Nakai Satoru, Hirose Tsuyoshi, Uwahodo Yasufumi, Imaoka Takeshi, Okazaki Hiroshi, Miwa Takashi, Nakai Masami, Yamada Sakiko, Dunn Bob, Burris Kevin D, Molinoff Perry B, Tottori Katsura, Altar C Anthony, Kikuchi Tetsuro
Second Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi, Tokushima 771-0192, Japan.
Eur J Pharmacol. 2003 Jul 4;472(1-2):89-97. doi: 10.1016/s0014-2999(03)01857-0.
Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.
在给小鼠口服阿立哌唑、氟哌啶醇和利培酮后，对其僵住症以及纹状体和边缘系统多巴胺代谢变化进行了研究。与急性（单次给药）治疗相比，在较宽剂量范围内，慢性（21天）阿立哌唑治疗可使僵住症持续时间缩短，而慢性氟哌啶醇治疗时僵住症持续时间仍会存在。在僵住症达到最大程度时，急性阿立哌唑并未改变新纹状体多巴胺代谢物/多巴胺比率或高香草酸（HVA）水平，仅使二羟基苯乙酸（DOPAC）略有增加。在嗅结节中也观察到类似效应。慢性阿立哌唑治疗后，这两个区域的多巴胺代谢基本未发生变化。急性给予氟哌啶醇或利培酮可使两个脑区的DOPAC、HVA以及代谢物/多巴胺比率升高，且慢性治疗后这些指标仍维持在较高水平。阿立哌唑对纹状体和边缘系统多巴胺代谢的细微影响，以及慢性给药后僵住症持续时间的缩短，表明与氟哌啶醇或利培酮相比，阿立哌唑在多巴胺神经化学作用和行为后遗症方面存在根本差异。
