Received for publication July 16, 2008.
Revised August 7, 2008.
Accepted for publication August 7, 2008.

Antidepressant-like pharmacological profile of a novel triple re-uptake inhibitor, PRC200-SS

Abstract

Due to the putative involvement of dopaminergic circuits in depression, triple re-uptake 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. PRC200-SS, a new triple re-uptake 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 rat and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable to imipramine. These results in these behavioral models did not appear 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 to levels for saline control. Further, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore it appears that PRC200-SS may represent a novel triple re-uptake inhibitor and possess antidepressant activity.

Key words: PRC200-SS, forced-swim test, microdialysis, self-administration, tail-suspension test, triple re-uptake inhitiors