ACUTE AND CHRONIC ANTIPSYCHOTIC DRUG THERAPY--BIOCHEMICAL ASSESSMANT

我们设计了一系列的实验来鉴定 典型（氟哌啶醇）或非典型引起的差异 （氯氮平）抗精神病药物，急性或慢性给药， 正常猴或双侧多巴胺损伤猴 神经元终止于背外侧前额叶皮层（模拟a 精神分裂症的假设缺陷）。 采用的技术， 目前正在我们的实验室（包括MRI定向立体定位 用于微透析探针的引导套管的植入 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对 单胺，氨基酸和肽类神经递质的流出， 皮质（背外侧和内侧前额叶皮质，运动前区和运动区 皮质）和皮质下（尾状核、壳核、丘脑核， 杏仁核）区域。 在长期给药动物中， 细胞外水平的上述 神经递质/神经调质将在两周后进行 开始抗精神病药物治疗方案，并将每6周一次随访， 最多一年。 急性或慢性治疗后，动物将 处死动物，取出大脑，切片，取出组织。 该打孔组织将被分开用于（1）体外释放 研究集中在突触前调节DA释放的不同 脑区，（2）神经降压素组织水平的死后分析， 胆囊收缩素、单胺及其代谢产物;（3）受体 结合研究，以检查多巴胺能、多巴胺能和 兴奋性氨基酸受体 所提出的实验提供了 一种有效的方法来评估治疗的神经化学作用， 不同种类的抗精神病药物。 此外，分析受损的大脑及其对 背外侧前额叶受损的生化后果 皮质多巴胺系统对皮质下区域，特别是 纹状体和杏仁核， 神经抑制剂可能会在有神经刺激的情况下重建大脑功能。 受损的背外侧前额叶皮层

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.