The Delayed Effects of Phencyclidine: Mechanisms

苯环己哌啶的延迟效应：机制

• 批准号: 6503165
• 负责人: SARAH M TURGEON
• 金额: $ 13.94万
• 依托单位: AMHERST COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-16 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6503165
• 关键词: amphetamines; behavior test; behavioral /social science research tag; dizocilpine; drug receptors; experimental brain lesion; gene expression; laboratory rat; neurochemistry; neuropharmacology; pharmacokinetics; phencyclidine; prefrontal lobe /cortex; protooncogene; psychopharmacology; substance abuse related behavior

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.

描述（由申请人提供）：苯环利定（PCP）是一种解离性麻醉剂，可在人类中产生拟精神症状，因此研究了其产生精神分裂症动物模型的能力。据报道，PCP的延迟效应，即中毒消退后出现的延迟效应，可诱发多种精神分裂症样行为，包括对安非他明的行为反应增强。此外，PCP预处理导致c-Fos的区域表达改变，表明神经元活性改变。这些研究的目的是研究PCP作用的可能药理学和神经解剖学位点，这是其对安非他明诱导的行为和c-Fos表达的延迟效应的基础。药理学上，PCP作为西格玛受体激动剂的作用与PCP的其他延迟效应有关。解剖学上，PCP诱导前额叶皮层多巴胺利用的延迟性降低，基于对前额叶皮层活动和皮层下多巴胺系统活动之间关系的研究发现，这种效应可能是其对安非他明诱导的行为和c-Fos表达的延迟效应的基础。因此，提出的实验将通过检查sigma受体激动剂模拟和sigma受体拮抗剂阻断PCP对安非他明诱导行为和c-Fos的影响的能力，来验证sigma受体激活在PCP延迟效应中发挥作用的假设。这些实验还将通过检查前额皮质内PCP注射模拟和前额皮质病变阻断PCP对安非他明诱导行为和c-Fos的影响的能力，来验证PCP在前额皮质中的作用是其延迟效应的基础的假设。由于西格玛受体和内侧前额叶皮层都与精神分裂症的病理生理有关，PCP在这些部位的作用代表了PCP诱导精神分裂症样行为的合理机制。这些实验将开始确定PCP在动物中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学提供见解。