Antipsychotic Drugs and Maternal Behavior: A Preclinical Investigation

描述(申请人提供)：关于母子关系的临床研究表明，患有精神分裂症的妇女的产妇护理质量一般低于健康母亲。患者和他们的临床医生都认识到的一个重要因素是抗精神病药物。据报道，典型和非典型抗精神病药物都会对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的神经生物学和行为作用机制。此R03应用的目的是使用大鼠模型来确定典型和非典型抗精神病药物对母体行为产生不良影响的行为和神经化学机制。项目假说是，在临床相关剂量下，抗精神病药物对母亲行为的干扰作用主要反映了对母亲动机的抑制作用，并通过多巴胺D2受体系统介导。大鼠母性行为之所以被选为模式系统，是因为它是一种跨越哺乳动物物种的生态有效和复杂的行为，并与人类母性行为有许多直接的特征。目的1将研究抗精神病药物对大鼠母体行为产生干扰作用的动机机制。目的2将确定神经化学基础(多巴胺和5-羟色胺)氯氮平诱导的母亲行为缺陷。具体地说，PI将寻求确定(1)治疗相关剂量的氟哌啶醇和氯氮平(D2在啮齿动物体内的占有率约为50%-80%)是否会通过降低母亲的动机而不是运动功能或镇静来扰乱母亲活跃的行为；(2)氯氮平(作为非典型抗精神病药物的代表)在多大程度上通过阻断多巴胺D2受体和/或5-HT2A受体来扰乱母亲的行为。该项目的创新之处在于，将同时使用行为学方法(母子分离、重复给药和测试)和药理学手段(氯氮孕酮)来梳理大鼠母性行为中涉及的各种不同行为过程中的特定抗精神病效果。。这一临床前项目旨在确定抗精神病药物对人类育儿行为产生不良副作用的重要心理和神经化学机制。从该项目中获得的知识可望加强对抗精神病药物对产妇护理质量的影响程度和这种影响的性质的了解。预计项目成果将提高对母亲使用精神药物的评价、未来药物开发和临床实践的有效性，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.