氯硝西泮抗点燃惊厥大鼠耐受性及依赖性机制

本工作以点燃惊厥大鼠为模型，观察给予氯硝西泮１ｗｋ及４ｗｋ后，其对点燃惊厥大鼠的抗惊作用及抗惊耐受性，并观察了耐受大鼠撤药１ｗｋ后行为改变。同时通过对大鼠脑组织ＧＡＢＡＡ－受体的检测，对其抗惊作用耐受性及依赖性机制进行了研究。结果显示：氯硝西泮对点燃惊厥大鼠有明显的抗惊作用，但长期应用可产生抗惊作用的耐受性，表现为惊厥等级的升高。撤药１ｗｋ后，惊厥等级明显升高，惊厥潜伏期明显缩短。模型大鼠的溶剂对照组较正常Ｗｉｓｔａｒ大鼠的ＧＡＢＡＡ－受体的Ｂｍａｘ值明显降低，而给予氯硝西泮可明显增加Ｂｍａｘ。但长期给予则Ｂｍａｘ降低，撤药１ｗｋ后Ｂｍａｘ又明显增加。提示：氯硝西泮抗点燃惊厥大鼠耐受性与ＧＡＢＡＡ－受体下调有关，而依赖性则与ＧＡＢＡＡ一受体上调有关。     

氯硝西泮抗点燃惊厥大鼠耐受性及依赖性机制

本工作以点燃惊厥大鼠为模型，观察给予氯硝西泮１ｗｋ及４ｗｋ后，其对点燃惊厥大鼠的抗惊作用及抗惊耐受性，并观察了耐受大鼠撤药１ｗｋ后行为改变。同时通过大对鼠脑组织ＧＡＢＡＡ－受体的检测。对其抗惊作用耐受性及依赖性机制进行了研究，结果显示，氯硝西泮对点燃惊厥大鼠有明显的抗惊作用，但长期应用可产生抗惊作用的耐受性，表明为惊厥等级的升高。撤药１ｗｋ后，惊厥等级明显升高，惊厥潜伏期明显缩短，模型大鼠的溶剂对     

氯巴占耐受听源性惊厥大鼠脑GABAA受体亚单位表达的变化

目的：探讨氯巴占耐受听源性惊厥大鼠中枢GABAA受体亚单位表达的变化和这种改变与氯巴占耐受性机制关系。方法：腹腔注射氯巴占2wk，产生听源性惊厥大鼠氯巴占耐受模型，用竞争性定量RT－PCR测定大鼠脑皮质运动区和海马区的GABAA受体α1,α3，α5，γ2L和γ2S亚单位mRNA的含量。结果：氯巴占耐受组大鼠皮质运动区α1亚单位下降27％，α5上升73％，γ2L下降43％，γ2S下降37％；海马区的α1下降28％，γ2L下降32％，γ2S下降31％，与对照组相比差异均有显著性。结论：听源性惊厥大鼠的氯巴占耐受机制与中枢GABAA受体α1，α5，γ2L和γ2S亚单位表达的适应性改变有关。     

氯巴占耐受听源性惊厥大鼠脑GABA_A受体亚单位表达的变化

目的　探讨氯巴占耐受听源性惊厥大鼠中枢GABAA受体亚单位表达的变化和这种改变与氯巴占耐受性机制关系。方法　腹腔注射氯巴占 2wk ,产生听源性惊厥大鼠氯巴占耐受模型。用竞争性定量RT PCR测定大鼠脑皮质运动区和海马区的GABAA 受体α1、α3、α5、γ2L和γ2S亚单位mRNA的含量。结果　氯巴占耐受组大鼠皮质运动区α1亚单位下降 2 7% ,α5上升 73% ,γ2L下降 4 3% ,γ2S下降 37% ;海马区的α1下降 2 8% ,γ2L下降 32 % ,γ2S下降 31% ,与对照组相比差异均有显著性。结论　听源性惊厥大鼠的氯巴占耐受机制与中枢GABAA 受体α1、α5、γ2L和γ2S亚单位表达的适应性改变有关     

氯硝西泮抗惊厥作用耐受及停药后大鼠脑内NMDA受体放射自显影观察

氯硝西泮抗惊厥作用耐受及停药后大鼠脑内ＮＭＤＡ受体放射自显影观察廖建湘王丽左启华（北京医科大学第一医院儿科１０００３４）氯硝西泮是一种常用的抗癫痫药，但容易诱发耐受，而耐受后撤药又会导致撤药症状，从而限制其应用［１］。癫痫点燃动物模型脑组织及手术获...     

