The function of the ZFP189 transcription factor in the nucleus accumbens facilitates cocaine-specific transcriptional and behavioral adaptations

Here, we explore the function of a drug-associated repressive transcription factor (TF), ZFP189, whose expression in the nucleus accumbens (NAc) facilitates cocaine-induced molecular and behavioral adaptations. To uncover the molecular action of ZFP189, we created synthetic ZFP189 TFs of distinct transcriptional function, including ZFP189VPR, which activates the expression of target genes and exerts opposite transcriptional control to the endogenously repressive ZFP189. By virally delivering synthetic ZFP189 TFs to the NAc of mice, we discover that the molecular control exerted by synthetic or endogenous ZFP189 solely alters behavioral response to cocaine but not morphine or palatable food. Transcriptional adaptation occurred in response to cocaine, but not morphine. We demonstrate that NAc ZFP189 function drives the cocaine self-administration behaviors, whereas NAc ZFP189VPR impedes this worsening of cocaine taking behaviors. Collectively, this research illuminates the mechanisms through which a drug-associated TF specifically coordinates the brain adaptations necessary for the increasing of cocaine self-administration behaviors.