Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.