Uz Tolga, Akhisaroglu Mustafa, Ahmed Rehan, Manev Hari
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA.
Neuropsychopharmacology. 2003 Dec;28(12):2117-23. doi: 10.1038/sj.npp.1300254.
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.
对精神兴奋剂的敏感化可受昼夜节律影响。松果体是昼夜褪黑素合成的主要来源，可能影响对可卡因的行为敏感化；褪黑素节律正常的小鼠在夜间不会产生敏感化。诸如周期蛋白1（Per1）等生物钟基因在小鼠大脑中表现出有节律的区域和品系依赖性表达，而Per1基因发生突变的小鼠缺乏可卡因敏感化。在此，我们首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感化发展至关重要的脑区。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Per1 mRNA出现峰值。松果体切除的小鼠未表现出这种昼夜模式。我们分别在对照小鼠（未处理和假松果体切除）纹状体PER1蛋白水平高和低的时间分析了昼夜可卡因敏感化情况。只有纹状体Per1表达有昼夜变化的小鼠在夜间没有可卡因敏感化，而松果体切除的小鼠纹状体Per1没有昼夜变化，且无论昼夜节律如何都对可卡因敏感。我们的结果表明，纹状体昼夜Per1表达和昼夜运动可卡因敏感化均受松果体产物的强烈影响。由于我们发现了纹状体中褪黑素受体mRNA表达的证据，我们建议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，并确定预防和/或治疗成瘾的新靶点。
