Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice.
Role of MT1 melatonin receptors in methamphetamine-induced locomotor sensitization in C57BL/6 mice.
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DOI：
10.1007/s00213-013-3228-0
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发表时间：
2014-01
影响因子：
3.4
通讯作者：
Dubocovich ML
中科院分区：
文献类型：
--
作者：
Hutchinson AJ;Ma J;Liu J;Hudson RL;Dubocovich ML
褪黑激素可改变对精神兴奋剂的生理和行为反应，MT1 和 MT2 褪黑激素受体特别参与促进褪黑激素熟练小鼠中甲基苯丙胺诱导的敏化。评估低褪黑素表达的 C57BL/6 野生型和 MT1KO 小鼠单剂量甲基苯丙胺后运动敏化的差异，并与表达褪黑素的 C3H/HeN 小鼠进行比较。小鼠在新的测试场所的光照（ZT5-9）或黑暗（ZT 19-21）期间接受载体或甲基苯丙胺（1.2 mg/kg，腹腔注射）预处理（第1天）。禁欲八天（第 9 天）后通过甲基苯丙胺激发来评估运动敏感性。通过免疫荧光和蛋白质印迹分析评估TH蛋白表达。 C3H 和 C57 野生型小鼠在光照期间禁欲八天后，甲基苯丙胺预处理诱导了统计显着的运动敏化。 C57 小鼠的致敏程度在黑暗期减弱，而在 MT1 受体敲除 (MT1KO) 小鼠中完全消除。中脑边缘多巴胺系统中的酪氨酸羟化酶免疫反应性没有观察到差异。甲基苯丙胺预处理后（第 2-6 晚）额外暴露于测试场所可增强致敏性。 MT1 褪黑激素受体的缺失消除了单次冰毒预处理诱导的致敏作用。敏感程度也会因一天中的时间和情境线索而改变。我们的结论是，MT1 褪黑激素受体正在成为药物滥用障碍治疗干预的新靶点。
Melatonin modifies physiological and behavioral responses to psychostimulants, with the MT1 and MT2 melatonin receptors specifically implicated in facilitating methamphetamine-induced sensitization in melatonin-proficient mice. To assess differences in locomotor sensitization after a single dose of methamphetamine in low melatonin-expressing C57BL/6 wild-type and MT1KO mice, and comparing with melatonin-expressing C3H/HeN mice. Mice received a vehicle or methamphetamine (1.2 mg/kg, i.p.) pretreatment (Day 1) during the light (ZT5–9) or dark (ZT 19–21) periods in novel test arenas. Locomotor sensitization was assessed by methamphetamine challenge after an eight-day (Day 9) abstinence. TH protein expression was evaluated by immunofluorescence and Western blot analysis. Methamphetamine pretreatment induced statistically significant locomotor sensitization upon challenge after eight-day abstinence in C3H and C57 wild-type mice during the light period. The magnitude of sensitization in C57 mice was diminished in the dark period and completely abrogated in MT1 receptor knockout (MT1KO) mice. No differences were observed in tyrosine hydroxylase immunoreactivity in the mesolimbic dopamine system. Additional exposures to the test arenas after methamphetamine pretreatment (Nights 2–6) enhanced sensitization. Deletion of the MT1 melatonin receptor abolishes sensitization induced by a single METH pretreatment. The magnitude of sensitization is also altered by time of day and contextual cues. We conclude that the MT1 melatonin receptor is emerging as a novel target of therapeutic intervention for drug abuse disorders.