可乐定对苯二氮受体激动剂和反相激动剂与大鼠皮层受体结合特性的影响(英文)

本研究旨在探讨α_2受体激动剂可乐定对苯二氮(艹卓)受体激动剂抗焦虑和反相激动剂致焦虑作用影响的可能的分子机理。在10nmol/L至1μmol/L浓度范围内,可乐定对[~3H]氟硝安定与大鼠皮层相应受体低亲和位点结合无显著影响,但非竞争性拮抗其与高亲和位点的结合。在竞争取代实验中,激动剂安定和CL218 872均表现为双位点结合的亲和力,对低亲和位点无显著影响。反相激动剂DMCM竞争结合曲线亦具有双位点结合特性。可乐定可使这种双位点结合转变成三位点结合,出现一个超高亲和位点。可乐定对拮抗剂Ro15-1788竞争结合特性无显著影响。结果提示,α_2受体激动剂可乐定与受体结合可能导致与之相邻的苯二氮(艹卓)受体发生构象变化,这种构象变化有利于激动剂与受体结合,而不利于反相激动剂的结合。     

在条件反射性惊恐反应致焦虑模型上可乐定加强安定的抗焦虑作用

在大鼠条件反射性惊恐反应致焦虑模型上,安定剂量依赖性增加惊恐反应期(CFR)操作数目,显著降低无惩罚期(NPP)操作数目。可乐定(10μg/kg)对CFR和NPP操作均无显著影响,但能显著加强安定(0.3mg/kg)增加CFR操作。安定增加CFR操作的作用,可被中枢特异性苯二氮受体拮抗剂RO15-1788所拮抗。可乐定加强安定的上述作用,可被育亨宾阻断。结果提示,中枢去甲肾上腺素系统可能参与苯二氮类药物的抗焦虑作用。     

中枢突触前α_2受体和苯二氮受体激动剂对大鼠不同脑区单胺类递质释放的影响

<正> 为进一步探讨中枢去甲肾上腺素能递质系统和苯二氮(艹卓)受体系统之间的功能联系,本文观察突触前α_2受体激动剂可乐定(CLN)和安定(DZP)对大鼠脑皮层、杏仁核、海马和脑于中去甲肾上腺素(NE)、多巴胺(DA)和5-羟色胺(5-HT)释放的影响。 实验用人工脑脊液(Tris缓冲系统,通以氧气)。脑组织称重后,切成0.5-1.0 mm厚脑片,置于37℃ 1ml浴槽中温育10min,收集温育液为基础释放。更换高钾(65mM/KCl)液,温育15min后,收集该液为高钾释     

可乐定对苯二氮Zhuo受体激动剂和反相激动剂与大鼠皮层受体结合特性的影响

本研究旨在研讨α2受体激动剂可乐定对苯二氮Zhuo受体激动剂抗焦虑和反相激动剂致焦虑作用影响的可能的分子机理。在10nmol/L至1umol/L浓度范围内，可乐定对[^3H]氟硝安定与大鼠皮层相应受体低亲和位点结合无显著影响。但非竞争性拮抗其与高亲和位点的结合，在竞争取代实验中，激动剂安全和CL218872均表现为双位点结合的亲和力，对低亲和位点无显著影响，反相激动剂DMCM竞争结合曲线亦具有双位点结合特性，可乐定可使这种双位点结合转变成三位点结合，出现一个超高亲和位点，可乐定对拮抗剂Ro15-1788竞争结合特性无显著影响，结果提示，α2受体激动剂可乐定与受体结合可能导致与之相邻的苯二氮Zhuo受体发生构象变化，这种构象变化有利于激动剂与受体结合，而不利于反相激动剂的结合。     

可乐定对两种苯二氮受体激动剂程控操作效应的影响

Ⅰ,Ⅱ型苯二氮受体激动剂安定和可乐定均可剂量依赖性抑制大鼠程控操作。可乐定可协同安定的抑制。育亨宾可拮抗之。Ⅰ型苯二氮受体激动剂GL218,872对大鼠程控操作无显著影响。增加其剂量至10mg/kg,使程控操作速率最大降低32%。可乐定可显著加强该剂量的抑制作用,对其余小剂量组无显著影响。结果提示,苯二氮激活Ⅱ型受体对去甲肾上腺素系统功能抑制,可能是其镇静作用机理之一。     

