Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
Neuropsychopharmacology. 2013 Oct;38(11):2131-9. doi: 10.1038/npp.2013.110. Epub 2013 May 8.
Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.
尽管许多研究表明压力与精神分裂症的病理生理学有关，但对于压力的影响如何与遗传、发育和/或环境决定因素相互作用以促进疾病进展知之甚少。特别是，有人提出，在人类中，青春期的压力暴露可能与增加的压力敏感性倾向相结合，导致前驱症状并最终导致精神病。然而，这种相互作用的神经生物学基础尚未完全描述。我们实验室之前的工作表明，在妊娠第 17 天接受 DNA 甲基化剂甲基乙酰胺（MAM）处理的母鼠所生的大鼠，在成年时表现出与精神分裂症患者观察到的行为和解剖异常一致的异常。在这里，我们检查了精神分裂症 MAM 模型中的应激行为和神经内分泌反应。MAM 处理的雄性大鼠在青春期前、青春期和成年期接受急性和重复足底电击应激。对超声发声（USVs）、冻结和皮质酮反应进行了量化。我们发现，与生理盐水（SAL）处理的大鼠相比，幼年 MAM 处理的大鼠在急性足底电击应激时发出的叫声更多，发声时间更长，发声频率更高，并且表现出更多的冻结，而这种差异在老年动物中不存在。此外，青春期 MAM 处理的动物对急性足底电击的 HPA 轴皮质酮反应迟钝，在 10 天的应激暴露后没有适应。这些数据表明精神分裂症 MAM 模型中的应激反应异常，并表明这些动物在年轻时对压力的影响更敏感。
