ACUTE AND CHRONIC ANTIPSYCHOTIC DRUG THERAPY--BIOCHEMICAL ASSESSMANT

我们设计了一系列实验来确定关键的生化指标 由典型（卤代周期醇）或非典型引起的差异 （氯氮平）抗精神病药物，急性或长期给药，以 正常猴子或双侧多巴胺受损的猴子 终止于背外侧前额皮质的神经元（以模拟 假设精神分裂症的缺陷）。 采用的技术是 目前我们的实验室正在进行（包括 MRI 引导的立体定位 植入微透析探针的引导插管，允许 给定区域的重复采样），我们将首先确定 抗精神病药物氟哌啶醇和氯氮平的急性作用 单胺、氨基酸和肽神经递质的流出 皮质（背外侧和内侧前额皮质、前运动皮质和运动皮质） 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，评估 上述物质的细胞外水平 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后，每 6 周进行一次随访 最长一年。 经过急性或慢性治疗后，动物将 处死后，取出大脑、切片并去除组织穿孔。 该穿孔组织将被分割用于 (1) 体外释放 研究重点是不同个体对 DA 释放的突触前调节 脑区域，(2) 死后神经降压素组织水平分析， 胆囊收缩素、单胺及其代谢物，以及（3）受体 结合研究检查多巴胺能、血清素能和 兴奋性氨基酸受体。 所提出的实验提供了 评估治疗神经化学效应的有效方法 非人类灵长类动物中不同类别的抗精神病药物。 此外，分析受损大脑及其对 背外侧前额叶受损的生化后果 皮质多巴胺系统作用于皮质下区域，特别是 伏隔核、纹状体和杏仁核，并深入了解如何 精神安定药可能会在出现精神障碍的情况下重建大脑功能 背外侧前额皮质受损。

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.