Tolcapone: a potential new antidepressant detected in a novel animal model of depression.

The potential antidepressant properties of tolcapone, a new catechol-O-methyl transferase (COMT) inhibitor, were investigated in a novel animal model of depression. Chronic mild stress (CMS)-induced anhedonia in rats is recognized as a model of depression with predictive and etiological validity. Here, the effects of CMS on the hedonic state of animals were assessed using a self-stimulation paradigm in which rats self-activate the ventral tegmental area. Frequency thresholds for self-stimulation responses were determined prior to, during and after a 19 day period of exposure to a variety of intermittent, unpredictable, mild stressors. In vehicle-treated stressed animals, stimulation threshold was significantly increased after about 12 days, reflecting a gradual development of an "anhedonic" state. This anhedonia persisted throughout the stress period and subsequently disappeared over a 10 day period. This stress-induced anhedonic state was not observed in stressed rats concomitantly treated with tolcapone (10 or 30mg/kg b.i.d.). In non-stressed vehicle- or drug-treated animals, no significant change in self-stimulation threshold was consistently observed. These results suggest that selective, reversible COMT inhibitors such as tolcapone may offer an innovative approach to the treatment of depression, in addition to their potential therapeutic use in Parkinson's disease.