Effects of ketamine pretreatment on tetrabenazine-induced motivational impairments in male rats performing an effort-based decision-making task

Anhedonia, a core feature of major depressive disorder (MDD), consists of both consummatory and motivational elements; however, the exact behavioral and neurobiological mechanisms underlying anhedonia are not yet fully understood. Clinical studies using translational measurements of reward motivation, such as effort-based decision-making tasks, have demonstrated that patients are less willing to expend effort on rewards than controls, indicating an association between impairments in reward motivation and anhedonia. Ketamine, an N-methyl-D-aspartate receptor antagonist, has emerged as a rapid and potent antidepressant. This study investigated the effect of ketamine on reward motivation related to anhedonia in a rat effort-based decision-making task. This task allowed the rats to choose between high-effort/high-reward and low-effort/low-reward options under an operant conditioning paradigm. Tetrabenazine, a vesicular monoamine transport type-2 inhibitor that blocks dopamine storage and depletes dopamine, induces motivational impairments in rodents and humans. In this task, intraperitoneal (i.p.) administration of tetrabenazine (0.75 mg/kg) to rats caused a significant decrease in the number of lever presses to obtain reward (sucrose pellet) and increased chow consumption, indicating impairment of reward motivation. This impairment was attenuated by the intraperitoneal administration of bupropion (20 mg/kg). Under these experimental conditions, ketamine (30 mg/kg, i.p.) administration 24 h prior to tetrabenazine treatment prevented impairments in reward motivation, and increased the number of lever presses to obtain a reward. These findings indicate that ketamine has the potential to ameliorate impairments in reward motivation associated with anhedonia.