Antipsychotic Drugs and Maternal Behavior: A Preclinical Investigation

描述（由申请人提供）：关于母子关系的临床工作表明，精神分裂症妇女的孕产妇护理质量一般低于健康母亲。一个重要的影响因素，公认的病人和他们的临床医生是抗精神病药物。据报告，典型和非典型抗精神病药物都对孕产妇护理产生不利影响。PI的长期目标是了解抗精神病药物作用的神经生物学和行为机制。本R 03申请的目的是使用大鼠模型确定典型和非典型抗精神病药物对母体行为不良影响的行为和神经化学机制。项目假设是，在临床相关剂量下，抗精神病药物对母体行为的破坏性作用主要反映了对母体动机的抑制作用，并通过多巴胺D2受体系统介导。选择大鼠母性行为作为模型系统，因为它是一种生态有效的和复杂的行为，跨越哺乳动物物种，并与人类母性行为有许多直接的特征。目的1将探讨抗精神病药物对大鼠母性行为破坏作用的动机机制。目的2将确定氯氮平引起的母亲行为缺陷的神经化学基础（多巴胺与5-羟色胺）。具体而言，PI将寻求确定（1）治疗相关剂量的氟哌啶醇和氯氮平是否（啮齿类动物中约50%-80%的D2占用率）通过降低母鼠的动机（而不是运动功能或镇静）来破坏活跃的母性行为;（2）氯氮平的作用程度（作为非典型抗精神病药物的代表）通过阻断多巴胺D2受体和/或5-HT 2A受体来破坏母体行为。该项目的创新之处在于，将采用行为（母婴分离，重复给药和测试）和药理学手段（氯氮卓）来梳理特定的抗精神病药物对大鼠母性行为中涉及的各种不同行为过程的影响。.这个临床前项目旨在确定抗精神病药物对人类母性行为的不良副作用的重要心理和神经化学机制。从这个项目中获得的知识，预计将提高抗精神病药物影响孕产妇保健的质量和这种影响的性质的程度的理解。预计项目成果将提高对母亲使用精神药物的评价的有效性、未来的药物开发和临床实践，并最终对精神分裂症母亲的子女的健康和福祉产生积极影响。

DESCRIPTION (provided by applicant): Clinical work on the mother-child relationship shows that the quality of maternal care from women with schizophrenia is generally inferior to that from healthy mothers. One important contributing factor recognized by both patients and their clinicians is antipsychotic medications. Both typical and atypical antipsychotics are reported to adversely affect maternal care. The PI's long-term goal is to understand the neurobiological and behavioral mechanisms of action of antipsychotic drugs. The objective of this R03 application is to determine the behavioral and neurochemical mechanisms underlying the adverse effects of both typical and atypical antipsychotics on maternal behavior using a rat model. The project hypothesis is that at the clinical relevant dose, the disruptive effect of antipsychotics on maternal behavior primarily reflects a suppressive effect on maternal motivation and is mediated via the dopamine D2 receptor system. Rat maternal behavior is chosen as a model system because it is an ecologically valid and complex behavior that cuts across mammalian species and shares many direct features with human mothering behaviors. Aim 1 will examine the motivational mechanism underlying the disruptive effect of antipsychotics on rat maternal behavior. Aim 2 will identify the neurochemical basis (dopamine versus serotonin) of clozapine-induced maternal behavior deficits. Specifically, the PI will seek to determine (1) whether haloperidol and clozapine at the therapeutic relevant doses (~50%-80% D2 occupancy in rodents) produce a disruption of active maternal behaviors by decreasing mother rats' motivation, as opposed to motor function or sedation; (2) to what extent clozapine (as the representative of atypical antipsychotic drugs) disrupts maternal behavior via the blocking of dopamine D2 receptors and/or 5-HT2A receptors. This project is innovative in that both behavioral (mother-pup separation, repeated drug administration and testing) and pharmacological means (chlordiazepoxide) will be employed to tease apart the specific antipsychotic effects on various distinct behavioral processes involved in rat maternal behavior. . This preclinical project is designed to determine the important psychological and neurochemical mechanisms underlying the adverse side effects of antipsychotic medication on human mothering behavior. Knowledge gained from this project is expected to enhance understanding of the extent to which antipsychotic drugs impact the quality of maternal care and the nature of such impact. Project outcomes are expected to increase the effectiveness of the evaluation of psychotropic drug uses in mothers, future drug development and clinical practice and, ultimately, positively impact the health and well-being of children of mothers with schizophrenia.