The Delayed Effects of Phencyclidine: Mechanisms

描述（由申请方提供）：苯环利定（PCP）是一种在人体中产生拟精神病症状的游离麻醉剂，因此研究了其产生精神分裂症动物模型的能力。据报道，五氯苯酚的延迟效应，即中毒消退后出现的效应，可诱导各种精神分裂症样行为，包括对苯丙胺的行为反应增强。此外，PCP预处理产生c-Fos的区域表达的变化，表明改变了神经元的活动。这些研究的目的是调查可能的药理学和神经解剖学网站PCP的行动，这背后的安非他明诱导的行为和c-Fos表达的延迟效应。在药理学上，五氯苯酚作为σ受体激动剂的作用与五氯苯酚的其他延迟效应有关。解剖学上，PCP诱导延迟减少前额叶皮层多巴胺的利用，效果，可能是基于前额叶皮层活动和皮层下多巴胺系统活动之间的关系的研究结果，其延迟安非他明诱导的行为和c-Fos表达的影响。因此，所提出的实验将通过检查σ受体激动剂模拟和σ受体拮抗剂阻断PCP对苯丙胺诱导的行为和c-Fos的影响的能力来检验σ受体激活在PCP的延迟效应中起作用的假设。这些实验还将检验PCP在前额叶皮层中的作用是其延迟效应的基础这一假设，方法是检查前额叶皮层内注射PCP模仿和前额叶皮层病变阻断全身PCP对苯丙胺诱导的行为和c-Fos的影响的能力。由于sigma受体和内侧前额叶皮质都与精神分裂症的病理生理学有关，因此PCP在这些部位的作用代表了PCP可能诱导精神分裂症样行为的合理机制。这些实验将开始确定五氯苯酚在动物中产生精神分裂症样行为的机制，从而深入了解人类精神分裂症的潜在病理生理学。

DESCRIPTION (provided by applicant): Phencyclidine (PCP) is a dissociate anesthetic that produces psychotomimetic symptoms in humans and has thus been investigated for its ability to produce an animal model for schizophrenia. The delayed effects of PCP, those seen after intoxication has subsided, have been reported to induce a variety of schizophrenia-like behaviors including enhanced behavioral response to amphetamine. In addition, PCP pretreatment produces changes in the regional expression of c-Fos, indicating altered neuronal activity. The goal of these studies is to investigate possible pharmacological and neuroanatomical sites of PCP's action, which underlie its delayed effects on amphetamine-induced behavior and c-Fos expression. Pharmacologically, PCP's action as a sigma receptor agonist has been implicated in other delayed effects of PCP. Anatomically, PCP induces delayed decreases in prefrontal cortex dopamine utilization, an effect which could, based on findings regarding the relationship between prefrontal cortex activity and subcortical dopamine system activity, underlie its delayed effects on amphetamine-induced behavior and c-Fos expression. Thus the proposed experiments will test the hypothesis that sigma receptor activation plays a role in the delayed effects of PCP by examining the ability for a sigma receptor agonist to mimic and a sigma receptor antagonist to block the effects of PCP on amphetamine-induced behavior and c-Fos. These experiments will also test the hypothesis that PCP's action in the prefrontal cortex underlies its delayed effects by examining the ability for intra-prefrontal cortex PCP injections to mimic and prefrontal cortex lesions to block the effects of systemic PCPon amphetamine-induced behavior and c-Fos. Because both sigma receptors and the medial prefrontal cortex have been implicated in the pathophysiology of schizophrenia, PCP's actions at these sites represent plausible mechanisms by which PCP could be inducing schizophrenia-like behaviors. These experiments will begin to identify the mechanisms by which PCP produces schizophrenia-like behaviors in animals, providing insight into potential pathophysiologies underlying schizophrenia in humans.