Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide.
Clozapine and olanzapine exhibit an intrinsic anxiolytic property in two conditioned fear paradigms: contrast with haloperidol and chlordiazepoxide.
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DOI：
10.1016/j.pbb.2008.04.014
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发表时间：
2008-10
影响因子：
3.6
通讯作者：
Kapur, Shitij
中科院分区：
文献类型：
--
作者：
Mead, Alexa;Li, Ming;Kapur, Shitij
关键词：
精神分裂症患者出现精神病性恐惧和焦虑障碍的频率相对较高。非典型抗精神病药物被认为在减轻这些症状方面表现出更好的疗效。然而，关于其抗焦虑功效的临床和临床前证据是混杂的。在这项研究中，我们评估了两种非典型药物氯氮平和奥氮平可能的抗焦虑特性，并将它们与典型的氟哌啶醇和氯二氮环氧化物（一种镇静抗焦虑药物的原型）在两种临床前恐惧模型中进行了比较。在实验1中，我们采用恐惧诱发的被动回避和条件场所厌恶范式，考察氯氮平（20 mg/kg, sc）、氟哌啶醇（0.05 mg/kg, sc）和氯二氮环氧化物（10 mg/kg, ip）的影响。在实验2和3中，我们采用了双向主动回避条件反射模式，并进一步比较了氯氮平（20 mg/kg, sc）、氟哌啶醇（0.05 mg/kg, sc）、氯二氮平（10 mg/kg, ip）和三种剂量的奥氮平（0.5、1.0和2.0 mg/kg, sc）的效果。结果表明氯氮平和氯二氮环氧化物能显著减弱休克调节诱导的地方厌恶，减少排便量和22 kHz发声次数，氟哌啶醇则无显著作用。氯氮平也能减少休克调节引起的高热。与氯氮平类似，奥氮平也能显著减少排便量，降低休克调适引起的高热，但对22 kHz发声没有抑制作用。本研究表明氯氮平和奥氮平具有内在的抗焦虑特性，这不是由于其优越的抗“精神病”作用或其对运动功能或学习和记忆过程的有利作用。这些发现还表明，联合使用被动回避和主动回避条件反射模型可以更好地区分典型和非典型抗精神病药以及抗焦虑药。
Psychotic fear and anxiety disturbances are seen at a relatively high frequency in patients with schizophrenia. Atypical antipsychotics are believed to show superior efficacy in reducing these symptoms. However, clinical and preclinical evidence regarding their anxiolytic efficacy has been mixed. In this study, we evaluated the possible anxiolytic property of two atypicals clozapine and olanzapine and compared them with typical haloperidol and chlordiazepoxide (a prototype of sedative-anxiolytic drug) in two preclinical models of fear. In Experiment 1, we used a fear-induced passive avoidance and conditioned place aversion paradigm and examined the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc) and chlordiazepoxide (10 mg/kg, ip). In Experiments 2 and 3, we used a two-way active avoidance conditioning paradigm and further compared the effects of clozapine (20 mg/kg, sc), haloperidol (0.05 mg/kg, sc), chlordiazepoxide (10 mg/kg, ip) and three doses of olanzapine (0.5, 1.0, and 2.0 mg/kg, sc). Results show that clozapine and chlordiazepoxide, but not haloperidol, significantly attenuated the shock conditioning-induced place aversion, decreased the amount of defecations and the number of the 22 kHz vocalizations. Clozapine also reduced the shock conditioning-induced hyperthermia. Similar to clozapine, olanzapine also significantly decreased the amount of defecations and reduced the shock conditioning-induced hyperthermia, but it did not inhibit the 22 kHz vocalizations. This study demonstrates that clozapine and olanzapine possess an intrinsic anxiolytic property, which is not attributable to its superior anti-“psychotic” effect or its favorable effects on motor functions or learning and memory processes. These findings also suggest that the combined use of passive avoidance and active avoidance conditioning models can be useful in better differentiating typical and atypical antipsychotics as well as anxiolytics.
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影响因子：
3.4
作者：
FERNANDEZTOME, MP;SANCHEZBLAZQUEZ, P;DELRIO, J
通讯作者：
DELRIO, J
影响因子：
3.4
作者：
Burgdorf, J;Knutson, B;Shippenberg, TS
通讯作者：
Shippenberg, TS
影响因子：
2.7
作者：
Akwa, Y;Purdy, RH;Britton, KT
通讯作者：
Britton, KT
影响因子：
2.9
作者：
Greba, Q;Gifkins, A;Kokkinidis, L
通讯作者：
Kokkinidis, L
影响因子：
25
作者：
Amorapanth, P;LeDoux, JE;Nader, K
通讯作者：
Nader, K