Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning.
Distinct neural mechanisms underlying acute and repeated administration of antipsychotic drugs in rat avoidance conditioning.
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大鼠回避调节中抗精神病药的急性和重复给药的不同神经机制。
DOI：
10.1007/s00213-010-1925-5
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发表时间：
2010-09
影响因子：
3.4
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Li M;Sun T;Zhang C;Hu G
急性抗精神病药物治疗会破坏条件回避反应，反复治疗会引起致敏或耐受效应。然而，急性和反复抗精神病药物作用的神经化学机制仍有待确定。本研究考察了氟哌啶醇、氯氮平和奥氮平效应在大鼠双向条件回避模型中的神经受体机制。训练有素的Sprague-Dawley大鼠分别给予氟哌啶醇（0.05 mg/kg, sc）、氯氮平（10.0 mg/kg, sc）或奥氮平（1.0 mg/kg, sc）以及生理盐水、喹匹罗（一种选择性多巴胺D2/3激动剂，1.0 mg/kg, sc）或2,5-二甲氧基-4-碘安非他明（DOI，一种选择性5-HT2A/2C激动剂，2.5 mg/kg, sc），并在3天内测试它们的条件回避反应。无药再训练2 d后，通过激射试验评估重复治疗效果。喹匹罗预处理，而不是DOI，减轻了急性氟哌啶醇诱导的回避反应中断，并在较小程度上减轻了奥氮平诱导的中断。相比之下，DOI预处理能减弱氯氮平的急性效应，而非喹匹罗。在重复效应上，DOI预处理能减弱氟哌啶醇的强化破坏作用，而quinpirole预处理能减弱奥氮平的强化破坏作用，但能增强氯氮平的耐受性样作用。这些发现表明，急性氟哌啶醇和奥氮平主要通过阻断多巴胺D2受体来破坏逃避反应，而急性氯氮平主要通过阻断5-HT2A受体来发挥其破坏作用。氟哌啶醇的重复效应可能由5-HT2A/2C阻断启动的神经过程介导，而氯氮平和奥氮平的重复效应可能由D2/3阻断启动的神经过程介导。
Acute antipsychotic treatment disrupts conditioned avoidance responding, and repeated treatment induces a sensitization- or tolerance-like effect. However, the neurochemical mechanisms underlying both acute and repeated antipsychotic effects remain to be determined. The present study examined the neuroreceptor mechanisms of haloperidol, clozapine, and olanzapine effect in a rat two-way conditioned avoidance model. Well-trained Sprague–Dawley rats were administered with haloperidol (0.05 mg/kg, sc), clozapine (10.0 mg/kg, sc), or olanzapine (1.0 mg/kg, sc) together with either saline, quinpirole (a selective dopamine D2/3 agonist, 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI; a selective 5-HT2A/2C agonist, 2.5 mg/kg, sc), and their conditioned avoidance responses were tested over 3 days. After 2 days of drug-free retraining, the repeated treatment effect was assessed in a challenge test. Pretreatment of quinpirole, but not DOI, attenuated the acute haloperidol-induced disruption of avoidance responding and to a lesser extent, olanzapine-induced disruption. In contrast, pretreatment of DOI, but not quinpirole, attenuated the acute effect of clozapine. On the repeated effect, pretreatment of DOI, but not quinpirole, attenuated the potentiated disruption of haloperidol, whereas pretreatment of quinpirole attenuated the potentiated disruption of olanzapine but enhanced the tolerance-like effect of clozapine. These findings suggest that acute haloperidol and olanzapine disrupt avoidance responding primarily by blocking dopamine D2 receptors, whereas acute clozapine exerts its disruptive effect primarily by blocking the 5-HT2A receptors. The repeated haloperidol effect may be mediated by 5-HT2A/2C blockade-initiated neural processes, whereas the repeated clozapine and olanzapine effect may be mediated by D2/3 blockade-initiated neural processes.