氯巴占耐受听源性惊厥大鼠脑GABAA受体亚单位表达的变化

目的探讨氯巴占耐受听源性惊厥大鼠中枢GABAA受体亚单位表达的变化和这种改变与氯巴占耐受性机制关系.方法腹腔注射氯巴占2 wk,产生听源性惊厥大鼠氯巴占耐受模型.用竞争性定量RT-PCR测定大鼠脑皮质运动区和海马区的GABAA受体α1、α3、α5、γ2L和γ2S亚单位mRNA的含量.结果氯巴占耐受组大鼠皮质运动区α1亚单位下降27%,α5上升73%,γ2L下降43%,γ2S下降37%;海马区的α1下降28%,γ2L下降32%,γ2S下降31%,与对照组相比差异均有显著性.结论听源性惊厥大鼠的氯巴占耐受机制与中枢GABAA受体α1、α5、γ2L和γ2S亚单位表达的适应性改变有关.     

大鼠电惊厥后脑内生长抑素受体的变化

目的观察大鼠电惊厥后脑内生长抑素受体的变化。方法应用受体结合放射自显影术、计算机显微图象处理技术观测。结果正常大鼠大脑皮层、杏仁核、新纹状体、伏膈核、海马CA区、齿状回、嗅球、弓状核、下丘脑室周区、下丘脑腹内侧核、视前区内侧区、中央灰质、黑质等脑区内有125I-Tyr11-SS28特异性结合;电惊厥后，大鼠颞叶听皮质、梨状皮质、内嗅皮质、杏仁内侧核、海马CA区、齿状回、下丘脑腹内侧核等脑区125I-Tyr11-SS28的特异性结合比正常大鼠显著增加（P＜0.05）。结论电惊厥的发作可能与不同脑区内生长抑素受体的上调有关。     

卡马西平对青霉素点燃惊厥大鼠脑内GABA_A受体mRNA表达的作用

目的研究两种剂量卡马西平对青霉素慢性点燃大鼠的抗惊厥作用及对脑内GABAA受体mRNA表达的影响,从基因水平探讨卡马西平抗惊厥的作用机制。方法采用腹腔注射(ip)青霉素(3×106U.kg-1.d-1)慢性点燃大鼠惊厥模型,两种剂量卡马西平(50,100mg.kg-1×13d)ig给药,以痫性发作潜伏期和Racine惊厥行为分级标准为判定药效指标,观察卡马西平的抗惊厥作用。运用RT-PCR技术测定大鼠脑内GABAA受体mRNA表达量,分析卡马西平抗惊厥作用的新机制。结果两种剂量卡马西平ig给药后,均可使青霉素慢性点燃大鼠痫性发作的潜伏期延长,与模型对照组相比差异有统计学意义(P<0.01),同时使惊厥大鼠的发作程度均较模型对照组减轻。青霉素慢性点燃大鼠脑内GABAA受体mRNA表达减少,与正常对照组比较,差异有统计学意义(P<0.01);两种剂量卡马西平预防性干预组的GABAA受体mRNA表达量分别与模型对照组相比,差异均无显著性。结论两种剂量卡马西平对青霉素慢性点燃的惊厥发作均有明显的对抗作用,但抗惊厥机制与GABAA受体的基因表达无关。     

质子泵抑制剂对大鼠体内氯吡格雷抗血小板作用和代谢的影响

目的 研究各种质子泵抑制剂（proton pump inhibitors,PPIs）对大鼠体内氯吡格雷抗血小板作用和代谢的影响。方法 将40只SD ♂大鼠随机分为氯吡格雷组、氯吡格雷+雷贝拉唑组、氯吡格雷+泮托拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组,每组8只。氯吡格雷、雷贝拉唑、泮托拉唑、兰索拉唑和奥美拉唑的给药剂量分别为6.25,1.8,3.6,2.7,3.6 mg·kg^-1·d^-1,连续给药7 d。分别使用光学比浊法和血管扩张刺激磷酸蛋白检测法检测最大血小板聚集率（maximum platelet aggregation rate,MPA）和血小板反应指数（platelet response index,PRI）,并通过LC-MS/MS检测氯吡格雷及其活性代谢物H4的血药浓度。结果 氯吡格雷+雷贝拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组的MPA和PRI均显著高于氯吡格雷组,氯吡格雷+泮托拉唑组的MPA和PRI显著低于氯吡格雷+奥美拉唑组（P<0.05）。与氯吡格雷组比较,氯吡格雷+雷贝拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组的氯吡格雷血药浓度升高,H4血药浓度降低,但差异无统计学意义。结论 联用雷贝拉唑、兰索拉唑及奥美拉唑均会减弱氯吡格雷的抗血小板作用,其中泮托拉唑的抑制作用最弱,奥美拉唑的抑制作用最强。     

