An investigation of the behavioral mechanisms of antipsychotic action using a drug-drug conditioning paradigm.
An investigation of the behavioral mechanisms of antipsychotic action using a drug-drug conditioning paradigm.
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使用药物调节范式对抗精神病药作用的行为机制进行了研究。
DOI：
10.1097/fbp.0b013e32832a8f66
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发表时间：
2009-03
影响因子：
1.6
通讯作者：
Mead A
中科院分区：
文献类型：
--
作者：
Li M;He W;Mead A
非催眠剂量的抗精神病药物选择性地抑制大鼠的条件回避反应。在我们之前的研究中，我们使用了双向主动回避反应范式来证明抗精神病药物诱导的内感受状态是抗精神病药物回避-破坏作用的机制之一。在这项研究中，我们试图通过一种新的药物-药物调节程序进一步研究这种机制。我们利用了这样一个事实，即典型的抗精神病药氟哌啶醇和非典型的抗精神病药奥氮平都会破坏条件回避反应，而氯二氮环氧化物（一种抗焦虑药）则不会。我们推断，如果抗精神病药物的内感受状态在导致回避反应中断（抗精神病药物疗效的指标）方面是重要的，那么将氯二氮环氧化物（一种提示药物条件刺激）与氟哌啶醇或奥氮平（一种提示药物无条件刺激）配对应该会使氯二氮环氧化物表现出这种特性，并表现得像抗精神病药物一样。氯二氮环氧化物在与氟哌啶醇反复配对后，在破坏回避反应方面表现出获得性抗精神病药物样性质，但与奥氮平没有。与此相反，奥氮平与氟哌啶醇反复配伍后，其抗回避效果明显减弱，氟哌啶醇无明显减弱。本研究提示氟哌啶醇诱导的内感受性药物状态直接参与其抗回避作用，氯二氮环氧化物可能减弱抗精神病药物（尤其是奥氮平）的抗回避作用。从抗精神病药物的抗回避效应预测临床效果的角度来看，本研究提示抗精神病药物诱导的内感受性药物状态可能是调节抗精神病药物临床效果的重要行为机制。
Antipsychotic drugs at noncataleptic doses selectively suppress conditioned avoidance response in rats. In our previous study, we had used a two-way active avoidance response paradigm to show that the antipsychotic-induced interoceptive state is one of the mechanisms underlying the avoidance-disruptive effect of antipsychotics. In this study, we sought to further examine this mechanism using a novel drug–drug conditioning procedure. We made use of the fact that both the typical neuroleptic haloperidol and the atypical neuroleptic olanzapine disrupt conditioned avoidance responding, whereas chlordiazepoxide (an anxiolytic) does not. We reasoned that if the antipsychotic interoceptive state is important in causing a disruption on avoidance responding (an index of antipsychotic efficacy), pairing chlordiazepoxide (a cueing drug conditional stimulus) with haloperidol or olanzapine (a cued drug unconditional stimulus) should engender chlordiazepoxide to exhibit this property and behave like an antipsychotic drug. Chlordiazepoxide exhibited an acquired antipsychotic-like property in disrupting avoidance responding after being repeatedly paired with haloperidol, but not with olanzapine. In contrast, it significantly attenuated the antiavoidance efficacy of olanzapine but not haloperidol after being repeatedly paired with these drugs. This study suggests that the haloperidol-induced interoceptive drug state is directly involved in its antiavoidance action, and chlordiazepoxide may attenuate the antiavoidance efficacy of antipsychotics (especially olanzapine). To the extent that the antiavoidance effect predicts clinical effects of antipsychotic treatment, this study suggests that the antipsychotic-induced interoceptive drug state may be an important behavioral mechanism mediating the clinical effects of antipsychotic treatments.