近年来，抗精神病药用药人群在青少年精神疾病患者中快速增加，但目前很少有研究深入关注此类药物对大脑功能的长期影响及其神经生物学机制。青春期大脑发育变化迅速，前临床研究提示在青春期用药会对神经受体功能造成特殊影响。故迫切需要考察青春期抗精神病药使用对大脑发育所造成的长期影响及并阐明其机制。最近的研究发现青春期使用抗精神病药可引起长期持续的敏化现象，然而并不清楚其产生机制以及性别差异的作用。因此，本项目将考察青春期使用抗精神病药奥氮平和利培酮引起的敏化效应的行为特征，并通过RT-PCR、免疫印迹和脑内微注射的技术考察前额叶、纹状体和海马内的5-HT2A和多巴胺D2受体系统在抗精神病药敏化中的作用机制，并揭示母体免疫激活、药物剂量以及性别等因素的效应。本项目结果将会阐明抗精神病药对大脑功能的长期影响及敏化的神经生物学机制，有助于进一步认清抗精神病药的治疗机制，并为临床用药和新药开发提供参考。

In recent years, there has been a significant increase in antipsychotic use in children and adolescents with severe mental illnesses. However, research on the long-term effects and related neurobiological mechanisms of antipsychotic exposure on the brain development is lacking. Adolescence is a critical period with rapid brain development. Preclinical studies suggest various neurotransmitter systems undergo maturational changes during adolescence. Exposure to antipsychotic drug during this period also alters these neuroreceptors in unique ways. Thus there is an urgent need to evaluate the possible long-term impacts of antipsychotic medications on brain functions and to examine the underlying mechanisms. Recent studies show that repeated administration of many antipsychotic drugs in adolescence can induce a long-term antipsychotic sensitization. However, the specific neurobiological mechanisms underlying such a long-term effect have not been examined. Whether such a development of drug response patterns follows a sex-dependent way has never been explored. The proposed project will investigate the behavioral characteristics and neurobiological mechanisms underlying antipsychotic sensitization from adolescence to adulthood. We will especially focus on the dopamine D2 and serotonin 2A receptor systems in the prefrontal cortex, striatum, and hippocampus, using RT-PCR, western blotting and intracranial microinjection techniques. The effects of maternal immune activation, drug doses and sex will be elucidated as well. It is expected to contribute to knowledge regarding the behavioral and brain changes caused by early adolescent antipsychotic exposure, as well as the underlying neurobiological mechanisms. Project outcomes are expected to improve the understanding of treatment effects of antipsychotic drugs, and to positively impact clinical practice involving pediatric patients with schizophrenia and to facilitate drug development.