EVALUATION OF PCP AND SIGMA EFFECTS ON DA PHYSIOLOGY

PCP 和 Sigma 对 DA 生理学影响的评估

• 批准号: 3214442
• 负责人: ARTHUR S FREEMAN
• 金额: $ 10.98万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3214442
• 关键词: NMDA receptors; PCP receptor; afferent nerve; albino rat; behavioral medicine; dopamine receptor; drug abuse; drug interactions; electrophysiology; experimental brain lesion; laboratory rabbit; mesencephalon; neurochemistry; neuropharmacology; neurotoxins; nontherapeutic iontophoresis; norepinephrine; opioid receptor; phencyclidine; psychopharmacology; receptor binding; reinforcer; serotonin; single cell analysis; stimulant /agonist; tissue /cell culture

The drug of abuse, phencyclidine (PCP), has profound effects on dopaminergic (DA) neuronal systems which originate in the midbrain. These systems have been implicated in many of the behavioral effects of PCP as well as its reinforcing properties and abuse potential. PCP is will known to block Da reuptake and enhance DA release. In addition to indirect DA agonist action, PCP acts as a non-competitive antagonist of the excitatory amino acid N-methyl-d-aspartate at a site designated the "PCP receptor," and also interacts with haloperidol-sensitive sigma binding sites ("sigma receptors"). PCP has complex effects on the electrophysiological activity of nigrostriatal (NS) and mesoaccumbens (MA) DA cells. These effects are not due solely to the indirect DA agonist properties of PCP. It is likely that actions of PCP at PCP and/or sigma receptors contribute significantly to its overall effects on DA cell physiology. The multiple actions of the drug, however, have precluded clear assessments of the contributions the separate receptors make to the overall effects of PCP on DA cell activity. The recent availability of compounds which are selective for the PCP and sigma sites has provided tools which are required to begin to examine in greater detail the mechanism of action of PCP on the basal physiology and pharmacology of DA neurons. The proposed in vivo and in vitro studies will employ extracellular single-unit recording techniques in an evaluation of the effects of PCP receptor and sigma receptor ligands onrat DA cell activity. These studies will also look into possible sites of action for the effects of these drugs on DA cell activity. The in vivo studies will examine antidromically identified NSDA and MADA cell subpopulations. The abuse of PCP often involves repeated use os the drug. This might be expected to result in changes in the autoregulatory capacity of DA cells due to prolonged indirect stimulation of DA receptors. Thus, the effects of repeated administration of PCP on the responsiveness of impulse- regulating somatodendritic DA autoreceptors will be determined. It is hoped that these studies will lead to a better understanding of the acute and chronic effects of PCP on midbrain DA neurons.

滥用药物（PCP）的药物对 多巴胺能（DA）神经元系统，起源于中脑。 这些 系统已与PCP的许多行为影响有关 以及它的加强特性和滥用潜力。 PCP将知道 阻止DA再摄取并增强DA释放。 除了间接DA 激动剂作用，PCP充当兴奋性的非竞争力拮抗剂 位于指定“ PCP受体”的位置的氨基酸N-甲基-D-天冬氨酸 并与氟哌啶醇敏感的Sigma结合位点相互作用（“ Sigma） 受体”）。PCP对电生理活性具有复杂的影响 黑质纹状体（NS）和中含中含量（MA）DA细胞。 这些效果是 不仅归因于PCP的间接DA激动剂特性。 很可能 PCP在PCP和/或Sigma受体上的作用显着贡献 它对DA细胞生理的总体影响。该行动 但是，药物排除了对贡献的明确评估 单独的受体使PCP对DA细胞活性的总体影响。 最新的化合物可用于PCP和PCP和 Sigma站点提供了需要开始检查的工具 更详细介绍PCP对基础生理学的作用机理和 DA神经元的药理学。 提出的体内和体外研究将 在评估中采用细胞外单单元记录技术 PCP受体和Sigma受体配体Onrat DA细胞的影响 活动。 这些研究还将研究可能的行动部位 这些药物对DA细胞活性的影响。 体内研究将 检查抗细胞鉴定的NSDA和MADA细胞亚群。 这 PCP的滥用通常涉及重复使用OS该药物。 这可能是 预计会导致DA细胞自动调节能力的变化 由于DA受体的间接刺激延长。 因此，效果 PCP反复给药的冲动反应性 将确定调节体育体的自身受体。 这是 希望这些研究能够更好地了解急性 PCP对中脑DA神经元的慢性影响。