The Delayed Effects of Phencyclidine: Mechanisms

描述(申请人提供)：苯环利定(PCP)是一种游离麻醉剂，会在人类中产生类似精神分裂症的症状，因此已因其制造精神分裂症动物模型的能力而受到调查。五氯苯酚的延迟效应是在中毒消退后出现的，据报道，它会导致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预处理引起c-Fos区域表达的变化，表明神经元活动发生了变化。这些研究的目的是探讨五氯苯酚可能的药理和神经解剖学作用部位，这是其对苯丙胺诱导的行为和c-Fos表达的延迟效应的基础。从药理上讲，PCP作为Sigma受体激动剂的作用与PCP的其他延迟效应有关。从解剖学上讲，五氯苯酚导致前额叶皮质多巴胺利用的延迟性下降，根据关于前额叶皮质活动和皮质下多巴胺系统活动之间关系的研究结果，这种效应可能是其对苯丙胺诱导的行为和c-Fos表达的延迟效应的基础。因此，拟议的实验将通过检测sigma受体激动剂模拟和sigma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Sigma受体激活在PCP延迟效应中发挥作用的假设。这些实验还将检验这一假设，即PCP在前额叶皮质的作用是其延迟效应的基础，方法是检查前额叶皮质内注射PCP模拟前额叶皮质病变的能力，以阻断全身PCP对苯丙胺诱导的行为和c-Fos的影响。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，PCP在这些部位的作用代表了PCP可能通过其诱导精神分裂症样行为的机制。这些实验将开始确定五氯苯酚在动物身上产生精神分裂症样行为的机制，为人类精神分裂症潜在的病理生理提供洞察力。

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.