可乐定对自家血灌流毁脑脊髓大鼠后肢血管平滑肌的作用

本实验观察了可乐定对自家血恒速灌流的毁脑脊髓大鼠(pithed rat)后肢血管平滑肌的作用和该处突融后膜两种α受体亚型的存在。可乐定引起灌流压(PP)升高,呈剂量依赖关系,但效能远比选择性α_1受体激动剂苯福林低。对预先用利血平处理的大鼠,可乐定的作用被显著增强。高度选择性的α_1受体阻断剂哌唑嗪0.3mg/kg iv可部分阻断可乐定100μg ia的作用,增加哌唑嗪的剂量并不能进一步增加对可乐定的阻断作用。对于哌唑嗪不能阻断的部分,α_1受体阻断剂育亨宾却能表现出十分明显的抑制作用。这些结果提示在大鼠后肢血管平滑肌突触后膜上存在有α_1和α_2肾上腺素受体,但α_1受体似乎占优势。     

丁螺环酮加强戊四氮致小鼠惊厥作用

新型非苯二氮(艹卓)类抗焦虑剂丁螺环酮(Bus)(1～10 mg·kg~1)使戊四氮(PTZ)致惊厥作用的CD_(50)下降12～37％,具有剂量依赖性和时间效应关系.色氨酸羟化酶抑制剂对氯苯丙氨酸(250 mg·kg~1)和单胺耗竭剂利血平(2mg·kg~1)均可增强PTZ致惊厥作用,但同时减弱Bus的增强作用.而α_2受体激动剂可乐定和赛拉嗪以及DA受体激动剂阿朴吗啡,拮抗剂氟哌啶醇均不影响Bus的增强作用.结果表明,Bus的增强作用有5-HT能神经元的参与.     

社交恐惧症药物治疗新进展

药物治疗是社交恐惧症(SP)的主要治疗手段,除传统的苯二氮艹卓类(BZ)抗焦虑药外,一些新型抗抑郁药因具有抗抑郁和抗焦虑双重作用,近年来被推荐用于SP的治疗,特别是选择性5羟色胺(5HT)再摄取抑制剂与选择性5HT和去甲肾上腺素(NA)再摄取抑制剂。一些新型的非苯二氮艹卓类抗焦虑药因疗效好,不良反应少,应用日趋广泛。本文重点对BZ和非苯二氮艹卓类抗焦虑药以及新一代抗抑郁药、部分抗惊厥药治疗SP的进展情况进行综述。     

半个世纪的争议——苯二氮()类药物临床应用50年

上个世纪50年代,苯二氮(艹卓)类药物进入临床使用,由于此类药物高效、安全、耐受性良好,目前苯二氮(艹卓)类药物已成为抗焦虑和失眠领域应用最广泛的药物。根据统计,全球有超过5000万人服用苯二氮(艹卓)类药物。苯二氮(艹卓)类药物目前仍是失眠和抗焦虑的一线治疗药物。 然而,由于许多原因,苯二氮(艹卓)类药物只是用于短期的抗焦虑及失眠的治疗,这是因为人们担心长期使用     

研制咪唑并喹啉和咪唑并嘧啶苯二氮类受体配基的途径

本文介绍了一系列强的苯二氮(艹卓)(BDZ)受体配基的研究过程。从构效关系研究产生了苯甲酰咪唑并喹啉RU32514,由此还产生了咪唑并嘧啶RU32698。RU32698在动物模型上有强的抗焦虑活性,几乎没有镇静作用,也无肌肉松弛作用。进一步研究得到噁二唑基咪唑并嘧啶RU33203,是一种强的BDZ受体部分激动剂,还得到嘧唑基咪唑并嘧啶RU33356,是第一个有拮抗剂/逆转激动列性质的化合物。     

Behavioral evidence for the role of noradrenaline in putative anxiolytic and sedative effects of benzodiazepines

