ACUTE AND CHRONIC ANTIPSYCHOTIC DRUG THERAPY--BIOCHEMICAL ASSESSMANT

急性和慢性抗精神病药物治疗--生化评估

• 批准号: 6243067
• 负责人: BITA MOGHADDAM
• 金额: $ 28.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243067
• 关键词: 3 methoxy 4 hydroxyphenylethyleneglycol; Macaca mulatta; amygdala; brain mapping; brain metabolism; clozapine; corpus striatum; dopamine receptor; drug administration rate /duration; experimental brain lesion; frontal lobe /cortex; glutamate receptor; haloperidol; microdialysis; motor cortex; neuropharmacology; neurotransmitter metabolism; nonhuman therapy evaluation; norepinephrine; nucleus accumbens; receptor binding; serotonin receptor; stereotaxic techniques

We have designed a series of experiments to identify key biochemical differences induced by either typical (haloperiodol) or atypical (clozapine) antipsychotic drugs, administered acutely or chronically, to normal monkeys or to monkeys with bilateral lesion of the dopamine neurons terminating in the dorsolateral prefrontal cortex (to model a hypothesized deficit in schizophrenia). Employing techniques that are currently ongoing in our laboratories (including MRI-directed stereotaxic implantation of guide cannulae for microdialysis probes which allow for repeated sampling of a given region), we will initially determine the acute actions of the antipsychotic drugs, haloperidol and clozapine on the outflow of monoamine, amino acids, and peptide neurotransmitters in cortical (dorsolateral and medial prefrontal cortices, premotor and motor cortices) and subcortical (caudate, putamen, nucleus accumbens, and amygdala) regions. In chronically treated animals, assessments of extracellular levels of the aforementioned neurotransmitters/neuromodulators will be performed two weeks following the start of antipsychotic regimen and will be followed every 6 weeks for up to one year. Following acute or chronic treatment, animals will be sacrificed, the brains removed, sectioned and tissue punches removed. This punched tissue will be divided for use in (1) in vitro release studies focused on presynaptic regulation of DA release in different brain regions, (2) postmortem analysis of tissue levels of neurotensin, cholecystokinin, monoamines and their metabolites, and (3) for receptor binding studies to examine changes in dopaminergic, serotonergic, and excitatory amino acid receptors. The proposed experiments provide a powerful method of assessing the neurochemical effects of treatment with different classes of antipsychotic drugs in the non-human primate. Furthermore, analysis of lesioned brains and their responsiveness to biochemical consequences of a compromised dorsolateral prefrontal cortical dopamine system on subcortical areas, particularly the accumbens, striatum and the amygdala and provide insight into how neuroleptics might reestablish brain function in the presence of a compromised dorsolateral prefrontal cortex.

我们设计了一系列实验来确定关键的生化 典型药物(氟哌啶醇)或非典型药物引起的差异 (氯氮平)抗精神病药物，急性或长期给药，以 正常猴子或有双侧多巴胺损害的猴子 终止于背外侧前额叶皮质的神经元(模拟 精神分裂症的假设缺陷)。使用的技术是 目前正在我们的实验室中进行(包括MRI引导的立体定位术 植入微透析探头的引导套管，允许 给定区域的重复采样)，我们将初步确定 抗精神病药物氟哌啶醇和氯氮平的急性作用 体内单胺类、氨基酸类和多肽类神经递质的外流 皮质(背外侧和内侧前额叶皮质、前运动和运动 皮质)和皮质下(尾状核、壳核、伏隔核和 杏仁核)区域。在长期治疗的动物中，对 前述细胞外水平 神经递质/神经调节剂将在两周后进行 开始抗精神病药物治疗，并将每6周跟踪一次 最多一年。经过急性或慢性治疗后，动物将被 牺牲，取出大脑，切开切片，取出组织拳头。 该穿孔组织将被分割用于(1)体外释放 突触前调节不同脑区DA释放的研究进展 脑区，(2)神经降压素组织水平的死后分析， 缩胆囊素、单胺及其代谢物；(3)受体 结合研究以检查多巴胺、5-羟色胺能和 兴奋性氨基酸受体。拟议的实验提供了一种 评估药物治疗的神经化学效应的有效方法 非人灵长类动物中不同类别的抗精神病药物。 此外，对受损大脑的分析及其对 额叶背外侧受损的生化后果 皮质下区域的皮质多巴胺系统，特别是 伏隔核、纹状体和杏仁体，并提供了对如何 抗精神病药可能会重建大脑功能 前额叶背外侧皮质受损。