Antipsychotic Drugs and Maternal Behavior: A Preclinical Investigation

抗精神病药物和母亲行为：临床前研究

基本信息

批准号：
7293747
负责人：
MING LI
金额：
$ 6.64万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7293747
关键词：
Adverse effects Affect Agonist Amisulpride Amphetamines Animal Model Anti-Anxiety Agents Antipsychotic Agents Applications Grants Behavior Behavioral Behavioral Mechanisms Biological Models Caring Child Development Child Rearing Chlordiazepoxide Clinical Clinical Drug Development Clozapine Cognitive Complex Data Development Disruption Dopamine Dopamine D2 Receptor Dose Drug effect disorder Drug usage Effectiveness Emotional Evaluation Future Goals Haloperidol Health Human Impairment Infant Inferior Investigation Knowledge Life Light Literature Maternal Behavior Mediating Modeling Mother-Child Relations Mothers Motivation Motor Nature Neurobiology Outcome Patients Pharmaceutical Preparations Postpartum Period Process Property Psychotropic Drugs Publishing Quinpirole Rattus Reporting Retrieval Review Literature Risperidone Rodent Role Schizophrenia Sedation procedure Serotonin Serotonin Receptor 5-HT2A Social Interaction Specificity System Techniques Testing Therapeutic Ursidae Family Woman Work atypical antipsychotic base child well being coping design innovation motivational processes neurobiological mechanism neurochemistry neurotransmission novel olanzapine pre-clinical psychologic pup quetiapine response sedative social

项目摘要

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.

描述（申请人提供）：母子关系的临床工作表明，精神分裂症女性的孕产妇护理质量普遍低于健康母亲。患者及其临床医生都认识到的一项重要影响因素是抗精神病药物。据报道，典型和非典型抗精神病药都会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的神经生物学和行为机制。该 R03 应用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亲行为产生不良影响的行为和神经化学机制。该项目假设是，在临床相关剂量下，抗精神病药物对母亲行为的破坏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。选择大鼠母性行为作为模型系统，因为它是一种生态上有效且复杂的行为，跨越哺乳动物物种，并与人类母性行为具有许多直接特征。目标 1 将研究抗精神病药物对大鼠母性行为的破坏作用背后的动机机制。目标 2 将确定氯氮平引起的母亲行为缺陷的神经化学基础（多巴胺与血清素）。具体来说，PI 将寻求确定 (1) 氟哌啶醇和氯氮平在治疗相关剂量（啮齿动物中约 50%-80% D2 占有率）是否会通过降低母鼠的动机（而不是运动）来破坏活跃的母性行为。功能或镇静作用； (2)氯氮平(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-HT2A受体在多大程度上扰乱母体行为。该项目的创新之处在于，将采用行为学手段（母仔分离、重复给药和测试）和药理学手段（利眠宁）来梳理大鼠母性行为中涉及的各种不同行为过程的特定抗精神病作用。。该临床前项目旨在确定抗精神病药物对人类母性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预计将加深对抗精神病药物影响孕产妇护理质量的程度以及这种影响的性质的了解。项目成果预计将提高母亲精神药物使用评估、未来药物开发和临床实践的有效性，并最终对患有精神分裂症的母亲的孩子的健康和福祉产生积极影响。