Imbesi M, Yildiz S, Dirim Arslan A, Sharma R, Manev H, Uz T
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, M/C 912, Chicago, IL 60612, USA.
Neuroscience. 2009 Jan 23;158(2):537-44. doi: 10.1016/j.neuroscience.2008.10.044. Epub 2008 Nov 5.
Using a transgenic mice model (i.e. "clock" knockouts), clock transcription factors have been suggested as critical regulators of dopaminergic behaviors induced by drugs of abuse. Moreover, it has been shown that systemic administration of psychostimulants, such as cocaine and methamphetamine regulates the striatal expression of clock genes. However, it is not known whether dopamine receptors mediate these regulatory effects of psychostimulants at the cellular level. Primary striatal neurons in culture express dopamine receptors as well as clock genes and have been successfully used in studying dopamine receptor functioning. Therefore, we investigated the role of dopamine receptors on neuronal clock gene expression in this model using specific receptor agonists. We found an inhibitory effect on the expression of mClock and mPer1 genes with the D2-class (i.e. D2/D3) receptor agonist quinpirole. We also found a generalized stimulatory effect on the expression of clock genes mPer1, mClock, mNPAS2 (neuronal PAS domain protein 2), and mBmal1 with the D1-class (i.e. D1) receptor agonist SKF38393. Further, we tested whether systemic administration of dopamine receptor agonists causes similar changes in striatal clock gene expression in vivo. We found quinpirole-induced alterations in mPER1 protein levels in the mouse striatum (i.e. rhythm shift). Collectively, our results indicate that the dopamine receptor system may mediate psychostimulant-induced changes in clock gene expression. Using striatal neurons in culture as a model, further research is needed to better understand how dopamine signaling modulates the expression dynamics of clock genes (i.e. intracellular signaling pathways) and thereby influences neuronal gene expression, neuronal transmission, and brain functioning.
利用转基因小鼠模型（即“生物钟”基因敲除模型），生物钟转录因子被认为是滥用药物诱导的多巴胺能行为的关键调节因子。此外，研究表明，可卡因和甲基苯丙胺等精神兴奋剂的全身给药可调节生物钟基因在纹状体中的表达。然而，尚不清楚多巴胺受体是否在细胞水平介导精神兴奋剂的这些调节作用。培养的原代纹状体神经元表达多巴胺受体以及生物钟基因，并已成功用于研究多巴胺受体的功能。因此，我们使用特异性受体激动剂在该模型中研究了多巴胺受体对神经元生物钟基因表达的作用。我们发现D2类（即D2/D3）受体激动剂喹吡罗对mClock和mPer1基因的表达有抑制作用。我们还发现D1类（即D1）受体激动剂SKF38393对生物钟基因mPer1、mClock、mNPAS2（神经元PAS结构域蛋白2）和mBmal1的表达有普遍的刺激作用。此外，我们测试了多巴胺受体激动剂的全身给药是否会在体内引起纹状体生物钟基因表达的类似变化。我们发现喹吡罗诱导小鼠纹状体中mPER1蛋白水平发生改变（即节律 shift）。总体而言，我们的结果表明多巴胺受体系统可能介导精神兴奋剂诱导的生物钟基因表达变化。以培养的纹状体神经元为模型，还需要进一步研究以更好地理解多巴胺信号如何调节生物钟基因的表达动态（即细胞内信号通路），从而影响神经元基因表达、神经元传递和脑功能。
