Behavioral mechanisms of antipsychotic action

抗精神病作用的行为机制

基本信息

批准号：
8212599
负责人：
MING LI
金额：
$ 28.77万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
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/8212599
关键词：
Acute Address Affect Amphetamines Animal Testing Animals Anti-Anxiety Agents Antidepressive Agents Antipsychotic Agents Area Attention 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 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

项目摘要

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）：抗精神病药已经在临床上使用了半个多世纪。在各种受体部位的作用，尤其是多巴胺D2，5-羟色胺5-HT2A和/或5-HT1A受体，对于抗精神病药的治疗作用至关重要。这些在神经生物学水平的行动如何转化为精神病症状的改善。主要研究者的长期目标是了解抗精神病药作用的行为和神经生物学机制。该应用的目的是通过临床前方法识别抗精神病药作用的行为机制。该项目假设是，抗精神病药通过双重动作实现其抗“精神病”效应：（a）选择性地削弱刺激的异常动机显着性（例如，精神病性思想或内部和外部提示）和（b）对刺激性的影响较弱的刺激效果，从而弱化了刺激性的刺激性状态。基于重复治疗方案的条件回避反应（CAR）模型（CAR）模型（PCP）诱导的超替代模型将用于检验该假设。 AIM 1旨在检查汽车模型中动机显着性动作的削弱。目的2是表征抗精神病药作用的第二种提出的机制：使用CAR模型的感知性药物状态。 AIM 3的结构是使用苯克林（PCP）诱导的超叠剂模型来从前两个目标进行跨效率的发现，并进一步检验我们的假设。该项目具有创新性，因为将采用几种新型的实验操纵技术来表征受抗精神病药影响的确切心理过程，并嘲笑与无关的抗精神病药作用相关的心理过程。此外，对抗精神病药作用敏感的多种行为模型将用于交叉估算结果和检验替代假设。由于抗精神病药将直接与非抗精神病药（例如氯氮二氮，氟西汀和西妥位）进行比较，因此数据的可靠性和药物作用的特异性将得到极大的增强。最后，重复的药物治疗方案而不是急性治疗方案将提供更好的临床状况建模，并确保确定的机制适用于诊所。公共卫生相关性：抗精神病药在大脑中如何起作用并改变心理加工以实现其治疗作用是未知的。该项目旨在揭示抗精神病药方式的心理机制。预计成功的项目完成将增强我们对抗精神病药作用的行为和神经生物学机制的理解。反过来，这种知识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。