ACTIONS OF CLOZAPINE - A MORE EFFECTIVE ANTIPSYCHOTIC

几种抗精神病药物，其中氯氮平是原型， 已被归类为非典型抗精神病药，主要是在 锥体外系副作用（EPS）发生率低的基础 对人体催乳素（PRL）分泌的影响极小。 来自氯氮平多中心临床试验的最新数据是 表明氯氮平比典型的 精神抑制剂在减少积极和消极的症状， 难治性精神分裂症患者 因此，它可以是 假设氯氮平可能有额外的机制， 与其抗精神病作用相关的作用。 这些动作可以 还有助于其对EPS和PRL分泌的独特作用。 我们从大鼠神经内分泌研究中获得的数据表明， 表明作用机制的质的差异， 典型和非典型抗精神病药。 特别是， 发现非典型抗精神病药物，与典型的 抗精神病药，产生：1）血清PRL短暂升高 浓度，2）血清皮质酮显着增加 浓度，和3）激活结节漏斗 多巴胺（TIDA）神经元。 拟议的总体目标 研究的目的是阐明介导这些的机制， 对非典型抗精神病药和 确定神经基质通过 氯氮平对TIDA神经元的作用类似于通过 这种抗精神病药作用于中脑边缘-皮层中的DA 神经元 这是为了检验假设，氯氮平 通过与DA 1，5-HT 2， 毒蕈碱和/或β 1-肾上腺素能受体。 的假设 神经降压素或促肾上腺皮质激素释放因子参与 非典型抗精神病药诱导的TIDA神经元活化也 将被审查。 这些研究将在大鼠中进行，其中 TIDA和中脑边缘-神经皮层DA能神经元活动 将通过生物化学测定进行评估， 抑制后DA前体DOPA的蓄积速率 DOPA脱羧酶和DOPAC浓度的中位数 隆起和内侧前额叶皮质。 建议的研究 本文重点讨论的机制，通过这些行动， 非典型抗精神病药可与 典型的神经抑制剂 建议这些结果 研究将提供一些深入了解的机制， 确定有效性和低EPS生产责任 氯氮平在治疗精神分裂症方面的应用。

Several antipsychotic agents, of which clozapine is prototypical, have been classified as atypical antipsychotics primarily on the basis of the low incidence of extrapyramidal side effects (EPS) and the minimal effect on prolactin (PRL) secretion in man. Recent data from a multicenter clinical trial of clozapine are suggestive that clozapine is more efficacious than typical neuroleptics in diminishing positive and negative symptoms in treatment-resistant schizophrenics. Hence, it can be hypothesized that clozapine may have additional mechanisms of action relevant to its anti-psychotic actions. These actions may also contribute to its unique effects on EPS and PRL secretion. We have obtained data from neuroendocrine studies in the rat that indicate qualitative differences in the mechanisms of action of typical and atypical antipsychotics. In particular, it has been found that atypical antipsychotics, in contrast to typical antipsychotics, produce: 1) a short-lived increase in serum PRL concentrations, 2) a marked increase in serum corticosterone concentrations, and 3) an activation of tuberoinfundibular dopamine (TIDA) neurons. The overall goal of the proposed studies is to elucidate the mechanisms which mediate these unique neuroendocrine responses to atypical neuroleptics and to ascertain the extent to which the neuronal substrates through which clozapine acts on TIDA neurons are similar to those through which this antipsychotic acts on mesolimbic-mesocortical DA neurons. It is proposed to test the hypothesis that clozapine activates TIDA neurons through an interaction with DA1, 5-HT2, muscarinic and/or 1-adrenergic receptors. The hypothesis that neurotensin or corticotropin releasing factor is involved in the atypical antipsychotic-induced activation of TIDA neurons also will be examined. These studies will be conducted in rats in which the activity of TIDA and mesolimbic-neurocortical DA neurons will be assessed through the biochemical determination of the rate of accumulation of the DA precursor, DOPA, after inhibition of DOPA decarboxylase and DOPAC concentrations in the median eminence and medial prefrontal cortex. The studies proposed herein focus on the mechanisms through which the actions of atypical antipsychotics can be differentiated from those of typical neuroleptics. It is suggested that the results of these studies will provide some insight into the mechanism which determine the efficacy and low EPS producing liability of clozapine with regard to the treatment of schizophrenia.