Behavioral mechanisms of antipsychotic action

抗精神病作用的行为机制

• 批准号: 7899418
• 负责人: MING LI
• 金额: $ 28.54万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899418
• 关键词: Acute; Address; Affect; Amphetamines; Animal Testing; Animals; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Area; Attention; Behavioral; Behavioral Mechanisms; Behavioral Model; Brain; Characteristics; Chlordiazepoxide; Citalopram; Clinic; Clinical; Clozapine; Consensus; Cues; Data; Dopamine; Dopamine D2 Receptor; Drug Exposure; Drug effect disorder; Ensure; Environment; Fluoxetine; Future; Goals; HTR2A gene; Haloperidol; Incentives; Knowledge; Lead; Learning; Memory; Modeling; Molecular; Neurobiology; Perception; Pharmaceutical Preparations; Phencyclidine; Principal Investigator; Procedures; Process; Psychopharmacology; Psychotic Disorders; Publishing; Rattus; Recording of previous events; Research; Role; Schizophrenia; Serotonin; Serotonin Receptor 5-HT1A; Site; Specificity; Stimulus; Structure; Symptoms; Techniques; Testing; The Sun; Therapeutic Effect; Thinking; Time; Translating; Treatment Protocols; Work; atypical antipsychotic; base; clinically relevant; conditioning; design; drug testing; experience; indexing; innovation; neglect; neurobiological mechanism; novel; olanzapine; pre-clinical; psychologic; public health relevance; receptor; response; theories; tool

DESCRIPTION (provided by applicant): Antipsychotics have been in clinical use for more than half a century. Actions at various receptor sites, notably dopamine D2, serotonin 5-HT2A, and/or 5-HT1A receptors, are critically important for the therapeutic effect of antipsychotic drugs. How these actions at the neurobiological level translate into improvement of psychotic symptoms remains unresolved. The Principal Investigator's long-term goal is to understand the behavioral and neurobiological mechanisms of action of antipsychotic drugs. The objective of this application is to identify the behavioral mechanisms of antipsychotic action through a preclinical approach. The project hypothesis is that antipsychotic drugs achieve their anti-"psychotic" effect via a dual action: (a) selectively weakening the aberrant motivational salience of stimuli (e.g., psychotic thoughts or abnormal perceptions, internal and external cues) and (b) producing a drug interoceptive state that allows the weakening effect on motivational salience of stimuli to be maintained over time. A conditioned avoidance response (CAR) model and phencyclidine (PCP)-induced hyperlocomotion model based on repeated treatment regimens will be innovatively used to test this hypothesis. Aim 1 is designed to examine the weakening of motivational salience action in the CAR model. Aim 2 is to characterize the second proposed mechanism of antipsychotic action: the interoceptive drug state using the CAR model. Aim 3 is structured to use the phencyclidine (PCP)-induced hyperlocomotion model to cross-validate findings from the first two aims and further test our hypothesis. This project is innovative because several novel experimental manipulation techniques will be employed to characterize the exact psychological processes affected by antipsychotics and tease apart the ones relevant to antipsychotic action from irrelevant ones. In addition, multiple behavioral models sensitive to antipsychotic action will be used to cross-validate findings and test alternative hypotheses. Because antipsychotics will be directly compared with non-antipsychotics (e.g. chlordiazepoxide, fluoxetine, and citalopram), the reliability of data and the specificity of drug action will be greatly enhanced. Finally, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical condition and ensure the mechanisms identified are applicable to clinics. PUBLIC HEALTH RELEVANCE: How antipsychotic drugs work in the brain and change the psychological processing to achieve their therapeutic effects is unknown. This project is designed to reveal the psychological mechanisms of how antipsychotic drugs work. Successful project completion is expected to enhance our understanding of the behavioral and neurobiological mechanisms of antipsychotic action. Such knowledge will, in turn, enhance our understanding of the neurobiological basis of psychosis and help screen future novel antipsychotic drugs.

描述（由申请人提供）：抗精神病药物在临床使用已有半个多世纪的历史。不同受体位点的作用，尤其是多巴胺 D2、血清素 5-HT2A 和/或 5-HT1A 受体，对于抗精神病药物的治疗效果至关重要。这些神经生物学水平的作用如何转化为精神病症状的改善仍然悬而未决。首席研究员的长期目标是了解抗精神病药物的行为和神经生物学作用机制。本申请的目的是通过临床前方法确定抗精神病药物的行为机制。该项目假设是，抗精神病药物通过双重作用实现其抗“精神病”效果：（a）选择性削弱刺激的异常动机显着性（例如精神病想法或异常知觉、内部和外部线索）和（b）产生一种药物内感受状态，允许随着时间的推移维持对刺激动机显着性的减弱作用。基于重复治疗方案的条件性回避反应（CAR）模型和苯环己哌啶（PCP）诱导的过度运动模型将被创新地用于检验这一假设。目标 1 旨在检查 CAR 模型中动机显着性行为的弱化。目标 2 是使用 CAR 模型描述第二种拟议的抗精神病作用机制：内感受药物状态。目标 3 的结构是使用苯环己哌啶 (PCP) 诱导的过度运动模型来交叉验证前两个目标的发现并进一步检验我们的假设。该项目具有创新性，因为将采用几种新颖的实验操作技术来描述受抗精神病药物影响的确切心理过程，并将与抗精神病药物作用相关的心理过程与不相关的心理过程区分开来。此外，对抗精神病药物作用敏感的多种行为模型将用于交叉验证研究结果并测试替代假设。由于抗精神病药将直接与非抗精神病药（如利眠宁、氟西汀和西酞普兰）进行比较，因此数据的可靠性和药物作用的特异性将大大增强。最后，重复的药物治疗方案而不是急性治疗方案将为临床状况提供更好的模型，并确保所确定的机制适用于临床。 公共卫生相关性：抗精神病药物如何在大脑中发挥作用并改变心理过程以实现其治疗效果尚不清楚。该项目旨在揭示抗精神病药物发挥作用的心理机制。项目的成功完成预计将增强我们对抗精神病作用的行为和神经生物学机制的理解。这些知识反过来将增强我们对精神病神经生物学基础的理解，并有助于筛选未来的新型抗精神病药物。