The effects of clonidine on the antianxiety and sedation of benzodiazepines (BZD) were assessed respectively in rats trained in a two-lever diazepam cue discrimination procedure and in single-lever fixed-ratio (FR) water-reinforced performance. Clonidine (10–60 g/kg) significantly shifted to the left the dose-effect curves of diazepam in the discrimination paradigm. This treatment also shifted generalization dose-effect curves of the diazepam cue to chlordiazepoxide and CL 218872 to the left in the drug discrimination procedure. The diazepam cue was antagonized in a dose-related manner by Ro 15-1788, but not by bicuculline. Clonidine also potentiated the rate-decreasing effects of diazepam on the FR schedule when the dose of diazepam was increased to 0.3 mg/kg, but not the milder rate-decreasing effect of CL 218872 until the dose of CL 218872 was increased to 10 mg/kg. The potentiating effects of clonidine on the stimulus control and depression of diazepam were antagonized by yohimbine. Yohimbine (1.0 mg/kg) also significantly shifted the dose-effect curve of diazepam cue to the right. Bicuculline (3 mg/kg) completely antagonized the rate-decreasing effect of diazepam (1 mg/kg), but significantly potentiated the rate-suppressant effect of clonidine (10 g/kg). These results suggest that the central noradrenaline (NA) system may be involved not only in the antianxiety, but also the sadative action of BZD. The nature of NA involvement in relation to the different subtypes of BZD receptors requires further exploration.     

Discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys

The present study characterized the discriminative-stimulus effects of triazolam and midazolam in rhesus monkeys. Six monkeys discriminated 0.1 mg/kg of triazolam from vehicle under a fixed-ratio 5 (FR 5) schedule of stimulus-shock termination (SST). Four monkeys subsequently discriminated 0.56 mg/kg of midazolam from vehicle under the same schedule of reinforcement. Benzodiazepine (BDZ) agonists midazolam and diazepam, and the barbiturate pentobarbital, substituted for triazolam, and the non-competitive N-methyl-D-aspartate (NMDA) antagonist ketamine did not. Triazolam, diazepam, lorazepam, flunitrazepam, as well as the barbiturates amobarbital and pentobarbital, substituted for midazolam, and ketamine did not. The BDZ antagonist flumazenil antagonized both the triazolam and midazolam discriminative stimuli. Bretazenil, a low-efficacy BDZ agonist, did not substitute for the midazolam discriminative stimulus in three of the monkeys and shifted the midazolam dose-effect curve to the right; in a fourth monkey, bretazenil substituted for midazolam and shifted the midazolam dose-effect curve to the left. Schild analyses with flumazenil or bretazenil, in combination with midazolam, yielded slopes that deviated significantly from unity. While clearly supporting the notion that BDZ agonists produce stimulus effects by acting at the gamma-aminobutyric acidA (GABA(A)) receptor complex, these data also suggest that the discriminative-stimulus effects of midazolam might be mediated by more than one BDZ receptor subtype.     

Effects of ethanol on cocaine discrimination in rats

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA(A)-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1-0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose-effect curve. Ethanol (0.1-1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1-2 g/kg) completely suppressed responding. Indirect GABA(A) agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA(A) antagonist pentylenetetrazol (PTZ) (10-40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA(A) receptor.     

中枢与外周α-肾上腺素能受体激动效应不一致性的原理分析

对戊巴比妥钠麻醉家兔,静脉注射α-肾上腺素能受体拮抗剂育亨宾(Yohimbine)或γ-氨基丁酸(GABA)受体拮抗剂苦味毒(picrotoxin)均可明显对抗侧脑室注射氯压定(clonidine)的降血压作用。但是育亨宾不能阻断侧脑室注射GABA的中枢降压作用,而苦味毒则能完全阻断其降压效应。家兔经GABA合成抑制剂氨基脲(Semicarbazide)静脉注射予处理后,动物于给药后3～4小时出现强烈惊厥,说明脑内GABA已降低到一定水平。此时用局部麻醉剂及肌松剂处理,在人工呼吸情况下,氯压定静脉注射的降压作用比不给氨基脲予处理的对照组动物显著减弱。以上结果启示,中枢肾上腺素能受体激动而产生的降压作用有可能是通过GABA能抑制性神经元而实现。     

