Cocaine sensitization and reward are under the influence of circadian genes and rhythm
Cocaine sensitization and reward are under the influence of circadian genes and rhythm
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DOI：
10.1073/pnas.142039099
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发表时间：
2002-06-25
影响因子：
11.1
通讯作者：
Spanagel, R
中科院分区：
文献类型：
--
作者：
Abarca, C;Albrecht, U;Spanagel, R
使用果蝇的研究表明，生物钟基因周期（Per）可以影响对可卡因的行为反应。在这里，我们表明，果蝇每基因，mPer 1和mPer 2的小鼠同源物，调节可卡因的敏化和奖励，这两种现象在人类和动物中广泛研究，因为它们对药物滥用的重要性。在对急性可卡因注射的响应中，mPer 1和mPer 2突变小鼠以及野生型小鼠与盐水对照水平相比表现出约5倍的活性增加，表明Per突变体对急性可卡因给药的敏感性没有初始差异。重复注射可卡因后，野生型小鼠表现出mPer 1基因敲除小鼠不存在的致敏行为反应。相比之下，mPer 2突变小鼠表现出对可卡因的超敏反应。条件性位置偏好实验揭示了类似的行为反应：mPer 1基因敲除小鼠表现出完全缺乏可卡因奖励，而mPer 2突变体表现出强烈的可卡因诱导的位置偏好。在另一组实验中，我们在不同的Zeitgeber时间测试了C57/BL 6 J小鼠，发现可卡因诱导的行为敏化和位置偏爱是在昼夜节律钟的控制下。总之，我们表明，可卡因成瘾的过程依赖于昼夜节律，并在相反的方式调制mPer 1和mPer 2基因。
Investigations using the fruit fly Drosophila melanogaster have shown that the circadian clock gene period (Per) can influence behavioral responses to cocaine. Here we show that the mouse homologues of the Drosophila Per gene, mPer1 and mPer2, modulate cocaine sensitization and reward, two phenomena extensively studied in humans and animals because of their importance for drug abuse. In response to an acute cocaine injection mPer1 and mPer2 mutant mice as well as wild-type mice exhibited an approximately 5-fold increase in activity compared with saline control levels, showing that there is no initial difference in sensitivity to acute cocaine administration in Per mutants. After repeated cocaine injections wild-type mice exhibited a sensitized behavioral response that was absent in mPer1 knockout mice. In contrast, mPer2 mutant mice exhibited a hypersensitized response to cocaine. Conditioned place preference experiments revealed similar behavioral reactions: mPer1 knockout mice showed a complete lack of cocaine reward whereas mPer2 mutants showed a strong cocaine-induced place preference. In another set of experiments, we tested C57/BL6J mice at different Zeitgeber times and found that cocaine-induced behavioral sensitization and place preference are under the control of the circadian clock. In conclusion, we demonstrate that processes involved in cocaine addiction depend on the circadian rhythm and are modulated in an opposing manner by mPer1 and mPer2 genes.