pregnancy in albino mice

We investigated whether dimethoate, an organophosphorus insecticide, causes abortion or fetal resorption in pregnant albino mice. Graded doses of 16, 20, 24, and 28 mg/kg body weight/d were administered orally from days 7 to day 15 of pregnancy. Laparotomy was performed on day 8 of pregnancy to note the number of implantations, and the animals were autopsied on day 19. The results revealed no inhibition of pregnancy in all dimethoate treated mice relative to a suitable control group. Treatment with 24 or 28 mg dimethoate caused a significant decrease in the number of implantations, live fetuses, and corpora lutea, but a decreased percent fetal survival and increased percent post-implantation loss and gestation length were not significant when compared with control mice. In all mice treated with 28 mg dimethoate, a significant decrease occurred in the body weight of the ovaries, uterus, and liver when compared with control mice. Following treatment with 16 or 20 mg dimethoate, however, no significant change was found in body and organ weights or in the number of implantations, live fetuses, and corpora lutea, percent post-implantation loss, and fetal survival, or gestation length compared with the corresponding parameters in control mice. The results of this study clearly indicate that dimethoate does not cause abortion or fetal resorption in pregnant mice. A significant decrease in the number of corpora lutea and percent fetal survival observed at higher doses of dimethoate could be due to a toxic effect on the embryo or to a hormonal imbalance.     

Dose- and time-response effects of pantethine on open-field behavior, and on central neurotransmission in rats

In this study the dose- and time-related effects of pantethine on open-field behavior and central neurotransmissions were investigated in rats. Pantethine administered in low doses (0.48-0.96 mM/kg SC) only marginally influenced the activity of the animals, but induced a significant decrease of hypothalamic noradrenaline level without influencing the concentrations of dopamine and DOPAC. Injected in higher doses (1.95-3.90 mM/kg SC), the compound produced a marked depression of both open-field activity and noradrenaline levels, but increased the concentrations of dopamine and DOPAC in the hypothalamus. Twelve hr after the administration of the substance, its effect was attenuated, and 24 hr after the treatment neither the behavioral nor the monoamine parameters differed significantly from the control values. Concerning the somatostatin, pantethine administered in high doses (1.95-3.90 mM/kg SC) decreased the striatal concentration of somatostatin 4 hr after the injection, and this effect was attenuated 24 hr after the treatment. These data suggest that the pantethine-induced behavioral changes are correlated with its effect on central catecholaminergic and somatostatinergic transmission.     

间充质干细胞的毒性作用研究

目的 研究间充质干细胞对小鼠的急性毒性作用, 初步探讨其毒性反应, 为间充质干细胞在临床上安全使用提供指导。方法 选用ICR小鼠, 根据预试结果, 实验分为3组:对照组和间充质干细胞高、低剂量组, 每组分别采用20只实验动物, 雌雄各半, 分别观察小鼠对间充质干细胞的反应。结果 实验期间, 各给药组小鼠各检查时间点平均体质量与对照组比较均无明显差异, 且小鼠被毛光泽, 精神状态和自主活动均正常, 分泌物和排泄物等均未见明显异常。表明间充质干细胞制剂静脉给药对小鼠体质量增长无明显影响。与对照组比较, 间充质干细胞低、高剂量组雄性小鼠脾、肺质量及系数明显升高, 高剂量组雌性大鼠肺脏系数明显升高。结论 间充质干细胞制剂无明显的毒副作用, 且在肺脏和脾脏等部位滞留。     

颅痛川芎胶囊小鼠急性毒性试验

目的观察颅痛川芎胶囊的急性毒性反应,为临床安全使用提供依据。方法采用灌胃给药,连续观察14 d,记录小鼠的急性毒性反应及死亡动物数量,从而计算半数致死量(LD50)。结果 LD50未测出,小鼠日最大给药量为16.0 g·kg-1·d-1,相当于成人日剂量的256倍。结论颅痛川芎胶囊无明显急性毒性反应。     

