Genetic deletion of MT(1) and MT(2) melatonin receptors differentially abrogates the development and expression of methamphetamine-induced locomotor sensitization during the day and the night in C3H/HeN mice.
Genetic deletion of MT(1) and MT(2) melatonin receptors differentially abrogates the development and expression of methamphetamine-induced locomotor sensitization during the day and the night in C3H/HeN mice.
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DOI：
10.1111/j.1600-079x.2012.01010.x
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发表时间：
2012-11
影响因子：
10.3
通讯作者：
Dubocovich ML
中科院分区：
文献类型：
--
作者：
Hutchinson AJ;Hudson RL;Dubocovich ML
本研究探讨了褪黑激素受体在甲基苯丙胺（methamphetamine，METH）诱导的C3 H/HeN小鼠运动敏化中的作用。每天用METH（1.2mg/kg，i. p.）导致野生型（WT）、MT 1 KO和MT 2KO小鼠发生自发致敏。在禁欲四整天后，METH攻击（1.2mg/kg，i. p.）在METH预处理的小鼠中触发了自发致敏的表达，但在载体（VEH）预处理的小鼠中没有。在MT 1/MT 2KO小鼠中，在光相期间致敏的发展显著减少，并且在METH攻击后致敏的表达完全消除。在黑暗阶段，MET预处理的WT、MT 1 KO和MT 2KO小鼠的运动致敏性的发展与VEH处理的对照组有统计学差异。然而，WT和MT 2KO，但不是MT 1 KO小鼠接受重复VEH预处理在黑暗阶段表达了致敏反应的甲基挑战，是相同的幅度后观察到的甲基预处理6天。我们的结论是，暴露于一个新的环境中的黑暗阶段，但不是在光的阶段，促进表达的方式依赖于MT 1褪黑激素受体激活内源性褪黑激素的敏感性的甲基挑战。我们认为MT 1和MT 2褪黑素受体是药物干预METH滥用的潜在靶点。
This study explored the role of the melatonin receptors in methamphetamine (METH)-induced locomotor sensitization during the light and dark phases in C3H/HeN mice with genetic deletion of theMT1 and/or MT2 melatonin receptors. Six daily treatments with METH (1.2 mg/kg, i.p.) in a novel environment during the light phase led to the development of locomotor sensitization in wild-type (WT), MT1KO and MT2KO mice. Following four full days of abstinence, METH challenge (1.2 mg/kg, i.p.) triggered the expression of locomotor sensitization in METH-pretreated but not in vehicle (VEH)-pretreated mice. In MT1/MT2KO mice, the development of sensitization during the light phase was significantly reduced and the expression of sensitization was completely abrogated upon METH challenge. During the dark phase the development of locomotor sensitization in METH-pretreated WT, MT1KO and MT2KO mice was statistically different from VEH-treated controls. However, WT and MT2KO, but not MT1KO mice receiving repeated VEH pretreatments during the dark phase expressed a sensitized response to METH challenge that is of an identical magnitude to that observed upon 6 days of METH pretreatment. We conclude that exposure to a novel environment during the dark phase, but not during the light phase, facilitated the expression of sensitization to a METH challenge in a manner dependent on MT1 melatonin receptor activation by endogenous melatonin. We suggest that MT1 and MT2 melatonin receptors are potential targets for pharmacotherapeutic intervention in METH abusers.