Models of Antipsychotic Prophylaxis for Schizophrenia

描述(由申请人提供)：临床证据表明，长期未经治疗的精神病可能与症状的严重性增加和整体生活质量下降有关。再加上精神分裂症极其虚弱的性质，人们对精神障碍的早期识别和治疗重新产生了兴趣，包括前驱症状。虽然早期干预的有效性、安全性和伦理学正在临床领域得到检验，但为了给这场辩论提供信息，有必要对动物预防性治疗的治疗潜力和长期后果进行临床前研究。由于某些形式的精神分裂症似乎可归因于早期发育障碍，许多动物研究已经检查了特定的发育操作对与精神分裂症相关的行为和神经回路的影响。两种发育大鼠模型，隔离饲养和新生大鼠腹侧海马区损伤，导致感觉运动门控缺陷和运动多动。使用这两种互补的发育操作很重要，因为它们的时间和侮辱方式不同，但会导致相似的行为和神经元异常。这些模型将允许检查预防性治疗的治疗潜力和个体发育期间慢性治疗的潜在副作用。隔离饲养是一种非药理学的环境干扰，剥夺了大鼠从断奶到成年期的社会接触。新生儿腹侧海马区损害涉及一种离散的神经解剖学损害，具有时间和区域特异性。这项应用的研究将测试长期早期服用抗精神病药物是否会防止隔离、养育或新生海马区损伤导致的感觉运动、门控和运动习惯缺陷的发展。考虑到模型对重复操作的潜在敏感性，最初将通过饮用水给药8周，然后在不同的时间点给药，以确定抗精神病药物治疗的关键发展窗口。其具体目的是：1：确定早期给药的最佳参数和作用效果。2.评价预防性抗精神病药治疗对隔离教养方式所致行为缺陷的影响。3.评价预防性抗精神病药治疗对新生大鼠行为障碍的影响。

DESCRIPTION (provided by applicant): Clinical evidence suggests that a prolonged period of untreated psychosis may be associated with increased severity of symptoms and decreased overall quality of life. Taken together with the extremely debilitating nature of schizophrenia, there is a renewed interest in the early identification and treatment of psychotic disorders, including prodromal symptoms. While the efficacy, safety, and ethics of early intervention are being examined in the clinical arena, preclinical studies on the therapeutic potential and long-term consequences of prophylactic treatments in animals are warranted in order to inform this debate. Because some forms of schizophrenia appear to be attributable to early developmental perturbations, many animal studies have examined the influences of specific developmental manipulations on behaviors and neural circuitry relevant to schizophrenia. Two developmental rat models, isolation rearing and neonatal ventral hippocampal lesions, result in both sensorimotor gating deficits and locomotor hyperactivity. The use of these two complementary developmental manipulations is important because they differ in their timing and mode of insult, but result in similar behavioral and neuronal abnormalities. These models will allow the examination of the therapeutic potential of prophylactic treatment and the potential side effects of chronic treatment during ontogeny. Isolation rearing is a non-pharmacological, environmental perturbation that deprives the rats of social contact from weaning through adulthood. Neonatal ventral hippocampal lesions involve a discrete, neuroanatomical insult that has temporal and regional specificity. Studies in this application will test whether long-term early administration of antipsychotic medications will prevent the development of isolation rearing or neonatal hippocampal lesion-induced deficits in sensorimotor gating and locomotor habituation. Considering the potential sensitivity of the models to repeated handling, antipsychotic drugs will be administered through the drinking water for an 8 week period initially and then at different time points to determine the critical developmental window of antipsychotic treatment. The specific aims are: 1: To determine the optimal parameters and functional effects of early developmental antipsychotic administration in rats. 2. To assess the effects of prophylactic antipsychotic treatment on isolation rearing induced behavioral deficits. 3. To assess the effects of prophylactic antipsychotic treatment on neonatal ventral hippocampal lesion induced behavioral deficits.