阿司咪唑对小鼠心脏的急性毒性研究

目的通过观察小鼠心电图的变化,研究阿司咪唑对心脏的急性毒性,了解其致心律失常的类型,推测其致心律失常的机制.方法用不同剂量的阿司咪唑对小鼠灌胃,分别记录不同时间的心电图变化.结果阿司咪唑使多数小鼠心率减慢,P-R间期和Q-T间期延长,随剂量增加,甚至可引起完全性房室传导阻滞和窦性停搏.少数情况也会出现窦性、室性心动过速等快速性心律失常.结论阿司咪唑可引起小鼠多型性心律失常,其中以缓慢性心律失常为主,并呈剂量依赖性.     

2-甲氧基雌二醇对小鼠急性毒性研究

目的:观察2-甲氧基雌二醇(2-methoxyestradiol,2-ME)灌胃给药的小鼠急性毒性反应。方法:经预试确定按最大给药量法设计试验,小鼠40只,♀♂各半,随机分为给药组和阴性对照组,给药组以2-ME2 000 mg.kg-1为最大给药剂量,40mL.kg-1为最大给药容量,在24 h内一次灌胃,阴性对照组以等容积的纯化水一次灌胃,给药后自由饮食饮水,连续2周观察小鼠体质量、行为活动以及死亡情况。结果:给药组小鼠观察期间内体质量及行为活动异常无变化,未见死亡。结论:2-ME灌胃给药对小鼠急性毒性甚低,提示该药为低毒化学物。     

铁叶绿酸钠对小鼠行为发育毒性的实验研究

铁叶绿酸钠为叶绿素衍生物,研究表明铁叶绿酸钠治疗妊娠期缺铁性贫血,疗效显著。由于妊娠期用药可能对子代产生行为发育毒性,因此本文重点针对铁叶绿酸钠在动物围产期用药后,可能对子代动物的神经行为发育产生的毒性进行了测试,试验结果表明在高、中、低三种剂量下其对子代小鼠无明显行为发育毒性。     

Cadmium-induced suppression of the primary immune response and acute toxicity in mice: differential interaction of zinc

Four groups of 6-week-old C3H mice were injected sc with either sterile saline, 2.8 mg Cd/kg body weight, 2.8 mg Zn/kg body weight, or 2.8 mg each of Cd and Zn/kg body weight. Forty-eight hours after the initial injection, all mice received a second dose of their respective treatments plus an iv injection of sheep red blood cells. On Days 2, 3, 4, and 5 postimmunization the mice were killed. Spleen cells were used in a hemolytic plaque-forming assay for the quantitation of the primary humoral response. Although the combined administration of zinc and cadmium completely prevented the fatal effects of the cadmium (0 vs 55% mortality), zinc failed to alleviate the cadmium-induced inhibition of the humoral response.     

Effects of irreversible dopamine receptor inactivation on locomotor activity and grooming in the 17- and 90-day-old rat

