近年来，青少年精神障碍患者使用抗精神病药明显增加。抗精神病药物在改善精神症状的同时，也对其它心理功能产生了重要影响。然而，目前对抗精神病药物治疗所引起患者的大脑及相应心理功能的长期改变却未有深入研究。 青春期是发育的独特时期，大脑功能发育迅速，可塑性强，在此期间用药会特异性地改变某些神经受体功能。 因而，迫切需要考察青春期抗精神病药物的使用对大脑及心理功能所造成的长期影响 。李鸣博士进行的动物研究表明青春期抗精神病药物使用可改变成年后药物的敏感性，引起超敏化或耐受， 但其临床意义却不清楚。因此，本研究将考察青春期抗精神药物（奥氮平和氯氮平）处理对大鼠成年后各项心理功能（注意、情绪、社会行为、拟精神病药反应性）的长期影响，探索抗精神病药物引起的超敏化和耐受性的心理行为机制，并揭示其临床意义。本研究的结果将不仅有助于改善临床治疗精神分裂症的手段，而且有助于新药的筛查。

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 consequences and related neurobiological mechanisms of antipsychotic exposure on the brain and behavioral development is lacking. Preclinical studies suggest various neurotransmitter systems—especially the dopamine and serotonin systems in the prefrontal cortex, striatum, and hippocampus—undergo maturational changes during adolescence. Antipsychotic exposure during this period also alters these neuroreceptors in unique ways not seen in adult animals. As pediatric treatment is administered at a critical time of rapid brain and behavioral development, there is a need to evaluate the possible long-term impacts of antipsychotic medications on psychological functions. The long-term objective is to understand the impacts of antipsychotic treatment during adolescence on the behavioral and neurobiological functions throughout the development. Ming Li’s studies show that repeated administration of antipsychotic drugs in adolescence can alter drug sensitivity in adulthood, causing a sensitized or attenuated effect. However, the specific neurobiological mechanisms underlying such a long-term effect have not been examined. The clinical significance of antipsychotic sensitization and tolerance is also not clear. The proposed project will investigate the effects of long-term adolescent antipsychotic treatment on basic psychological functions in adulthood (Aim 1), and the behavioral characteristics of sensitization and tolerance from adolescence to adulthood and determine their clinical significance (Aim 2). Adolescent offspring born to polyI:C challenged mother rats (a maternal immune activation model of schizophrenia) and subjected to stress will be used as “diseased” subjects and treated with different doses of olanzapine or clozapine through daily injections. When they become adults, their sensitivity to antipsychotic re-exposure and the magnitude and persistence of such altered sensitivity in a conditioned avoidance response test will be assessed, along with their attention, emotion regulation, social functioning and others. It is expected that maternal immune activation plus aversive stress exposure and different antipsychotic treatments will affect attention, emotion regulation, social functioning and social memory in adulthood in an interactive fashion.

近年来，青少年精神障碍患者使用抗精神病药明显增加。抗精神病药物可以改善精神症状，也影响其它心理功能。本课题以考察青春期抗精神病药物的使用对大脑及心理功能所造成的长期影响为目标，运用条件躲避反应（CAR）、PCP 高运动性模型探索了抗精神病药物在青春期使用引起的敏感性（敏化和耐受），以及运用 EPM、PPI和社交等其他多种反应心理功能的行为学测试手段，结合药理学等方法，考察了心理功能的变化及可能的心理和行为机制。研究结果发现：（1）通过Pv-Cre转基因小鼠，结合AAV-DIO-Tetanus toxin病毒注射，特异性损毁腹侧海马的Pv阳性中间神经元，我们建立新的精神分裂动物模型；（2）不同于其他抗精神病药，成年期不同给药方式（皮下/静脉注射）对喹比啰（quetiapine）诱发的条件躲避反应抑制效应不会产生敏化或者耐受；（3）我们通过药物-药物条件化范式考察了抗精神病药物与尼古丁的交互效应，尼古丁不能改变氟哌啶醇或氯氮平的长期抗精神病疗效，而氟哌啶醇能改变尼古丁的行为效应，但氯氮平和尼古丁的不产生相互影响；（4）我们首次发现了青春期奥氮平或氯氮平处理没有显著改变成年后的焦虑、注意和社交及精神病性行为功能；（5）青春期长期连续的奥氮平处理对奥氮平产生耐受性，也造成尼古丁耐受，慢性氯氮平处理对雌性的青春期大鼠产生对耐受性；（6）青春期间歇性氯氮平处理引起的对氯氮平的耐受性会持续到成年，并且这种耐受性效应在母本免疫失活的子代个体更为明显；（7）青春期间歇性阿立哌唑处理可以性别依赖性地引起对阿立哌唑的敏化，这种效应会持续到成年。综合以上结果提示，青春期和成年期的抗精神病药物使用可以改变成年后对药物的敏感性，产生敏化或耐受，并且改变尼古丁的行为效应，抗精神病药物引起的敏化或耐受与其对情绪和社会行为的影响是分离的。