Animal Model of Neuroleptic Malignant Syndrome

尽管抗精神病药物恶性综合征(NMS)是一种潜在的致命性疾病，但其潜在的致病机制尚不清楚。本文总结了我们建立的NMS动物模型。我们观察到体温过高(高达42ﾟC)。强直、自主神经不稳定和CPK升高(高达4000mU/ml)仅在Fawn-hoded(FH)大鼠中存在，而在SpragueDawley(SD)大鼠中则不存在，联合应用pargyline和色氨酸。接受这种联合治疗的13EA\：FH大鼠几乎100%在12小时内死亡。氟哌啶醇可增强FH大鼠的上述作用，氟哌啶醇是一种有效的多巴胺D_2受体阻断剂。此外，丹曲林可逆转NMS症状，可预防FH大鼠体温升高或CPK升高。FH大鼠神经化学特性的研究.FH ra…的神经化学特性研究更多的TS明确了下丘脑5-羟色胺(5-羟色胺)的加速代谢，而与SD大鼠相比，多巴胺的代谢没有变化。此外，我们还观察到5-MeODMT引起的体温升高和奎帕嗪引起的“湿狗”抖动明显增强，这表明FH大鼠对5-HT2受体具有超敏反应。在受体结合实验中，FH大鼠和SD大鼠大脑皮层或海马区的[~(3 H)H]-5-羟色胺、[~(3 H)]酮丝氨酸或[H_3]帕罗西汀结合的MAX或Kd值与FH和SD大鼠无差异，纹状体的[~(3 H)H]SCH23390、[~(3 H)]螺环酮或[~(3 H)]GBR12935结合的最大或最大Kd值与FH大鼠无差异。丹曲林处理后，不同5-羟色胺能神经元终末5-羟色胺合成无明显变化。丹曲林可剂量依赖性地抑制5-MeODMT引起的体温升高或呋喃西林引起的“湿狗”震颤。这些结果表明，NMS动物模型的症状和实验室结果可能是由于在过度的5-羟色胺能刺激下，由于膜调节和钙转运缺陷，导致钙过量释放到5-羟色胺受体或骨骼肌细胞质中。丹曲林治疗可能通过减少钙的释放量而干扰骨骼肌兴奋-收缩偶联，或5-羟色胺受体介导的体温升高。这些作用可能部分与丹曲林对NMS动物模型CPK升高或体温升高的治疗作用有关。较少

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