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

• 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
• 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; 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

 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：青少年是戏剧性转变下大脑和各种心理功能的时期。这也是各种严重精神疾病的症状经常表现出来的时候。近年来，精神分裂症和其他严重精神疾病的儿童和青少年的抗精神病药物使用显着增加（约6倍）。但是，缺乏对抗精神病药对大脑和行为发展的长期后果的研究。由于对精神病患者进行抗精神病药物治疗，因此有必要使用验证的精神分裂症模型来评估抗精神病药物对心理功能和大脑成熟的其他方面的短期和长期影响。 PI的长期目标是了解青少年期间抗精神病药物对整个发育过程中行为和神经生物学功能的影响。 PI实验室的先前工作表明，在成年和青少年大鼠的条件回避响应模型中，反复间歇性地间歇性给予敏感性（幅度升高）效应，而氯氮平的重复促进氯氮平的反复施用会诱导耐受性（幅度降低）效应。临床前研究还表明，反复进行的抗精神病药物改变了海马中的青少年神经发生。该R03项目将基于这些发现以评估奥氮平（AIM 1）和氯氮平耐受性（AIM 2）及其可能与已暴露于多余胞苷的大鼠母亲出生的神经发生变化的可能联系。此外，该项目将揭示MIA与抗精神病药诱导的神经发生模式变化之间的可能相互作用。一般的方法是使用Polyi：C在怀孕的雌性大鼠中产生免疫反应，然后通过连续药物给青春期后代诱导奥氮平的感觉或氯氮平耐受性，然后在动物成为成年人后测试其表达。抗精神病药物治疗后，合成核灵绳（BRDU）将用于鉴定神经元存活区域。最后，使用NEUN或神经胶质纤维酸性蛋白抗体将抗BRDU的双重标记用于进一步确认在抗毒性治疗的影响下产生的细胞的分化。该项目不仅会增加我们对抗精神病药作用的行为和神经生物学机制的理解，而且还允许详细研究这种暴露对神经元发展的长期影响。项目很重要，因为它将对精神药物评估，未来的药物开发和临床实践有影响。