Adolescence neurogenesis mechanisms of antipsychotic sensitization and tolerance

青春期抗精神病药物敏化和耐受的神经发生机制

基本信息

批准号：
9020254
负责人：
MING LI
金额：
$ 7.73万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-20 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9020254
关键词：
Adolescence Adolescent Adult Adverse effects Affect Age Anatomy Animal Disease Models Animals Antibodies Antipsychotic Agents Behavior Behavioral Behavioral Assay Behavioral Mechanisms Biological Assay Brain Bromodeoxyuridine Cell Differentiation process Cells Characteristics Child Chronic Clinical Clozapine Development Disease Disease model Dose Drug Evaluation Female Future Glial Fibrillary Acidic Protein Goals Health Hippocampus (Brain)Human Immunohistochemistry Immunologic Adjuvants Investigation Knowledge Label Laboratories Link Long-Term Effects Longitudinal Studies Mediating Mental Health Mental disorders Mission Modeling Molecular Abnormality Mothers Neurobiology Neurons Nucleosides Outcome Patients Pattern Personal Satisfaction Pharmaceutical Preparations Physiological Poly I Pregnancy Process Psychotropic Drugs Rattus Reaction Research Saline Schedule Schizophrenia Sensory Receptors Symptoms Synaptic Receptors Testing Therapeutic Time Treatment Efficacy Work adolescent offspring clinical practice clinically significant critical period design drinking water drug development drug sensitivity early adolescence immune activation innovation insight mature animal neurobiological mechanism neurogenesis neuron development neuronal survival neuropsychological novel olanzapine pediatric patients postnatal pre-clinical preclinical study pregnant psychologic response severe mental illness symptom management

项目摘要

DESCRIPTION: Adolescence is a period in which the brain and various psychological functions undergo dramatic transitions. It is also the time when symptoms of a variety of severe mental disorders often manifest. In recent years, there has been a significant increase (~6 folds) in antipsychotic use in children and adolescents with schizophrenia and other severe mental illnesses. However, research on the long-term consequences of antipsychotic exposure on the brain and behavioral developments is lacking. As antipsychotic treatment is administered to patients of psychiatric illnesses, there is a need to evaluate the possible short-term and long-term impacts of antipsychotic medications on psychological functions and other aspects of brain maturation at various ages using a validated preclinical disease model of schizophrenia. The PI's long-term goal is to understand the impacts of antipsychotic treatment during adolescence on the behavioral and neurobiological functions throughout development. Previous work from the PI's laboratory shows that repeated intermittent administration of olanzapine induces a sensitization-like (increase in magnitude) effect in a conditioned avoidance response model in both adult and adolescent rats, whereas repeated intermittent administration of clozapine induces a tolerance- like (decrease in magnitude) effect. Preclinical studies also suggest that repeated antipsychotic treatment alters adolescent neurogenesis in the hippocampus. This R03 project will build upon these findings to assess olanzapine sensitization (Aim 1) and clozapine tolerance (Aim 2) and their possible link to alterations in neurogenesis in adolescent rats born from rat mothers that have been exposed to polycytidilic:polyinosinic acid (PolyI:C) - a validated rat maternal immune activation (MIA) model of schizophrenia. In addition, the project will reveal possible interactions between MIA and antipsychotic-induced changes in patterns of neurogenesis. The general approach is to generate immune activation in pregnant female rats using PolyI:C, then induce olanzapine sensitization or clozapine tolerance in the adolescent offspring through continuous drug administration, then test its expression after the animals become adults. The synthetic nucleoside bromodeoxyuridine (BrdU) will be used to identify regions of neuronal survival following antipsychotic treatments. Finally, double labeling of anti-BrdU with NeuN or glial fibrillary acidic protein antibodies is used to further confirm the differentiation of cells generated under the influence of antipsychotic treatment. This project wil not only increase our understanding of the behavioral and neurobiological mechanisms of antipsychotic action, but also allow a detailed study of the long-term impacts of such exposure on neuronal development. This project is significant as it will have implications for psychotropic drug evaluation, future drug development, and clinical practice.

描述：青春期是大脑和各种心理功能发生剧烈转变的时期，也是各种严重精神障碍症状经常显现的时期，近年来明显增加（~6倍）。患有精神分裂症和其他严重精神疾病的儿童和青少年使用抗精神病药物然而，由于对精神病住院患者进行抗精神病治疗，因此缺乏关于接触抗精神病药物对大脑和行为发展的长期影响的研究。有必要使用经过验证的精神分裂症临床前疾病模型来评估抗精神病药物对不同年龄段的心理功能和大脑成熟其他方面可能产生的短期和长期影响。青春期期间抗精神病药物治疗对整个发育过程中行为和神经生物学功能的影响 PI 实验室先前的研究表明，反复间歇性服用奥氮平会诱发类似敏化的情况。在成年和青少年大鼠的条件性回避反应模型中，氯氮平的重复间歇给药会诱导耐受样（程度的减少）效应，而临床前研究还表明，重复的抗精神病药物治疗会改变青少年的神经发生。该 R03 项目将基于这些发现来评估奥氮平致敏性（目标 1）和氯氮平耐受性（目标 2）及其与改变的可能联系。暴露于多聚肌苷酸 (PolyI:C) 的大鼠母亲所生的青少年大鼠的神经发生 - 一种经过验证的精神分裂症大鼠母体免疫激活 (MIA) 模型此外，该项目还将揭示 MIA 和抗精神病药物之间可能存在的相互作用。 -诱导神经发生模式的变化，一般方法是使用PolyI:C在怀孕雌性大鼠中产生免疫激活，然后在青少年中诱导奥氮平敏化或氯氮平耐受。通过连续给药，然后在动物成年后测试其表达。合成的核苷溴脱氧尿苷（BrdU）将用于识别抗精神病治疗后的神经存活区域，最后，用 NeuN 或神经胶质纤维酸性双重标记抗 BrdU。蛋白质抗体用于进一步确认在抗精神病药物治疗的影响下产生的细胞的分化，该项目不仅将增加我们对抗精神病药物作用的行为和神经生物学机制的理解，还可以详细研究这种暴露对神经发育的长期影响，该项目意义重大，因为它将对精神药物评估、未来药物开发和临床实践产生影响。