Saredutant, an NK2 receptor antagonist, has both antidepressant-like effects and synergizes with desipramine in an animal model of depression

Previous work established that saredutant, an NK2 receptor antagonist, has antidepressant and anxiolytic-antistress effects in a variety of rodent models. The purpose of the present investigation was two-fold: to confirm the antidepressant-like effects of saredutant using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rat, and to assess whether saredutant might synergize with desipramine to produce antidepressant-like effects at doses not seen with the individual compounds. For the main study the FSL rats and the control Flinders Resistant Line (FRL) rats were treated with various doses of saredutant (1, 3, and 10 mg/kg in FSL, 3 mg/kg in the FRL), the tricyclic desipramine (5 mg/kg) as a positive control, or vehicle for 14 consecutive days and then tested in the social interaction and forced swim tests about 22 h later. For the synergism study, the FSL rats were treated with subeffective doses of saredutant (1 mg/kg) or desipramine (2.5 mg/kg) or both for 14 consecutive days and then the behavior tests were performed. Saredutant, like desipramine, increased social interaction (at 10 mg/kg) reduced immobility (at 3 and 10 mg/kg), and had no effect on locomotor activity in the FSL rats, but did not affect any of these variables in the FRL rat. Neither saredutant (1 mg/kg) nor desipramine (2.5 mg/kg) affected any variable by themselves; however, their combination significantly lowered swim test immobility. These findings confirm the antidepressant-like effects of saredutant in a genetic animal model of depression. Moreover, they suggest that saredutant might also act as an add-on therapy for individuals who are not fully responding to their antidepressant treatment. (C) 2010 Published by Elsevier Inc.