McClung Colleen A, Nestler Eric J
The University of Texas Southwestern Medical Center, Department of Psychiatry and Center for Basic Neuroscience, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Nat Neurosci. 2003 Nov;6(11):1208-15. doi: 10.1038/nn1143. Epub 2003 Oct 19.
DeltaFosB (a truncated form of FosB) and CREB (cAMP response element binding protein) are transcription factors induced in the brain's reward pathways after chronic exposure to drugs of abuse. However, their mechanisms of action and the genes they regulate remain unclear. Using microarray analysis in the nucleus accumbens of inducible transgenic mice, we found that CREB and a dominant-negative CREB have opposite effects on gene expression, as do prolonged expression of DeltaFosB and the activator protein-1 (AP-1) antagonist DeltacJun. However, unlike CREB, short-term and prolonged DeltaFosB induction had opposing effects on gene expression. Gene expression induced by short-term DeltaFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged DeltaFosB expression increased drug reward. Gene expression after a short cocaine treatment was more dependent on CREB, whereas gene expression after a longer cocaine treatment became increasingly DeltaFosB dependent. These findings help define the molecular functions of CREB and DeltaFosB and identify clusters of genes that contribute to cocaine addiction.
DeltaFosB（FosB的一种截短形式）和CREB（环磷酸腺苷反应元件结合蛋白）是长期接触滥用药物后在大脑奖赏通路中被诱导产生的转录因子。然而，它们的作用机制以及所调控的基因仍不清楚。通过对可诱导转基因小鼠伏隔核进行微阵列分析，我们发现CREB和一种显性负性CREB对基因表达有相反的影响，DeltaFosB的长期表达与激活蛋白-1（AP-1）拮抗剂DeltacJun的作用效果也相反。然而，与CREB不同，短期和长期诱导DeltaFosB对基因表达有相反的影响。短期DeltaFosB诱导和CREB诱导的基因表达惊人地相似，且二者都降低了可卡因的奖赏效应，而DeltaFosB的长期表达则增强了药物奖赏。短期可卡因处理后的基因表达更依赖于CREB，而较长时间可卡因处理后的基因表达则越来越依赖于DeltaFosB。这些发现有助于明确CREB和DeltaFosB的分子功能，并识别出导致可卡因成瘾的基因簇。
