Behavioral mechanisms of antipsychotic action

描述(申请人提供)：抗精神病药物在临床上已经使用了半个多世纪。不同受体部位的作用，尤其是多巴胺D2、5-羟色胺5-HT2a和/或5-HT1a受体，对抗精神病药物的疗效至关重要。神经生物学水平上的这些行动如何转化为精神病症状的改善仍未解决。首席调查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。这一应用的目的是通过临床前的方法来确定抗精神病作用的行为机制。项目假说是，抗精神病药物通过双重作用实现其抗精神病效果：(A)选择性地削弱刺激(例如，精神病思想或异常知觉、内部和外部线索)的异常动机突显；(B)产生一种药物相互感知状态，允许对刺激动机突显的减弱效应随着时间的推移而保持。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)诱导的多动模型将创新性地用于检验这一假说。目标1旨在研究汽车模型中动机显著作用的减弱。目的2是利用CAR模型描述第二种被提出的抗精神病作用机制：内感药物状态。AIM 3的结构是使用苯环利定(PCP)诱导的超运动模型来交叉验证前两个AIM的发现，并进一步验证我们的假设。这个项目是创新的，因为将使用几种新的实验操作技术来表征抗精神病药物影响的确切心理过程，并梳理出与抗精神病药物作用相关的和无关的。此外，对抗精神病药物敏感的多个行为模型将用于交叉验证研究结果并测试替代假说。由于抗精神病药物将直接与非抗精神病药物(如氯氮卓酮、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提高。最后，重复药物治疗方案而不是急性药物治疗方案将更好地模拟临床情况，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.