DEVELOPMENTAL MODELS OF GATING DEFICITS IN SCHIZOPHRENIA

描述：(改编自《调查者摘要》)隔离抚养 大鼠是一种发育特异性的非药物操作，它导致 感觉运动门控的缺陷，通过脉冲前对惊吓的抑制来衡量， 这与在精神分裂症患者身上观察到的情况类似。在老鼠身上，这些门控 典型的和非典型的抗精神病药物都可以逆转这种缺陷。 修改后的续签申请的具体目的是使用隔离 饲养手法以更好地了解神经生物学底物 潜在的精神分裂症谱系障碍。在AIM 1中，剂量反应研究是 建议进一步描述选定的药理药剂的作用 关于隔离饲养对大鼠的影响。首先，预测效度。 隔离教养诱导的脉冲前抑制缺陷作为一种模型 抗精神病药物的效果将通过测试已知的抗精神病药物来评估 药物和来自其他精神治疗类别的药物。第二，额外的 对特定受体具有相对选择性作用的化合物将是 审查以测试关于这些特定事件参与的假设 受体在隔离饲养行为效应中的中介作用。目标 两项研究将检验隔离饲养的效果后，操作几个 神经底物与两种疾病的病理生理机制有关 精神分裂症与脉前抑制的调节，包括 海马体、内侧前额叶皮质、纹状体和腹侧苍白球。 神经化学选择性损伤和多巴胺能离散微量注射 5-羟色胺能拮抗剂将用于阐明神经生物学 底物的隔离饲养导致了门控缺陷。目标3将确定 特定于区域的神经化学变化与特定的 隔离导致脉冲前抑制的缺陷。这些假设密切相关 与目标2中使用不同方法解决的问题相联系 学习。因此，目标2和目标3承诺提供应 使我们能够识别已知调节PPI的电路的哪些部分 与隔离饲养对这一动物模型的影响最相关 在精神分裂症患者中观察到感觉运动门控缺陷。

DESCRIPTION: (Adapted from the Investigator's Abstract) Isolation rearing of rats is a developmentally specific non-pharmacological manipulation that leads to deficits in sensorimotor gating, measured by prepulse inhibition of startle, that mimic those observed in schizophrenic patients. In rats, these gating deficits are reversed by both typical and atypical antipsychotic medications. The specific aims of this revised renewal application are to use the isolation rearing manipulation to better understand the neurobiological substrates underlying schizophrenia-spectrum disorders. In Aim 1 dose-response studies are proposed to further characterize the effects of selected pharmacological agents on isolation rearing effects in rats. First, the predictive validity of isolation-rearing-induced deficits in prepulse inhibition as a model of antipsychotic drug effects will be assessed by testing known antipsychotic drugs and drugs from other psychiatric treatment classes. Second, additional compounds having relatively selective actions at particular receptors will be examined to test hypotheses regarding the involvement of these particular receptors in the mediation of the behavioral effects of isolation rearing. Aim 2 studies will examine isolation rearing effects after manipulations of several neural substrates that are implicated in both the pathophysiology of schizophrenia and the regulation of prepulse inhibition, including the hippocampus, medial prefrontal cortex, striatum, and ventral pallidum. Neurochemically selective lesions and discrete microinjections of dopaminergic and serotonergic antagonists will be used to elucidate the neurobiological substrates of the isolation rearing induced gating deficit. Aim 3 will identify regionally specific neurochemical changes that are correlated specifically with isolation-induced deficits in prepulse inhibition. These hypotheses are closely linked to the questions being addressed using different methods in the Aim 2 studies. Thus, Aims 2 and 3 promise to provide converging evidence that should enable us to identify which parts of the circuitry known to regulate PPI are most relevant to the effects of isolation rearing on this animal model of the sensorimotor gating deficits observed in schizophrenia.