Until recently, several weeks of treatment were required in order to obtain a clinically significant antidepressant response using pharmacotherapy. The present study, using the mouse forced swimming test, investigated possible antidepressant augmentation strategies, together with the probable mechanisms involved in such potentiations. It is clear from this and other similar studies that it is possible to enhance the activity of antidepressant drugs with the addition of other compounds (ie, clonidine, quinine, glyburide, pindolol, or buspirone). These data indicate that direct/indirect manipulation of serotonergic receptor systems potentiates the effect antidepressant drugs (ie, selective serotonergic reuptake inhibitors) in the mouse forced swimming test, and thus establish this model as a reliable preclinical tool for the investigation of possible antidepressant augmentation strategies. It also appears that this model can be used as a method for identifying the mechanisms involved in such treatment strategies.