7一氯苄基四氢巴马汀对大鼠α肾上腺素受体及心电图的影响

在大鼠肛尾肌标本，７－氯苄基四氢巴马汀（７－ｃｈｌｏｒ－ＢＴＨＰ）１０μｍｏｌ·Ｌ－１能竞争性地抑制苯福林致肛尾肌收缩的量效曲线，使量效曲线右移，最大效应不变，其ｐＡ２值为５．９，但对可乐定抑制电场刺激所致的大鼠输精管收缩的量效曲线无影。在毁脊髓大鼠，７－ｃｈｌｏｒ－ＢＴＨＰ５ｍｇ·ｋｇ－１在不同刺激频率下可使心率减慢，但对电刺激所致的血压升高无影响。７－ｃｈｌｏｒ－ＢＴＨＰ恒速灌注，能剂量依赖性地延长心电图Ｐ－Ｒ间期及减慢心率，直至动物死亡也未见过速性心律失常发生。     

Anticonvulsant, but not antiepileptic, action of valproate on audiogenic seizures in metaphit-treated rats

1. The blocking effects of valproate (2-propylpentanoic acid), a standard anti-epileptic drug, on metaphit (1-[1-(3-isothiocyanatophenyl)-cyclohexyl]-piperidine)-induced audiogenic seizures as a model of generalized, reflex audiogenic epilepsy in adult Wistar male rats were studied. 2. Rats were stimulated using an electric bell (100 +/- 3 dB, 5-8 kHz, 60 s) 60 min after i.p. metaphit (10 mg/kg) injection and afterwards at hourly intervals. For power spectra and electroencephalograph (EEG) recordings, three gold-plated screws were implanted into the skull. Different doses of valproate (50, 75 and 100 mg/kg) were injected i.p. into rats with fully developed metaphit seizures after the eighth audiogenic testing. 3. In metaphit-treated animals, the EEG appeared as polyspikes, spike-wave complexes and sleep-like patterns, whereas the power spectra were increased compared with the corresponding controls. 4. Valproate reduced the incidence and intensity of convulsions and prolonged the duration of the latency period in a dose-dependent manner 4 h after administration. 5. The ED(50) of valproate in the first hour after injection was 63.19 mg/kg (95% confidence interval 51.37-77.71 mg/kg). 6. None of the doses of valproate applied eliminated the EEG signs of metaphit-provoked epileptiform activity. 7. Taken together, these results suggest that all doses of valproate examined acted to suppresse behavioural but not epileptic EEG spiking activity in metaphit-induced seizures.     

Intra-Accumbens trh prolongs maintenance of tolerance to hypothermic effect of ethanol in rats

Tolerance to the hypothermic effect of ethanol (Et–OH) developed in male Wistar rats treated daily with 5 g/kg of 20 per cent ET–OH v/v i.g. for 6 days. On Day 6 Et–OH treatment was discontinued and the animals were divided into two groups injected into the nucleus accumbens septi (NAS), either with pGlu-His-Pro-NH₂ (TRH) or saline. The peptide was injected via permanently implanted cannulae in doses of 10 or 30 m?g in 0.5 m?l on each side once daily. The effect of such treatment on the maintenance of Et–OH tolerance was assessed by measuring the temperature decrement in response to a challenge dose of Et–OH (5 g/kg i.p.) given on Day 10. It was found that in saline-treated rats the initial tolerance declined. TRH-injected groups exhibited constantly low response to hypothermic action of Et–OH. In a control experiment TRH was shown to have no effect on the body temperature after intra-accumbens application in Et–OH-naive rats.     

