LAUSR

&NA; 3,4‐methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with cocaine‐like properties. In a previous work, we exposed adolescent mice to MDPV, finding sensitization to cocaine effects, and a higher vulnerability to cocaine abuse in adulthood. Here we sought to determine if such MDPV schedule induces additional behavioral‐neuronal changes that could explain such results. After MDPV treatment (1.5 mg kg−1, twice daily, 7 days), mice were behaviorally tested. Also, we investigated protein changes in various brain regions. MDPV induced aggressiveness and anxiety, but also contributed to a faster habituation to the open field. This feature co‐occurred with an induction of &Dgr;FosB in the orbitofrontal cortex that was higher than its expression in the ventral striatum. Early after treatment, D2R:D1R ratio pointed to a preponderance of D1R but, upon withdrawal, the ratio recovered. Increased expression of Arc, CDK5 and TH, and decrease in DAT protein levels persisted longer after withdrawal, pointing to a neuroplastic lasting effect similar to that involved in cocaine addiction. The implication of the hyperdopaminergic condition in the MDPV‐induced aggressiveness cannot be ruled out. We also found an initial oxidative effect of MDPV, without glial activation. Moreover, although initially the dopaminergic signal induced by MDPV resulted in increased &Dgr;FosB, we did not observe any change in NF&kgr;B or GluA2 expression. Finally, the changes observed after MDPV treatment could not be explained according to the autoregulatory loop between &Dgr;FosB and the epigenetic repressor G9a described for cocaine. This provides new knowledge about the neuroadaptive changes involved in the vulnerability to psychostimulant addiction. HIGHLIGHTSAdolescent mice treated with MDPV were tested at early and late withdrawal.MDPV group showed increased entries to center in the open field test.The rise in cortical &Dgr;FosB by MDPV correlates with this risky behavior.MDPV induced lasting overexpression of Arc, CDK5 and changes in dopaminergic status.24 h after treatment, oxidative markers and G9a N‐methyltransferase were increased.