The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice
The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice
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DOI：
10.1038/sj.npp.1300254
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发表时间：
2003-12-01
影响因子：
7.6
通讯作者：
Manev, H
中科院分区：
文献类型：
--
作者：
Uz, T;Akhisaroglu, M;Manev, H
对精神刺激剂的敏感度会受到昼夜节律的影响。松果体是昼夜褪黑激素合成的主要来源，可能会影响行为对可卡因的敏化；褪黑激素节律正常的小鼠在晚上不会敏化。时钟基因，如Perod1(PER1)，在小鼠大脑中显示出节律性的区域和菌株依赖的表达，而PER1基因的突变小鼠缺乏可卡因敏感性。在这里，我们第一次展示了小鼠纹状体中PER1蛋白水平的昼夜变化，纹状体是对可卡因运动敏化发展至关重要的大脑区域。在雄性C3H/HeJ小鼠中，我们发现纹状体PER1蛋白水平在白天达到峰值；在此之前16小时出现PER1mRNA峰值。去松果体的小鼠没有表现出这种昼夜节律。我们分析了在对照组小鼠纹状体PER1蛋白水平高和低的情况下，昼夜节律可卡因的敏化作用。只有纹状体PER1表达有昼夜节律变化的小鼠显示夜间没有可卡因敏化，而去松果体的小鼠纹状体PER1表达没有昼夜变化，无论昼夜节律如何，都会对可卡因敏感。我们的结果表明，纹状体PER1的昼夜节律表达和昼夜运动性可卡因敏化都受到松果体产物的强烈影响。由于我们发现了褪黑素受体在纹状体中表达的证据，我们认为对松果体驱动机制的进一步研究将有助于我们更好地理解药物滥用的机制，并为预防和/或治疗成瘾寻找新的靶点。
Sensitization to psychostimulants can be influenced by circadian rhythms. The pineal gland, the main source of circadian melatonin synthesis, may influence behavioral sensitization to cocaine; mice with normal melatonin rhythms do not get sensitized at night. Clock genes such as Period1 (Per1) show rhythmic region- and strain-dependent expression in the mouse brain, and mice mutant for the Per1 gene lack cocaine sensitization. Here, for the first time we show circadian changes of PER1 protein levels in the mouse striatum, a brain region crucial for the development of locomotor sensitization to cocaine. In male C3H/HeJ mice, we found peak striatal PER1 protein levels during the day; this was preceded by a Per1 mRNA peak 16 h earlier. Pinealectomized mice did not show this circadian pattern. We analyzed circadian cocaine sensitization at times when striatal PER1 protein levels in control mice ( naive and sham-pinealectomized) were high and low, respectively. Only mice with circadian changes in striatal Per1 expression showed the night-time absence of cocaine sensitization, whereas pinealectomized mice were without circadian changes in striatal Per1 and were sensitized to cocaine regardless of diurnal rhythm. Our results indicate that both the striatal circadian Per1 expression and diurnal locomotor cocaine sensitization are strongly influenced by pineal products. Since we found evidence for the expression of melatonin receptor mRNA in the striatum, we suggest that further studies on pineal-driven mechanisms will help us better understand the mechanisms of drug abuse and identify novel targets for the prevention and/or treatment of addictions.