Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
J Neurosci. 2012 May 30;32(22):7577-84. doi: 10.1523/JNEUROSCI.1381-12.2012.
The molecular mechanism underlying induction by cocaine of ΔFosB, a transcription factor important for addiction, remains unknown. Here, we demonstrate a necessary role for two transcription factors, cAMP response element binding protein (CREB) and serum response factor (SRF), in mediating this induction within the mouse nucleus accumbens (NAc), a key brain reward region. CREB and SRF are both activated in NAc by cocaine and bind to the fosB gene promoter. Using viral-mediated Cre recombinase expression in the NAc of single- or double-floxed mice, we show that deletion of both transcription factors from this brain region completely blocks cocaine induction of ΔFosB in NAc, whereas deletion of either factor alone has no effect. Furthermore, deletion of both SRF and CREB from NAc renders animals less sensitive to the rewarding effects of moderate doses of cocaine when tested in the conditioned place preference (CPP) procedure and also blocks locomotor sensitization to higher doses of cocaine. Deletion of CREB alone has the opposite effect and enhances both cocaine CPP and locomotor sensitization. In contrast to ΔFosB induction by cocaine, ΔFosB induction in NAc by chronic social stress, which we have shown previously requires activation of SRF, is unaffected by the deletion of CREB alone. These surprising findings demonstrate the involvement of distinct transcriptional mechanisms in mediating ΔFosB induction within this same brain region by cocaine versus stress. Our results also establish a complex mode of regulation of ΔFosB induction in response to cocaine, which requires the concerted activities of both SRF and CREB.
可卡因诱导 ΔFosB 的分子机制，ΔFosB 是一种与成瘾有关的重要转录因子，目前尚不清楚。在这里，我们证明了两种转录因子，环磷酸腺苷反应元件结合蛋白（CREB）和血清反应因子（SRF），在介导小鼠伏隔核（NAc）内这种诱导中的必要作用，NAc 是大脑奖励区域的关键部位。可卡因可激活 NAc 中的 CREB 和 SRF，并与 fosB 基因启动子结合。使用病毒介导的 Cre 重组酶在单或双 floxed 小鼠的 NAc 中表达，我们表明，从该脑区删除这两种转录因子可完全阻断可卡因诱导 NAc 中 ΔFosB 的产生，而单独删除任一因子则没有影响。此外，从 NAc 中删除 SRF 和 CREB 可使动物在条件性位置偏爱（CPP）程序中对中等剂量可卡因的奖赏作用的敏感性降低，并且还阻断了对较高剂量可卡因的运动敏化作用。单独删除 CREB 则具有相反的效果，可增强可卡因 CPP 和运动敏化作用。与可卡因诱导的 ΔFosB 不同，我们之前已经表明，慢性社会应激诱导的 NAc 中的 ΔFosB 需要 SRF 的激活，而单独删除 CREB 则不会影响其诱导。这些惊人的发现表明，在相同的脑区中，可卡因与应激介导 ΔFosB 诱导涉及不同的转录机制。我们的研究结果还确立了 cocaine 诱导 ΔFosB 产生的复杂调节模式，该模式需要 SRF 和 CREB 的协同作用。
