Behavioral mechanisms of antipsychotic action

抗精神病作用的行为机制

• 批准号: 8411240
• 负责人: MING LI
• 金额: $ 27.6万
• 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/8411240
• 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

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.

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。