Behavioral and Biochemical Effects of Chronic Quetiapine and Venlafaxine in a Nonhuman Primate Model of Stress Induced Depression

30 Wake Forest School of Medicine This study examined the effects of venlafaxine and quetiapine in a nonhuman primate model predictive of antidepressant drug effects. Twelve experimentally naïve male cynomolgus monkeys were trained to respond under a food-reinforcement schedule shown to have predictive validity in models of antidepressant activity (a differentialreinforcement-of-low rates; DRL schedule). In addition, monkeys were exposed to social stress by being an intruder in another social pen once per month, immediately before operant test sessions. Monkeys were treated chronically (3 months) with either quetiapine (3.0 mg/kg, p.o., s.i.d.), venlafaxine (1.5 mg/kg, p.o., b.i.d.) or served as controls (n=4/group). At the end of testing, brains were examined for several markers related to depression and antidepressant drug action. Being an intruder disrupted DRL performance with no evidence of improvement over time in the control animals. Chronic quetiapine treatment improved performance in three of four monkeys, while half of the animals treated with venlafaxine showed an antidepressant-like effect. BDNF variant 5 mRNA was significantly increased in the anterior hippocampus of quetiapine-treated monkeys. CREB protein expression was increased in the anterior and posterior hippocampus of venlafaxine-treated monkey, while phosphorylated CREB was decreased in the anterior hippocampus of the quetiapine-treated group. These findings suggest that quetiapine and venlafaxine’s antidepressant-like effects are mediated, at least in part, through the hippocampus.