Animal Model of Neuroleptic Malignant Syndrome

虽然抗精神病药恶性综合征（NMS）是强效抗精神病药治疗的潜在致命后果，但其潜在的发病机制尚不清楚。本报告总结了我们开发的NMS动物模型（13ea \: d）。我们观察到高温（高达42ºC）。联用pargyline和色氨酸后，仅在FH大鼠中出现僵硬、自主神经不稳定和CPK升高（高达4,000mU/ml），而在SD大鼠中没有。接受这种联合治疗的13ea \: FH大鼠几乎100%在12小时内死亡。氟哌啶醇是一种有效的多巴胺d2受体阻滞剂，可增强FH大鼠的这些作用。此外，有报道称，丹曲林预处理可以逆转NMS症状，防止FH大鼠出现高热或CPK升高。FH大鼠神经化学特征的研究。研究了FH的神经化学特性，进一步阐明了下丘脑中脑5-羟色胺（5-HT）的加速转化。与SD大鼠相比，多巴胺周转量没有变化。此外，我们观察到5- meodmt诱导的热疗和喹帕嗪诱导的“湿狗”摇在FH大鼠中有s13EA\：显著增强，表明5-HT_2受体的超敏性。在受体结合实验中，FH和SD大鼠大脑皮层和海马区[^3H]5-HT、[^3H]酮色林和[H_3]帕罗西汀结合的B13EA\: max和Kd值与纹状体区[^3H]SCH23390、[^3H] spiperone和[^3H]GBR12935结合的B13EA\: max和Kd值无显著差异。丹曲林处理后，各5-羟色胺能神经元末端区域的5-羟色胺合成未发生变化。然而，丹曲林预处理以剂量依赖的方式显著阻止5- meodmt诱导的高热或桂哌嗪诱导的“湿狗”震颤。上述结果提示，NMS动物模型的症状和实验结果可能是由于13ea中钙的膜调节和运输缺陷导致钙过量释放到5-HT_2受体或骨骼肌细胞质中，存在过度的5-羟色胺能刺激。丹曲林治疗可能通过减少钙的释放量而干扰骨肌的兴奋-收缩偶联或5-羟色胺受体介导的热疗。这些作用可能部分与丹曲林对NMS动物模型CPK升高或高热的治疗作用有关。少

Although the neuroleptic malignant syndrome(NMS) is a potentially lethal consepuence of treatment with potent neuroleptics, the underlying pathogenetic mechanisms remain unclear. This presentation summarized the animal model of NMS which we develope13EA\ : d. We observed hyperthermia (up to 42ﾟC). rigidity, autonomic instability, and elevated CPK (up to 4,000mU/ml) only in Fawn-Hooded (FH) rats but not in Sprague-Dawley (SD) rats, by the combined treatment with pargyline and tryptophan. Nearly 100% of13EA\ : FH rats receiving this combined treatment died within 12 hrs. These effects in FH rats were potentiated by pretreatment with haloperidol, which is a potent dopamine D_2 receptor blocker. Moreover, pretreatment with dantrolene, which has been repor13EA\ : ted to reverse the symtoms of NMS, prevented the occurrence of hyperthermia or elevated CPK in FH rats. The investigation about neurochemical characteristics of FH rats.The investigation about neurochemical characteristics of FH ra … More ts clarified the accelerated turnover of serotonin(5-HT) in N.hypothalamicus ant., with no changes noted in the dopamine turnover in comparison with SD rats. In addition, we observed a s13EA\ : ignificant enhancement of 5-MeODMT-induced hyperthermia and quipazine-induced "wet dog" shakes, which indicates the hypersensitivity of 5-HT_2 receptor, in FH rats. In the receptor binding assay, There was no differrence between FH and SD rats in B13EA\ : max or Kd values for [^3H]5-HT, [^3H] ketanserin or [H_3] paroxetine binding in the cerebral cortex or hippocampus and [^3H]SCH23390, [^3H] spiperone or [^3H]GBR12935 binding in the striatum. Dantrolene treatment resulted in no change of 5-HT synthesis in the terminal regions of various serotonergic neurons. However, dantrolene pretreatment prevented significatly 5-MeODMT-induced hyperthermia or guipazine-induced "wet dog" shakes in a dose dependent manner.These resutlts suggest that symptomes and laboratory findings of animal model of NMS may result from excessive release of calcium into 5-HT_2 receptor or sketetal muscle cytoplasm due to defective membrane regulation and transport of calcium in the13EA\ : presence of exaggerated serotonergic stimulation.Dantrolene treatment may interfere with excitation-contraction coupling in sketletal muscle, or 5-HT receptor-mediated hyperthermia, perhaps by decreasing the amount of calcium released. These effects may be related, in part, to the therapeutic effi13EA\ : cacy of dantrolene for elevated CPK or hyperthermia in animal model of NMS. Less