Purpose <p>3,4-Methylenedioxypyrovalerone (MDPV) is a potent psychostimulant substance endowed with addictive properties. As mammalian target of rapamycin (mTOR) mediates neuroadaptive changes responsible for development of addiction, the current study evaluated whether rapamycin, a potent and selective inhibitor of mTOR, prevents induction and expression of behavioral sensitization in mice treated with MDPV.</p> Methods <p>Locomotor sensitization was used as an animal model of early phase of addiction. C57BL/6JRj mice were treated with rapamycin before administration of MDPV during the induction phase of sensitization, or during the final 5&#xa0;days of the withdrawal. Sensitization was assessed based on the measurement of locomotor activity after treatment with MDPV.</p> Results <p>Rapamycin administered on days 1–7 inhibited induction of sensitization characterized by increased horizontal and vertical locomotor activity on day 7 compared to day 1. Additionally, when given during the withdrawal from MDPV, rapamycin blocked expression of sensitization, defined as augmented response to MDPV on day 21 compared to day 1.</p> Conclusions <p>Abolishment of locomotor sensitization to MDPV by rapamycin suggests that neuroadaptive changes underlying this phenomenon are dependent on the mTOR signaling and warrants further research on possible application of mTOR inhibitors in treatment of addiction.</p>