Asai Hidetoshi, Asahi Toshio, Yamamura Michio, Yamauchi-Kohno Rikako, Saito Akira
Pharmacology Research Laboratories, Tanabe Seiyaku Co., Ltd., Toda-shi, Saitama, Japan.
Pharmacol Biochem Behav. 2005 Dec;82(4):646-51. doi: 10.1016/j.pbb.2005.11.004. Epub 2005 Dec 20.
In order to determine whether acute tolerance develops by taltirelin hydrate ((-)-N-[(S)-hexahydro-1-methyl-2,6-dioxo-4-pyrimidinylcarbonyl]-l-histidyl-l-prolinamide tetrahydrate; taltirelin), a thyrotropin-releasing hormone (TRH) analog, we examined the motor behavior, TRH receptors and dopamine D(2) receptors following 2 weeks treatment in rats. Taltirelin selectively bound to TRH receptors and increased the spontaneous motor activity by a single administration, suggesting that the motor effect of taltirelin is mediated by TRH receptors. Following repeated treatment with TRH, there was a significant reduction in the increment of spontaneous motor activity. In contrast, after repeated treatment with taltirelin at a dose that increased the motor activity to a similar extent to TRH by a single administration, there was no apparent change in its motor effect. In accord with the motor activity, we found a significant reduction in the [(3)H]methyl-TRH binding to TRH receptors in the brain following repeated treatment with TRH but not taltirelin. However, the [(3)H]spiperone binding to dopamine D(2) receptors in the corpus striatum did not change by repeated taltirelin and TRH treatments. Thus, the down-regulation of TRH receptors would be a main cause of the behavioral tolerance. These results suggest that taltirelin hardly develops the behavioral tolerance due to the lack of down-regulation of TRH receptors.
为了确定水合他替瑞林（(-)-N-[(S)-六氢-1-甲基-2,6-二氧代-4-嘧啶基羰基]-L-组氨酰-L-脯氨酰胺四水合物；他替瑞林），一种促甲状腺激素释放激素（TRH）类似物，是否会产生急性耐受性，我们在大鼠接受2周治疗后检测了其运动行为、TRH受体和多巴胺D(2)受体。他替瑞林选择性地与TRH受体结合，并通过单次给药增加自发运动活性，这表明他替瑞林的运动效应是由TRH受体介导的。在用TRH重复治疗后，自发运动活性的增加显著降低。相比之下，在以单次给药使运动活性增加到与TRH相似程度的剂量用他替瑞林重复治疗后，其运动效应没有明显变化。与运动活性一致，我们发现用TRH而非他替瑞林重复治疗后，大脑中TRH受体上的[(3)H]甲基-TRH结合显著减少。然而，纹状体中多巴胺D(2)受体上的[(3)H]螺哌隆结合在他替瑞林和TRH重复治疗后没有改变。因此，TRH受体的下调将是行为耐受性的主要原因。这些结果表明，由于缺乏TRH受体的下调，他替瑞林几乎不会产生行为耐受性。
