Anxiolytic Property of Atypical Antipsychotics

非典型抗精神病药的抗焦虑特性

基本信息

批准号：
7547379
负责人：
MING LI
金额：
$ 16.45万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7547379
关键词：
Accounting Acute Address Adverse effects Animal Model Animals Anti-Anxiety Agents Antidepressive Agents Antipsychotic Agents Anxiety Behavioral Behavioral Mechanisms Behavioral Paradigm Body Temperature Chlordiazepoxide Citalopram Clinical Clinical Treatment Clozapine Cognition Communities Data Defecation Delusions Development Disease Disputes Dose Drug Evaluation Drug usage Elements Emotions Environment Evaluation Exhibits Exploratory/Developmental Grant Extinction (Psychology)Fright Future Goals Gold Hallucinations Haloperidol Hand Involuntary Movements Knowledge Learning Measurable Measures Memory Modeling Motivation Motor Muscle Rigidity Neurobiology Patients Pharmaceutical Preparations Physiological Posture Property Psychotic Disorders Psychotropic Drugs Quality of life Rattus Reaction Relative (related person)Research Risk Risperidone Schizophrenia Solid Staging Stimulus Stretching Symptoms Syndrome Testing Therapeutic Effect Time Training Treatment Protocols Tremor Ultrasonics Upper arm Urination Work atypical antipsychotic base clinical practice comparative efficacy conditioned fear design drug development drug efficacy emotional reaction indexing innovation neurobiological mechanism novel novel strategies olanzapine pre-clinical prevent response tool treatment strategy vocalization

项目摘要

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.

描述（由申请人提供）：典型和非典型抗精神病药是用于治疗精神分裂症的主要药物。尽管两组对精神病（例如妄想、幻觉）的疗效相似，但目前尚不清楚非典型人群在与动机、情绪和认知相关的症状上是否比典型人群具有内在和优越的益处，而与它们有利的运动副作用无关。 PI 的长期目标是了解抗精神病药物的神经生物学和行为机制。该 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）对恐惧和焦虑的行为和生理指标表现出抗焦虑作用的程度，作为描绘恐惧和焦虑的广泛努力的一部分。典型和非典型抗精神病药物对非精神病症状的关键差异。该项目假设是利培酮和奥氮平具有内在的抗焦虑特性，可以防止新的恐惧反应的发展并消除现有的恐惧反应。将创新性地使用条件回避反应模型来检验这一假设。该模型不仅对抗“精神病”功效具有很高的预测有效性，而且还包含反映恐惧和焦虑要素的多种可测量和非运动反应（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影响可能产生的影响。其可靠性和敏感性将根据高架十字迷宫（焦虑动物模型的金标准）得到进一步验证。目标 1 是确定重复氟哌啶醇（典型）、利培酮、奥氮平（非典型）、利眠宁（抗焦虑药）、西酞普兰（具有抗焦虑特性的抗抑郁药）治疗对该模型中获得各种条件性恐惧反应和条件性回避反应的行为影响。目标 2 将探讨它们对消除这些反应的影响。目标 3 将通过检查重复抗精神病药物治疗对高架十字迷宫（最广泛使用的焦虑动物模型之一）中各种焦虑测量的行为影响来验证这种新方法。该项目的创新之处在于，将使用单一行为范式来同时识别药物的抗精神病和抗焦虑功效，同时仔细控制其他混杂因素（例如药物对学习、记忆或运动功能的影响）。数据的可靠性预计会很高，因为各种剂量的典型和非典型药物将直接与抗焦虑药物进行比较，并且将收集恐惧/焦虑的多种测量结果。此外，重复的药物治疗方案而不是急性治疗方案将为临床治疗状况提供更好的模型。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育阶段缓解焦虑或恐惧的程度。这些发现预计将对精神药物的开发和评估以及精神分裂症患者的治疗产生积极影响。