Sakai Norio, Thome Johannes, Newton Samuel S, Chen Jingshan, Kelz Max B, Steffen Cathy, Nestler Eric J, Duman Ronald S
Division of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
Mol Pharmacol. 2002 Jun;61(6):1453-64. doi: 10.1124/mol.61.6.1453.
To investigate the role of cAMP response element-binding protein (CREB) in the adaptive responses to psychotropic drugs, we have developed inducible, brain region-specific CREB transgenic mice using the tetracycline-regulated gene expression system. The tetracycline transactivator (tTA) was placed under the control of 1.8-kilobase neuron-specific enolase (NSE) promoter for this purpose. Different patterns of CREB overexpression were found in striatum, nucleus accumbens, and cingulate cortex in different lines of bitransgenic mice, and CREB expression was blocked by addition of doxycycline, an analog of tetracycline. Overexpression of CREB influenced the expression of other members of the CREB/ATF family of transcription factors, consistent with previous reports. In addition, psychostimulant induction of dynorphin, a neuropeptide regulated by drugs of abuse, was up-regulated in striatum. Finally, there was a significant reduction in cocaine-induced locomotor activity in the CREB bitransgenic mice. These results are consistent with a role for CREB in mediating adaptive changes that occur in response to drugs of abuse.
为了研究环磷腺苷反应元件结合蛋白（CREB）在对精神药物适应性反应中的作用，我们利用四环素调控基因表达系统开发了可诱导的、脑区特异性CREB转基因小鼠。为此，将四环素反式激活因子（tTA）置于1.8千碱基神经元特异性烯醇化酶（NSE）启动子的控制之下。在不同品系的双转基因小鼠中，纹状体、伏隔核和扣带回皮质发现了不同模式的CREB过表达，并且通过添加强力霉素（一种四环素类似物）可阻断CREB表达。与先前报道一致，CREB的过表达影响了转录因子CREB/ATF家族其他成员的表达。此外，在纹状体中，由滥用药物调控的神经肽强啡肽的精神兴奋剂诱导上调。最后，CREB双转基因小鼠中可卡因诱导的运动活性显著降低。这些结果与CREB在介导对滥用药物产生的适应性变化中所起的作用一致。
