Behavioral mechanisms of antipsychotic action

描述（由申请人提供）：抗精神病药物已在临床上使用超过半个世纪。在各种受体位点的作用，特别是多巴胺D2、5-羟色胺5-HT 2A和/或5-HT 1A受体，对于抗精神病药物的治疗效果至关重要。这些在神经生物学水平上的行为如何转化为精神病症状的改善仍然没有解决。主要研究者的长期目标是了解抗精神病药物作用的行为和神经生物学机制。本申请的目的是通过临床前方法确定抗精神病药物作用的行为机制。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”作用：（a）选择性地削弱刺激的异常动机显著性（例如，精神病思想或异常感知、内部和外部线索）和（B）产生药物内感受状态，其允许随着时间的推移维持对刺激的动机显著性的减弱效果。基于重复治疗方案的条件性回避反应（CAR）模型和苯环利定（PCP）诱导的过度运动模型将创新性地用于检验这一假设。目的1是为了研究CAR模型中动机突显行为的弱化。目的2是描述第二个提出的抗精神病药物作用机制：使用CAR模型的内感受性药物状态。目的3是使用苯环利定（PCP）诱导的hypermotortion模型交叉验证前两个目的的发现，并进一步验证我们的假设。这个项目是创新的，因为几个新的实验操作技术将被用来描述确切的心理过程受抗精神病药物和梳理除了相关的抗精神病药物的行动无关的。此外，对抗精神病药物敏感的多种行为模型将用于交叉验证结果和检验替代假设。由于抗精神病药物将直接与非抗精神病药物（如利血平、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提供更好的临床状况建模，并确保所确定的机制适用于临床。

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.