Time-dependent sensitization of antipsychotic effect in adolescent male and female rats
Time-dependent sensitization of antipsychotic effect in adolescent male and female rats
复制标题
青春期雄性和雌性大鼠抗精神病药作用的时间依赖性敏感性
DOI：
10.1016/j.bbr.2017.04.013
复制
发表时间：
2017-06-15
影响因子：
2.7
通讯作者：
Li, Ming
中科院分区：
文献类型：
--
作者：
Ding, Xiaojing;Li, Xiaonan;Li, Ming
精神活性药物的许多行为和生物学效应通常在甚至一次药物暴露后经历时间依赖性变化。本研究探讨是否一个或两个曝光的氟哌啶醇，奥氮平或氯氮平也会引起一个时间依赖性的变化，在青春期大鼠的行为影响，以及这种变化是否有性别差异。青春期Sprague-Dawley大鼠（< 40日龄）首次接受单次氟哌啶醇注射治疗（0.05和0.1 mg/kg，sc），氯氮平（10.0和20.0 mg/kg，sc），2次奥氮平注射（1.0和2.0 mg/kg，sc）或溶剂，并在条件性回避反应（CAR）模型或PCP中进行检测（3.20 mg/kg，sc）诱导的过度运动模型，以评估药物的抗精神病样行为作用。一周或三周后，用药物激发大鼠，并重新评估其回避反应和PCP诱导的过度运动。单次氟哌啶醇和两次奥氮平诱导致敏，而单次氯氮平诱导耐受效应。3周时间点的1次试验氟哌啶醇致敏性显著高于1周时间点，尤其是在雌性动物中。在条件性回避反应模型中，两个性别组的氯氮平耐受性也表现出时间依赖性增加。PCP模型中的奥氮平致敏性表现出性别依赖性的时间依赖性变化。总体而言，可以在青春期动物中证明时间依赖性抗精神病药物致敏和耐受性。许多药理学（例如特定药物、药物剂量）、个体（例如男性与女性）和环境（例如特定行为模型）因素在抗精神病药物致敏和耐受性强度的调节中发挥作用。
Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (< 40 days old) were first treated with one single injection of haloperidol (0.05 and 0.1 mg/kg, sc), clozapine (10.0 and 20.0 mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0 mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20 mg/kg, sc)-induced hyperlocomotion model to assess the drug's antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP -induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance.