Rationale The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences. Objective To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use. Methods We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship. Results Both naphyrone administration patterns induced time-dependent increases in locomotor activity ( p  < 0.001 and p  < 0.0001, respectively) and social interaction ( p  < 0.05 and p  < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior ( p  < 0.01) and reduced resignation ( p  < 0.01) whereas binge administration induced non-anxiety-like behavior ( p  < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine ( p  < 0.0001) and norepinephrine ( p  < 0.05 and p  < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive E max model with an EC 50 of 672 μg/L. Conclusions Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.