Adolescence neurogenesis mechanisms of antipsychotic sensitization and tolerance

 描述：青春期是大脑和各种心理功能发生戏剧性转变的时期。这也是各种严重精神障碍症状经常出现的时候。近年来，在患有精神分裂症和其他严重精神疾病的儿童和青少年中，抗精神病药物的使用显著增加(~6倍)。然而，关于抗精神病药物暴露对大脑和行为发育的长期后果的研究还很缺乏。由于抗精神病药物治疗是对精神疾病患者进行的，因此需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心理功能和大脑成熟的其他方面可能产生的短期和长期影响。PI的长期目标是了解青春期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实验室以前的工作表明，在成年和青少年大鼠的条件性回避反应模型中，重复间歇给药奥氮平都会诱导敏化样(幅度增加)效应，而重复间歇给药则会引起耐受样(幅度降低)效应。临床前研究还表明，反复的抗精神病药物治疗改变了青少年海马区的神经发生。这项R03项目将以这些发现为基础，评估奥氮平敏化(AIM 1)和氯氮平耐受性(AIM 2)，以及它们与暴露于多胞体：多肌苷酸(PolyI：C)-一种有效的精神分裂症大鼠母体免疫激活(MIA)模型-的大鼠母亲所生的青春期大鼠神经发生变化的可能联系。此外，该项目将揭示MIA和抗精神病药物诱导的神经发生模式变化之间可能的相互作用。一般的方法是用PolyI：C在怀孕雌性大鼠体内产生免疫激活，然后通过持续给药诱导青春期后代对奥氮平或氯氮平的敏感性或耐受性，并在动物成年后检测其表达。合成的核苷溴脱氧尿苷(BrdU)将用于确定抗精神病药物治疗后神经元存活的区域。最后，用NeuN或胶质纤维酸性蛋白抗体对抗BrdU进行双重标记，以进一步证实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，而且还将允许详细研究这种暴露对神经元发育的长期影响。该项目具有重要意义，因为它将对精神药物评价、未来的药物开发和临床实践产生影响。

 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.