The role of delta opioid receptors in the anxiolytic actions of benzodiazepines

The anxiolytic effects of benzodiazepines appear to involve opioid processes in the amygdala. In previous experiments, overexpression of enkephalin in the amygdala enhanced the anxiolytic actions of the benzodiazepine agonist diazepam in the elevated plus maze. The effects of systemically administered diazepam are also blocked by injections of naltrexone into the central nucleus of the amygdala. The current studies investigated the role of delta opioid receptors in the anxiety-related effects of diazepam. Three days following bilateral stereotaxic injections of viral vectors containing cDNA encoding proenkephalin or beta-galactosidase (control vector), the delta opioid receptor antagonist naltrindole (10 mg/kg, s.c.) attenuated the enhanced anxiolytic effects of 1-2 mg/kg diazepam in rats overexpressing preproenkephalin in the amygdala. Despite this effect, naltrindole failed to attenuate the anxiolytic action of higher diazepam doses (3 mg/kg) in animals with normal amygdalar enkephalin expression. Similarly, the mu opioid receptor antagonist, beta-funaltrexamine (20 mg/kg, s.c.), had no effect on the anxiolytic effect of diazepam alone. These data support a role for delta opioid receptors in the opioid-enhanced anxiolytic effects of diazepam.     

Interoceptive stimuli produced by cocaine are blocked during diazepam withdrawal

Rats were trained to select one lever after an intraperitoneal (ip) injection of cocaine (10 mg/kg), and an alternate lever after saline injection under a FR10 schedule of food reinforcement. Following chronic administration of cocaine (20 mg/kg/8hr), but not diazepam (80 mg/kg/8hr) for 7 days, the dose-effect curve for the generalization of cocaine shifted twofold to the right. Subsequently, in the rats receiving chronic diazepam, RO 15-1788, a drug known to precipitate diazepam withdrawal, failed to substitute for cocaine: however, the discriminability of cocaine (5 mg/kg) was reduced from 83% to 13% selection of cocaine-appropriate lever after 72 hr following the last diazepam, injection. These data suggest that chronic administration of cocaine, but not diazepam, produced tolerance to the discriminative stimulus properties of cocaine, and following chronic diazepam administration and withdrawal, the stimulus properties of cocaine are antagonized.     

Potentiation of 5-methoxy-n,n-dimethyltryptamine-induced head-twitches by diazepam: Evidence for involvement of adenosine uptake inhibition

Previous work shows that benzodiazepines potentiate head-twitches induced by 5-HT agonists and that this action is not mediated via the GABA receptor complex. In the present study the involvement of adenosinergic mechanisms in this effect has been examined, as in addition to their actions at the GABA receptor, benzodiazepines also inhibit adenosine uptake. The adenosine antagonists caffeine (0.3-30 mg/kg ip) and 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (0.03-1 mg/kg ip) dose-dependently inhibited the ability of diazepam (4 mg/kg ip) to potentiate head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 2.5 mg/kg ip) without affecting head-twitches induced by 5-MeODMT alone at a higher dose (10 mg/kg), which induced a similar number of head-twitches to the combination of 5-MeODMT and diazepam. The adenosine uptake inhibitors papaverine, mioflazine, and dilazep all potentiated head-twitches induced by 5-MeODMT, but this effect was seen at only a single dose of each compound. The benzodiazepine antagonist flumazenil did not inhibit the potentiation of head-twitches by diazepam but did itself potentiate head-twitches at 30 mg/kg, consistent with its ability to inhibit adenosine uptake. In contrast, the adenosine uptake inhibitor dipyridamole and the peripheraltype benzodiazepine receptor antagonist Ro 5-4864, which also inhibits adenosine uptake, failed to potentiate head-twitches. The adenosine agonists N⁶-cyclohexyladenosine, 5'-(N-ethylcarboxamido-adenosine), and (–)-N⁶-(R-phenylisopropyl)adenosine were similarly without effect. These results confirm previous findings that the potentiation of head-twitches by benzodiazepines is not mediated via an action at benzodiazepine receptors and suggest that inhibition of adenosine uptake is an important component of the mechanism involved. © 1993 wiley-Liss, Inc.     

The possible modulation of morphine analgesia by the supramolecular GABA receptor complex

In the present study, the mechanism of the antagonistic action of 0.5 mg/kg diazepam on the analgesic effect of morphine was investigated. While Ro 15-1788, a benzodiazepine receptor antagonist, was found to partially reverse the inhibitory action of diazepam on morphine analgesia, a chloride channel blocking agent, picrotoxin, produced complete antagonism of the action of diazepam. Furthermore, picrotoxin potentiated the partial antagonistic effect of Ro 15-1788 at a normally ineffective dose to affect the 0.5 mg/kg diazepam-morphine dose-response curve. These overall effects of picrotoxin on the supramolecular GABA receptor complex are discussed.