Division of Biochemistry, Department of Medicine, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland.
Neurobiol Dis. 2010 Jan;37(1):86-98. doi: 10.1016/j.nbd.2009.09.010. Epub 2009 Sep 26.
Chronic cocaine induces high expression of the brain-specific Neural-Zinc-Finger transcription factor-2b (NZF-2b/7ZFMyt1), particularly in the mesolimbic dopaminergic pathway, resulting in a 11-fold increase in NZF-2b/7ZFMyt1 expression in the Nucleus Accumbens (NAc). Overexpression of this gene in the NAc with a NZF-2b/7ZFMyt1-expressing lentivirus resulted in >55% decrease in locomotor activity upon chronic cocaine administration, compared to control animals. In contrast knocking-down the gene in the NAc with lentiviruses expressing shRNAs against NZF-2b/7ZFMyt1 induced strong hyperlocomotor activity upon cocaine. Strong inhibition of BDNF is observed upon NZF-2b/7ZFMyt1 expression, concomitant with strong induction of transcription factors REST1 (RE silencing transcription factor-1) and NAC1, probably leading to regulation of gene expression by interaction with histone deacetylases. These changes lead to decreased responsiveness of the animal to the locomotor-activating effects of cocaine, indicating that NZF-2b/7ZFMyt1 expression plays an important role in phenotypic changes induced by the drug.
慢性可卡因诱导脑特异性神经锌指转录因子-2b（NZF-2b/7ZFMyt1）的高表达，特别是在中脑边缘多巴胺能通路中，导致伏隔核（NAc）中 NZF-2b/7ZFMyt1 的表达增加了 11 倍。用表达 NZF-2b/7ZFMyt1 的慢病毒在 NAc 中过表达该基因，与对照动物相比，在慢性可卡因给药后，运动活性降低了>55%。相比之下，用表达针对 NZF-2b/7ZFMyt1 的 shRNAs 的慢病毒在 NAc 中敲低该基因，会在可卡因作用下诱导强烈的过度运动活性。观察到 NZF-2b/7ZFMyt1 表达时 BDNF 强烈抑制，同时转录因子 REST1（RE 沉默转录因子-1）和 NAC1 强烈诱导，可能导致通过与组蛋白去乙酰化酶相互作用来调节基因表达。这些变化导致动物对可卡因的运动激活作用的反应性降低，表明 NZF-2b/7ZFMyt1 的表达在药物诱导的表型变化中起着重要作用。
