Ballard Michael E, Basso Ana M, Gallagher Kelly B, Browman Kaitlin E, Fox Gerard B, Drescher Karla U, Gross Gerhard, Decker Michael W, Rueter Lynne E, Zhang Min
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Psychopharmacology (Berl). 2007 Jan;190(1):1-11. doi: 10.1007/s00213-006-0577-y. Epub 2006 Nov 9.
Neuroleptic dysphoria encompasses a range of unpleasant subjective responses and, as a result, is difficult to study in preclinical animal models.
Based on the learned helplessness model of depression, increases in escape failures (EFs) in the drug-induced helplessness test (DH) are proposed to reflect drug-induced depressive-like state, a contributing factor to neuroleptic dysphoria in humans.
Effects of the typical antipsychotic haloperidol and the atypical antipsychotics risperidone, olanzapine, aripiprazole, quetiapine, and clozapine were investigated in the DH test. We further characterized this test by examining compounds affecting motor function, cognition, anxiety, and those with antidepressant activity.
The antipsychotics haloperidol, risperidone, aripiprazole, and olanzapine, all increased EFs, while quetiapine had no effect, and clozapine reduced EFs. Amphetamine, diazepam, and ciproxifan, had no effect on EFs. Scopolamine significantly reduced EFs and MK-801 showed a trend toward reducing EFs at doses not significantly sti mulating locomotor activity. Subchronic, but not acute, imipramine and subchronic fluoxetine significantly reduced EFs at doses significantly suppressing locomotor activity. Dissociation appears to exist between performance in the DH test and compound effects on catalepsy or locomotor activity.
After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.
抗精神病药烦躁涵盖一系列令人不适的主观反应，因此难以在临床前动物模型中进行研究。
基于抑郁症的习得性无助模型，药物诱导的无助试验（DH）中逃避失败（EFs）的增加被认为反映了药物诱导的抑郁样状态，这是人类抗精神病药烦躁的一个促成因素。
在DH试验中研究了典型抗精神病药氟哌啶醇以及非典型抗精神病药利培酮、奥氮平、阿立哌唑、喹硫平和氯氮平的作用。我们通过研究影响运动功能、认知、焦虑的化合物以及具有抗抑郁活性的化合物，进一步对该试验进行了表征。
抗精神病药氟哌啶醇、利培酮、阿立哌唑和奥氮平均增加了EFs，而喹硫平无作用，氯氮平降低了EFs。苯丙胺、地西泮和西普罗芬对EFs无影响。东莨菪碱显著降低了EFs，MK-801在未显著刺激运动活性的剂量下有降低EFs的趋势。亚慢性而非急性的丙咪嗪以及亚慢性氟西汀在显著抑制运动活性的剂量下显著降低了EFs。DH试验中的表现与化合物对僵住症或运动活性的影响之间似乎存在分离。
在讨论了药物诱导的EFs变化的潜在其他解释后，我们提出DH试验是评估可能导致抗精神病药烦躁的药物诱导的抑郁样状态的有用试验。
