Tanaka M, Suemaru K, Watanabe S, Cui R, Li B, Araki H
Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan.
Methods Find Exp Clin Pharmacol. 2008 Oct;30(8):607-13. doi: 10.1358/mf.2008.30.8.1268818.
In this study we examined the behavioral pharmacological side effects after recovery from the loss of righting reflex induced by three benzodiazepine receptor agonists - zolpidem, brotizolam and flunitrazepam - in ddY mice. All agents caused marked motor incoordination in the rotarod test and muscle flaccidity in the traction test until 15 min after recovery of righting reflex. Thereafter, the short-acting hypnotics zolpidem and brotizolam showed a faster recovery than the long-acting benzodiazepine flunitrazepam. However, head twitch responses were observed in the mice treated with flunitrazepam, but zolpidem and brotizolam had no such effect. The flunitrazepam-induced head twitch response was antagonized by ketanserin, a 5- HT(2A) receptor antagonist. These results indicate that flunitrazepam, a long-acting benzodiazepine that is nonselective for type I and II benzodiazepine receptors, induces head twitch responses with muscle flaccidity after recovery from the loss of righting reflex caused by these drugs. In addition, these findings suggest the involvement of a 5-HT(2A)-GABA(A) receptor/benzodiazepine interaction in this phenomenon.
在本研究中，我们检测了ddY小鼠在由三种苯二氮䓬受体激动剂——唑吡坦、溴替唑仑和氟硝西泮——诱导的翻正反射消失恢复后出现的行为药理学副作用。所有药物在翻正反射恢复后的15分钟内，在转棒试验中均引起明显的运动不协调，在牵引试验中均引起肌肉松弛。此后，短效催眠药唑吡坦和溴替唑仑的恢复速度比长效苯二氮䓬氟硝西泮更快。然而，在接受氟硝西泮治疗的小鼠中观察到了头部抽搐反应，而唑吡坦和溴替唑仑则没有这种作用。氟硝西泮诱导的头部抽搐反应被5-羟色胺受体拮抗剂酮色林所拮抗。这些结果表明，氟硝西泮作为一种对I型和II型苯二氮䓬受体无选择性的长效苯二氮䓬，在由这些药物引起的翻正反射消失恢复后，会诱导头部抽搐反应并伴有肌肉松弛。此外，这些发现提示5-羟色胺（2A）-γ-氨基丁酸（A）受体/苯二氮䓬相互作用参与了这一现象。
