Regulation of gene expression and cocaine reward by CREB and ΔFosB

ΔFosB (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 ΔFosB and the activator protein-1 (AP-1) antagonist ΔcJun. However, unlike CREB, short-term and prolonged ΔFosB induction had opposing effects on gene expression. Gene expression induced by short-term ΔFosB and by CREB was strikingly similar, and both reduced the rewarding effects of cocaine, whereas prolonged ΔFosB 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 ΔFosB dependent. These findings help define the molecular functions of CREB and ΔFosB and identify clusters of genes that contribute to cocaine addiction.