Abarca Carolina, Albrecht Urs, Spanagel Rainer
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, J5, 68159 Mannheim, Germany.
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9026-30. doi: 10.1073/pnas.142039099.
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.
对果蝇黑腹果蝇的研究表明，生物钟基因周期（Per）可影响对可卡因的行为反应。在此我们表明，果蝇Per基因的小鼠同源物mPer1和mPer2可调节可卡因敏化和奖赏，由于这两种现象对药物滥用的重要性，它们在人类和动物中得到了广泛研究。对急性注射可卡因的反应，mPer1和mPer2突变小鼠以及野生型小鼠与生理盐水对照水平相比，活动增加了约5倍，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，野生型小鼠表现出敏化的行为反应，而mPer1基因敲除小鼠则没有。相反，mPer2突变小鼠对可卡因表现出超敏反应。条件性位置偏爱实验揭示了类似的行为反应：mPer1基因敲除小鼠表现出完全缺乏可卡因奖赏，而mPer2突变体则表现出强烈的可卡因诱导的位置偏爱。在另一组实验中，我们在不同的授时因子时间测试了C57/BL6J小鼠，发现可卡因诱导的行为敏化和位置偏爱受生物钟的控制。总之，我们证明了可卡因成瘾所涉及的过程依赖于昼夜节律，并由mPer1和mPer2基因以相反的方式调节。
