Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system
Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system
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氯氮平对纹状体和边缘系统多巴胺周转的影响
DOI：
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发表时间：
1973
期刊：
影响因子：
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通讯作者：
Günter Stock
中科院分区：
文献类型：
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作者：
N. Andén;Günter Stock
抗精神病药物和锥体外系作用通常被认为是抗精神病药物的主要特性(Bobon，Janssen&Bobon，1970)。最近，一种名为氯氮平的化合物“被描述为在不产生任何明显的锥体外系副作用的情况下有效地抑制人类的精神反应(Berzewski，Helmchen等人，1969；Gross&Langner，1969；De Maio，1972)。此外，在动物实验中，这种药物也被观察到与经典的抗精神病药物不同，因为它不会产生目录麻痹，只对阿朴吗啡和苯丙胺引起的刻板印象有微弱的拮抗作用(Stille，Lauener&Eichenberger，1971；Stille&Hippius，1971)。抗精神病药产生的最具特征的生化变化是大脑多巴胺周转增加(Bobon和其他人，1970)。本文通过测定兔脑内主要代谢物高香草酸(HVA)，研究了氯氮平对多巴胺代谢的影响。由于多巴胺同时存在于纹状体和边缘系统的一些核中(分别约占兔脑中多巴胺总量的75%和25%；Cn，1972)，因此这两个区域被分别分析。成年大耳白兔，体重1~21.9 kg，生前不同时间间隔静脉注射L氯氮平5 mg·kg-1，或在生前4h静脉注射不同剂量的氯氮平或经典的抗精神病药氟哌啶醇。冰冻的皮氏盘中的大脑被快速解剖，两只动物的大脑部分被混合在一起。首先，去除纹状体。然后，将边缘系统的大部分包括所有的多巴胺核(杏仁核、视前区、嗅结节、伏隔核、终纹间质核和隔核，但不包括海马体或扣带回)通过鼻裂在视交叉前切开切除。最后，切下枕叶皮质，其重量介于纹状体和边缘系统之间。在干冰上冷冻组织，用0.1N盐酸提取，阴离子交换层析和氧化后，用荧光分光光度法测定HVA(AndCn，Roos&Werdinius，1963；Korf，Roos&Werdinius，1971)。将纹状体匀浆分成两份，其中一份加入3pg的HVA。全程回收率为90/11%(平均I/S，n=67)。没有对复苏做出任何修正。氯氮平(5微克/公斤，L静脉注射)产生了HVA浓度的增加
Antipsychotic and extrapyramidal actions are often considered to be the main properties of neuroleptic drugs (Bobon, Janssen & Bobon, 1970). Recently, a compound, clozapine," has been described to efficiently inhibit psychotic reactions in man without producing any clearcut extrapyramidal side-effects (Berzewski, Helmchen & others, 1969; Gross & Langner, 1969; De Maio, 1972). Also in animal experiments, this drug has been observed to differ from the classical neuroleptic drugs in the sense that it produces no catalepsy and only a weak antagonism of the stereotypes induced by apomorphine and amphetamine (Stille, Lauener & Eichenberger, 1971 ; Stille & Hippius, 1971). The most characteristic biochemical change produced by neuroleptic drugs is an increase in the turnover of the brain dopamine (Bobon & others, 1970). In the present work, the clozapine-induced influence on the turnover of dopamine has been studied in determining its principal metabolite, homovanillic acid (HVA), in the rabbit brain. Since dopamine occurs both in the corpus striatum and in some nuclei of the limbic system (about 75 and 25 %, respectively, of the total dopamine in the rabbit brain; AndCn, 1972), these two regions have been analysed separately. Adult, white rabbits, 1-2 1.9 kg, were injected intravenously with 5 mg kg-l clozapine at different time intervals before death or with different doses of clozapine, or the classical neuroleptic agent haloperidol, 4 h before death by intravenous injection of air. The brains were rapidly dissected on ice-cold Petri dishes.The brain parts from two animals were pooled. First, the corpus striatum was removed. Then, the greater part of the limbic system including all the dopamine nuclei (amygdala, preoptic area, olfactory tubercle, part of the nucleus accumbens, nucleus interstitialis striae terminalis, and septum, but not hippocampus or gyms cinguli) was removed by incisions just in front of the optic chiasma and through the rhinal fissures. Finally, pieces of the occipital cortex, whose weights were between those of the corpus striatum and the limbic system, were cut out. The HVA was determined spectrofluorimetrically after freezing the tissue on dry ice, extraction with 0.1 N HCI, anionic exchange chromatography and oxidation (AndCn, Roos & Werdinius, 1963; Korf, Roos & Werdinius, 1971). The homogenate of the corpus striatum was divided into two aliquots and 3 pg HVA were added to one of them. The recovery through the whole procedure was 90 f 1 1 % (mean i s.e., n = 67). No correction for recovery was made. Clozapine (5 nig kg,-l i.v.) produced an increase in the concentration of HVA both