Anxiolytic Property of Atypical Antipsychotics

描述（由申请人提供）：典型和非典型抗精神病药物是用于治疗精神分裂症的主要药物。尽管两组治疗精神病（如妄想、幻觉）的疗效相似，但目前尚不清楚非典型药物作为一类是否在与动机、情感和认知相关的症状上比典型药物具有内在和优越的益处，而不依赖于它们有利的运动副作用。PI的长期目标是了解抗精神病药物作用的神经生物学和行为机制。本R21申请的目的是使用临床前方法来确定两种一线非典型药物（利培酮和奥氮平）在恐惧和焦虑的行为和生理测量中表现出抗焦虑作用的程度，作为描述典型和非典型抗精神病药物在非精神病症状上的关键差异的广泛努力的一部分。该项目的假设是利培酮和奥氮平在防止新的恐惧反应的发展和消除现有的焦虑反应方面具有内在的抗焦虑特性。一个条件回避反应模型将被创造性地用于检验这一假设。该模型不仅对抗“精神病”疗效具有很高的预测有效性，而且还包括反映恐惧和焦虑因素的多种可测量和非运动性反应（例如，体温，排便，排尿，超声波发声），从而能够评估各种抗精神病药物的抗焦虑特性，同时仔细匹配它们的抗“精神病”功效，并梳理出它们对学习或运动功能的任何可能影响。其可靠性和敏感性将在焦虑动物模型的金标准——高架+迷宫中进一步验证。目的1是确定在该模型中，氟哌啶醇（典型）、利培酮、奥氮平（非典型）、氯二氮平（抗焦虑药）、西酞普兰（具有抗焦虑特性的抗抑郁药）反复治疗对获得各种条件恐惧反应和条件回避反应的行为影响。目的2将探讨它们对这些反应消失的影响。目的3将通过检查反复抗精神病药物治疗对升高+迷宫中各种焦虑测量的行为影响来验证这种新方法，升高+迷宫是最广泛使用的焦虑动物模型之一。这个项目的创新之处在于，一个单一的行为范式将被用来同时确定药物的抗精神病和抗焦虑功效，而其他混杂因素（例如，药物对学习、记忆或运动功能的影响）正在被仔细控制。预计数据的可靠性将很高，因为将直接将大范围的典型和非典型药物剂量与抗焦虑药物进行比较，并将收集恐惧/焦虑的多种测量值。此外，重复药物治疗方案而不是急性药物治疗方案将提供更好的临床治疗条件的建模。该项目旨在揭示两种最广泛使用的非典型抗精神病药物利培酮和奥氮平在不同发展阶段缓解焦虑或恐惧的程度。预计这些发现将对精神药物的开发和评价以及精神分裂症患者的治疗产生积极影响。

DESCRIPTION (provided by applicant): Typical and atypical antipsychotics are the primary drugs used to treat schizophrenia. Although both groups show similar efficacy against psychosis (e.g., delusions, hallucinations), it is unclear whether atypicals as a class have intrinsic and superior benefits over typicals on symptoms related to motivation, emotion and cognition, independent of their favorable motor side effects. The PI's long-term goal is to understand the neurobiological and behavioral mechanisms of action of antipsychotic drugs. The objective of this R21 application is to use a preclinical approach to identify the extent to which two first-line atypicals (risperidone and olanzapine) exhibit an anxiolytic effect on behavioral and physiological measures of fear and anxiety, as part of broad efforts to delineate the critical differences between typical and atypical antipsychotics on non-psychotic symptoms. The project hypothesis is that risperidone and olanzapine have an intrinsic anxiolytic property in preventing the development of new fearful reactions and in extinguishing existing ones. A conditioned avoidance response model will be innovatively used to test this hypothesis. This model not only has high predictive validity for anti-"psychotic" efficacy, but also encompasses multiple measurable and non- motoric responses reflecting elements of fear and anxiety (e.g., body temperature, defecation, urination, ultrasonic vocalization), which enable evaluation of the anxiolytic properties of various antipsychotics, while carefully matching their anti-"psychotic" efficacy and teasing out any possible influence from their effects on learning or motor functions. Its reliability and sensitivity will be further validated against the elevated plus maze (the gold standard of animal model of anxiety). Aim 1 is to identify behavioral effects of repeated haloperidol (typical), risperidone, olanzapine (atypical), chlordiazepoxide (anxiolytic), citalopram (antidepressant with anxiolytic property) treatment on the acquisition of various conditioned fear responses and conditioned avoidance responding in this model. Aim 2 will explore their effects on the extinction of these responses. Aim 3 will validate this novel approach by examining the behavioral effects of repeated antipsychotic treatment on various measures of anxiety in the elevated plus maze, one of most widely used animal models of anxiety. This project is innovative in that a single behavioral paradigm will be used to concurrently identify antipsychotic and anxiolytic efficacies of the drugs, while other confounding factors (e.g., drug effects on learning, memory or motor functions) are being carefully controlled. The reliability of the data is expected to be high because a wide range of doses of typical and atypical drugs will be compared directly with anxiolytic drugs and multiple measures of fear/anxiety will be collected. Furthermore, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical treatment condition. This project is designed to reveal the extent to which the two most widely prescribed atypical antipsychotic drugs, risperidone and olanzapine, alleviate anxiety or fear at different stages of development. Such findings are expected to have a positive impact on the development and evaluation of psychotropic drugs and on the treatment of patients with schizophrenia.