氯硝基安定抗惊厥作用耐受及停药前后对大鼠下丘脑室旁核CRHmRNA表达的影响

氯硝基安定抗惊厥作用耐受性及依赖性机制目前尚不清楚。近来发现促肾上腺皮质激素释放激素（ＣＲＨ）具有促惊厥作用，并参与应激过程。我们用原位杂交方法观察了氯硝基安定抗大鼠点燃惊厥耐受及停药前后下丘脑室旁核ＣＲＨｍＲＮＡ表达的变化，发现耐受时ＣＲＨｍＲＮＡ表达增强，停药７ｄ时不再变化。提示ＣＲＨ参与了耐受性与依赖性过程。     

The effect of changes in sound pressure level and frequency on the seizure response of audiogenic seizure susceptible rats

An apparatus for pure tone stimulation of audiogenic seizure (AGS)-susceptible rats is described, and the effect of change in sound pressure level and frequency on AGS response in Uaz:AGS (SD) rats is shown. By use of pure tone stimulation, the prevalence of AGS response in rats of this strain, which have been bred for seizure-susceptibility, is 77%. With increasing frequency, the intensity-response curves show a shift to lower sound pressure levels, the ED₅₀ for 20 kHz (83.8 dB) being significantly lower than the ED₅₀ for 5 (110.5 dB) and 10 kHz (97.5 dB). Repeated exposure to seizure-inducing sound at weekly intervals leads to more severe seizures in individual rats. This should be taken into consideration as one possible confounding factor when using this method for assaying the efficacy of anticonvulsant drugs.     

口服氯硝西泮治疗失眠27例

氯硝西泮是苯并二氮杂(艹卓)类衍生物,有抗惊厥和镇静的作用,本文用氯硝西泮与甲喹酮对46例失眠病人进行了对照研究,氯硝西泮组有效率达81％,其效果优于甲喹酮,在服用过程中,未见明显副反应。结果表明:氯硝西泮是一种有效的安眠镇静药。     

Influence of phenobarbital on the disposition of clonazepam and antipyrine in the dog

Clonazepam (1 mg/kg) and antipyrine (0.1 mg/kg) were administered simultaneously by intravenous bolus injection to three dogs. After 2 weeks of chronic phenobarbital administration, the studies were repeated. Plasma concentration-time curves in all studies were biexponential. Phenobarbital administration increased total plasma clearances of clonazepam and antipyrine by 102% and 98.5%, respectively. Volumes of distribution were not altered, and consequently reductions in terminal exponential half-lives observed after phenobarbital were attributed to increases in clearances.     

Evidence that tolerance develops to the anxiolytic effect of diazepam in rats

The development of tolerance to the anxiolytic effect of diazepam was studied using suppression of defensive burying as an animal model of anxiolytic action. Although tolerance to the suppressive effect of diazepam was not apparent after chronic administration of diazepam when the rats were tested with a low-intensity shock, anxiolytic tolerance was detected under exactly the same drug regimen when the rats were tested with somewhat higher intensity shocks: under the latter conditions, chronically treated rats buried significantly more than acutely treated rats. Furthermore, this tolerance effect did not appear to depend upon the injection environment, the control vehicle, or the strain of rat; under each of these experimental variations rats chronically treated with diazepam buried significantly more than acutely treated rats when they had received a moderately high intensity shock. These results suggested that tolerance to the anxiolytic effects of benzodiazepines may be detectable when the stimuli eliciting anxiety are relatively intense.     

Development of tolerance to the analgesic effect of clonidine in rats cross-tolerance to morphine

Summary The site of action of naloxone to induce jumping in morphine tolerant/dependent rats appears to be dissociated from structures where apomorphine initiates its action to reinduce jumping in previously withdrawn animals. These findings suggest that dopaminergic pathways do not directly affect the neuronal circuit involved in withdrawal jumping behavior, but instead exert a facilitatory influence on neurons that become supersensitive during the state of withdrawal. Thus, an increased response to apomorphine during naloxone-precipitated opiate withdrawal does not necessarily imply a specific supersensitivity of the dopaminergic system.     

Influence of ethacrynic acid on the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock seizure model

The aim of this study was to determine whether ethacrynic acid (EA), a loop diuretic with anticonvulsant activity, would affect the protective action of the conventional antiepileptics (AEDs) carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB) in the mouse maximal electroshock seizure (MES) model. The effects of acute and chronic treatment with EA on these AEDs were examined. At a single dose of 100 mg/kg ip, EA enhanced the antielectroshock activity of VPA, decreasing its ED₅₀ value from 225.6 to 146.6 mg/kg (p < 0.05), but enhancement was not observed following continuous administration of EA (12.5 mg/kg) for seven days. Combined treatment of EA with other AEDs had no effect on their ED₅₀ values. The observed interaction between EA and VPA was pharmacodynamic in nature as EA did not alter free plasma (non-protein-bound) and total brain concentrations of VPA. Taking into consideration the clinical use of both drugs, this interaction between EA and VPA can be important for patients receiving these drugs.