NEUROCHEMICAL PHARMACOLOGY OF PHENCYCLIDINE

苯环利定的神经化学药理学

• 批准号: 3207113
• 负责人: KENNETH Maurice JOHNSON
• 金额: $ 9.28万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-30 至 1988-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3207113
• 关键词: aminoacid inhibitor; antidepressants; aspartate; behavioral medicine; caudate nucleus; central nervous system; centrally acting drug; dosage; drug metabolism; experimental brain lesion; gamma aminobutyrate; glutamates; hippocampus; neurochemistry; neuropharmacology; neurotransmitter biosynthesis; occipital lobe /cortex; phencyclidine; physical chemical interaction; psychopharmacology; psychotomimetic drug; radiotracer; sedative /hypnotic; substantia nigra; tissue /cell culture

The proposed research will continue to investigate the neurochemical pharmacology of phencyclidine (PCP) in the rat. In order to determine the potential behavioral significance of our observations we will compare the effects of drugs within several distinct classes which either have or do not have PCP-like behavioral properties. We propose to continue our studies on the effects of a variety of drugs from several classes on turning behavior in rats with unilateral destruction of the nigrostriatal dopaminergic pathway. Our preliminary data suggests that turning behavior may be elicited via an action on the PCP/sigma receptor. Our most recent work shows that drugs like cyclazocine which are PCP-like in the turning model, do not directly elicit significant dopamine (DA) release or inhibit DA reuptake in striatal tissue. This suggest the involvement of non-striatal dopaminergic mechanisms and/or non-dopaminergic striatal mechanisms in turning behavior. We have recently determined that PCP-like drugs may elicit turning behavior via an interaction with glutamate receptors on cholinergic striatal neurons. Since glutamate receptors are known to mediate an excitatory effect on many neurotransmitter systems in many areas of the brain including those related to turning behavior, we propose to investigate the effect of PCP and related drugs on the interaction between dopaminergic, cholinergic, and glutamatergic systems in the substantia nigra, nucleus accumbens, and striatum. We propose to extensively characterize the glutamate receptor subtype(s) on which PCP is acting and to determine whether this effect occurs at the recognition site, at the ionic conductance site which is regulated by glutamate, or at some distal site. We will also determine whether this effect of PCP on ACh release occurs in brain areas other than the striatum and whether PCP-like drugs block the effect of glutamate-induced release of other neurotransmitters (primarily DA and glutamate itself). We also propose to extend the investigation of these mechanisms to brain areas believed to play a role in the effect that PCP has on emotionality (prefrontal cortex) and memory (hippocampus).

拟议的研究将继续研究神经化学 大鼠苯基二肽（PCP）的药理学。 为了确定 我们观察的潜在行为意义，我们将比较 药物在具有或有几个不同类别的影响 没有PCP样行为属性。 我们建议继续我们的 研究多个类别的各种药物对 大鼠的转弯行为，并单侧破坏骨纹状体 多巴胺能途径。 我们的初步数据表明转弯行为 可以通过对PCP/Sigma受体的作用引起。 我们最近的 工作表明，诸如Cyclazocine之类的药物在转弯中类似PCP 模型，请勿直接引起明显的多巴胺（DA）释放或抑制 DA在纹状体组织中重新摄取。 这表明参与 非纹状体多巴胺能机制和/或非多巴胺能纹状体 转弯行为的机制。 我们最近确定了类似pcp的 药物可能通过与谷氨酸的相互作用引起转向行为 胆碱能纹状体神经元的受体。 由于谷氨酸受体是 已知可以介导许多对许多神经递质系统的兴奋作用 大脑的许多区域，包括与转弯行为有关的区域，我们 建议研究PCP和相关药物对 多巴胺能，胆碱能和谷氨酸能系统之间的相互作用 黑质，伏隔核和纹状体。 我们建议 广泛表征PCP所在的谷氨酸受体亚型 行动并确定这种效果是否发生在识别地点， 在由谷氨酸调节的离子电导部位或某些调节的位置 远端。 我们还将确定PCP是否对ACH的影响 释放发生在纹状体以外的大脑区域以及是否类似pcp 药物阻止谷氨酸引起的其他释放的作用 神经递质（主要是DA和谷氨酸本身）。 我们还建议 将这些机制的调查扩展到被认为的大脑区域 在PCP对情绪（前额叶皮层）的影响中发挥作用 和内存（海马）。