|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1990 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1989 : ¥1,400,000 (Direct Cost : ¥1,400,000)
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
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