Ogawa N, Mizukawa K, Haba K, Sato H
Institute for Neurobiology, Okayama University Medical School, Japan.
Eur Neurol. 1990;30 Suppl 1:31-40. doi: 10.1159/000117171.
Chronic administration of iminodipropionitrile (IDPN), a neurotoxin, to rats produces a persistent behavioral syndrome characterized by lateral and vertical head twitching, random circling and hyperactivity. Conventionally, this IDPN-induced dyskinesia has been considered to be due to abnormalities in the serotonin neuronal system. However, the present study also demonstrated marked alterations in the dopamine (DA) and acetylcholine (ACh) neuronal systems. These were activation of DA neurons in the nucleus accumbens and thalamus + midbrain, decreased activity in the other brain areas and a decrease in D1 DA receptors. ACh contents were decreased in most brain areas while muscarinic ACh receptors were increased in the striatum, superior colliculus and geniculate nucleus. These alterations in the ACh neuronal system may be secondary to abnormalities in the DA neuronal system. IDPN-induced dyskinesia was enhanced by administration of L-dopa, which increases DA concentration, but was completely inhibited by ceruletide, which inhibits DA release. The dyskinesia was also inhibited by sulpiride, a central antagonist of D2 DA receptors. Interestingly, apomorphine and bromocriptine, which are DA receptor agonists, did not aggravate, but decreased dyskinesia in the IDPN-treated rats. These results strongly suggest that dyskinesia is caused not by abnormality of postsynaptic receptors in the DA neuronal system but by abnormally enhanced function of the presynaptic DA neurons themselves. In addition, ceruletide may be useful in the treatment of dyskinesia, and bromocriptine alone or in combination with L-dopa may be effective in Parkinson's disease without the development of dyskinesia. Thus, the IDPN-treated rat model is useful for clarifying the biochemical pathophysiology of dyskinesia and developing drugs for its treatment.
长期给大鼠施用神经毒素亚氨基二丙腈（IDPN）会产生一种持续的行为综合征，其特征为头部左右摆动和上下抽动、随机转圈以及多动。传统上，这种由IDPN诱发的运动障碍被认为是由于血清素神经元系统异常所致。然而，本研究还表明多巴胺（DA）和乙酰胆碱（ACh）神经元系统也发生了显著变化。这些变化包括伏隔核、丘脑 + 中脑的DA神经元激活，其他脑区活动减少以及D1 DA受体减少。大多数脑区的ACh含量降低，而纹状体、上丘和膝状核中的毒蕈碱型ACh受体增加。ACh神经元系统的这些变化可能继发于DA神经元系统的异常。施用可增加DA浓度的左旋多巴会增强IDPN诱发的运动障碍，但可抑制DA释放的雨蛙肽则可完全抑制该障碍。该运动障碍也可被D2 DA受体的中枢拮抗剂舒必利抑制。有趣的是，作为DA受体激动剂的阿扑吗啡和溴隐亭并未加重，反而减轻了IDPN处理大鼠的运动障碍。这些结果强烈表明，运动障碍不是由DA神经元系统中突触后受体异常引起的，而是由突触前DA神经元自身功能异常增强所致。此外，雨蛙肽可能对运动障碍的治疗有用，单独使用溴隐亭或与左旋多巴联合使用可能对帕金森病有效且不会引发运动障碍。因此，IDPN处理的大鼠模型有助于阐明运动障碍的生化病理生理学并开发其治疗药物。
