NEURAL SUBSTRATES OF PCP'S EFFECT ON SENSORIMOTOR GATING

精神分裂症（SZ）是一种使人衰弱的神经精神障碍， 表现为各种行为缺陷当前抗精神病药 药物，虽然成功地治疗了SZ的许多核心症状， 严重限制了它们的使用， 粒细胞缺乏的副作用。对神经基质的理解 调节这种疾病的特定缺陷可能会导致揭示 SZ中涉及的新机制，并可能最终导致 开发更安全的新疗法。前脉冲抑制（PPI）（一种测量 感觉运动门控，其中轻度的预刺激会减弱 对强烈刺激的惊吓反应的大小）是正常的 SZ患者缺乏的跨种属发生率。该减值 在PPI中，通过给予 非竞争性NMDA拮抗剂，如精神原苯环己哌啶 （五氯苯酚）。这个项目的目标是使用这种缺乏的动物模型， PPI以更好地了解PCP的拟精神病作用， 揭示SZ患者感觉运动门控受损的新底物。 最初，假设多个受体介导PPI- 五氯苯酚的破坏性影响将使用选择性和混合 轮廓拮抗剂，以阻止PCP的影响。第二个假设 多个大脑区域介导这些效应将被测试， 颅内药物微输注技术。总而言之，该项目旨在 以确定PCP的药理学和神经解剖学机制- 在PPI中诱导赤字，以进一步了解 SZ中感觉运动门控缺陷的神经基质。

Schizophrenia (SZ) is a debilitating neuropsychiatric disorder that is manifested through a variety of behavioral deficits. Current antipsychotic medications, while successful in treating many of the core symptoms of SZ, are seriously limited in their use by profound extrapyramidal or agranulocytotic side effects. An understanding of the neural substrates mediating specific deficits of this disorder may lead to the revelation of novel mechanisms involved in SZ and might ultimately result in the development of new safer treatments. Prepulse inhibition (PPI) (a measure of sensorimotor gating in which a mild prestimulus attenuates the magnitude of the startle response to an intense stimulus) is a normal cross-species occurrence that is deficient in SZ patients. This impairment in PPI has been successfully modelled in rats by administration of noncompetitive NMDA antagonists such as the psychotogen phencyclidine (PCP). The goal of this project is to use this animal model of deficient PPI to better understand the psychotomimetic effects of PCP and ultimately uncover novel substrates of impaired sensorimotor gating in SZ patients. Initially, the hypothesis that multiple receptors mediate the PPI- disruptive effects of PCP will be tested using both selective and mixed profile antagonists to block the effects of PCP. The second hypothesis that multiple brain regions mediate these effects will be tested using intracranial drug microinfusion techniques. In summary, this project seeks to determine the pharmacological and neuroanatomical mechanisms of PCP- induced deficits in PPI in order to further our understanding of the neural substrates of deficient sensorimotor gating in SZ.