Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats

Background: Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats. Methods: Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50mg/kg; PO) was given 25minutes or 24hours prior to evaluation. The effects of DOV (12.5 to 50mg/kg; PO) in the FST were evaluated 25minutes posttreatment. Results: DOV (6.25 to 50mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50mg/kg) was sustained for up to 120hours after a single dose. Administration of a single dose of DOV (25, 50mg/kg) 24hours before testing suppressed alcohol responding for 48hours by 59 to 62%. DOV (12.5 to 50mg/kg) also dose-dependently reduced immobility of P rats in the FST. Conclusions: DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.