Ontogenetic differences in the behavioral recovery of R(-)-propylnorapomorphine (NPA) treated rats were assessed following irreversible DA receptor antagonism by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). In the first two experiments, 17-and 90-day-old rats were given EEDQ (7.5 or 15.0 mg/kg, IP) or vehicle after half the rats were initially treated with the selective DA D-1 and D-2 antagonists SCH 23390 and sulpiride. (The sulpiride/SCH 23390 treatment protects DA receptors from EEDQ-induced inactivation.) NPA's (0.1 or 1.0 mg/kg) effects on locomotor activity and grooming were assessed 1, 2, 4 and 8 days after the EEDQ pretreatment. In a third experiment, the effects of habituating the 17- and 90-day-old rats to the testing chamber were assessed 1, 2 and 4 days after EEDQ pretreatment. In this experiment, some groups received successive treatments of saline or NPA prior to behavioral testing. To assess the possible effects of drug-sensitization other groups received saline on days 1 and 2 and NPA on day 4. In 90-day-old rats, EEDQ eliminated, for up to 4 days, the ability of NPA to enhance locomotor activity and depress grooming. Prior treatment with DA antagonist drugs was sufficient to protect DA receptors from EEDQ-induced inactivation, since these groups exhibited normal behavioral responses after challenge with NPA. In contrast, EEDQ did not eliminate, and may have enhanced, NPA's effects on the locomotor activity and grooming of 17-day-old rat pups. Habituating the rats to the testing chamber decreased the locomotor activity of the mature rats, but not the 17-day-old rat pups. Drug sensitization did affect locomotor activity, but could not account for the behavioral recovery exhibited by the mature rats and pups. These results indicate that the behavioral effects of EEDQ differ dramatically in young rats compared to adults. The neurochemical bases for these ontogenetic differences remain unknown.     

Effects of 5-hydroxytryptamine on defecation in open-field behavior in rats

An attempt was made to elucidate the role of the serotonergic nervous sytem in defecation resulting from environmental stimulation in rats. The open-field (OF) test and shuttle box method were used to study the defecation. 5-Hydroxytryptophan (5-HTP) significantly decreased the number of fecal boluses excreted in both emotional situations, namely, in both OF and shuttle box. The fecal excretion was significantly reduced compared with the controls after intraventricular injection of 5-hydroxytryptamine (5-HT). Animals pretreated with p-chlorophenylalanine (pCPA) and 5,6-dihydroxytryptamine (5,6-DHT) tended to show a slight increase in the OF defecation. 5-HTP was equally effective in diminishing the OF performance of pCPA-treated rats. The inhibitory effects of 5-HTP on the defecation were also observed after depletion of biogenic amines by reserpine treatment. Home cage defecation was increased after 5-HTP administration, decreased under pretreatment with pCPA and not influenced by intraventricular injection of 5-HTP. These results suggested that the defecation after environmental stimuli was due to a change in 5-HT levels in the brain.     

羟丙基甲基纤维素邻苯二甲酸酯的小鼠急性口服毒性试验

目的探讨小鼠口服羟丙基甲基纤维素邻苯二甲酸酯的急性毒性。方法小鼠一日内连续3次灌胃给予羟丙基甲基纤维素邻苯二甲酸酯,观察和记录小鼠的行为、摄食量、体重、呼吸频率和死亡情况,连续观察14d。未死亡小鼠处死后行尸检。结果在日剂量为15g·kg^-1剂量下,小鼠的行为活动无异常,摄食量与对照组相比无明显差异,呼吸频率无改变,仅体重增加比对照组略有下降（P〉0．05）,主要脏器无明显病理改变,观察期内无小鼠死亡。结论羟丙基甲基纤维素邻苯二甲酸酯毒性极低,作为包衣材料安全性高。     

Studies on the mechanism of acute toxicity of nitriles in mice

Acute toxicity and metabolism of 21 nitriles in mice were studied in relation to their chemical structures. All the test nitriles liberated cyanide ions both in vivo and in vitro, with the exception of benzonitrile, although the extent of liberation and the effect of carbon tetrachloride (CCl₄) pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into three groups. In group 1 (13 compounds), acute toxicity was greatly reduced by CCl₄ pretreatment, in group 2 (seven compounds), toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher (0.68–0.80 g CN/g brain) at death in the brains of mice given group-1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. After oral doses of each nitrile, the time course for cyanide levels in the liver varied among the compounds. The difference between group-1 and -2 compounds lay in the dose-cyanide liberation relationship in liver, and in the kinetics for cyanide liberation in the hepatic microsomal enzyme system. Double-reciprocal plots of enzyme activity showed a linear relationship for nitriles of group 1 and a non-linear one for group 2. The relationship between log (1/LD₅₀) and log P for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear.