Abstract Brain-derived neurotrophic factor (BDNF) dynamic changes were investigated in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) during use and the early phases of cocaine abstinence after 14 sessions (2 h self-administration/d; 0.25 mg/0.1 ml.6 s infusion) by employing a ‘yoked control-operant paradigm'. The effect on BDNF was region-specific and dependent on the withdrawal time. In the NAc, BDNF protein levels increased immediately after the last self-administration session, with a larger increase in passively cocaine-exposed rats. In the mPFC, BDNF expression was elevated 24 h after the last self-administration session, independently of how the drug was encountered. No changes were found in NAc and mPFC 7 d after the last self-administration session. Analysis of transcript levels in the mPFC indicated that action on exon I might contribute to BDNF's cortical induction. These findings indicate a finely tuned modulation of BDNF expression during use and early phases of cocaine abstinence.