Regaining Effort-Based Food Motivation: The Drug Methylphenidate Reverses the Depressive Effects of Tetrabenazine in Female Rats

Tetrabenazine (TBZ), a vesicular monoamine transporter type 2 (VMAT-2) inhibitor, depletes dopamine and induces motivational deficits and other depressive symptoms in humans. Methylphenidate (MPH) is a dopamine transport blocker that is used to enhance motivational function. Previous studies have shown that in male rats, TBZ induces a shift in effort-related choice such that a low-effort bias is induced. In male rats this occurs at a dose range of 0.75-1.0 mg/kg TBZ, and this effect is reversible with co-administration of MPH. Recent studies have shown that females need a higher dose of TBZ (2.0 mg/kg) to show the low-effort bias. The present study tested the ability of MPH to reverse the effects of 2.0 mg/kg TBZ in female rats using an effort-based choice task. Food-restricted female rats (n=8) were trained on a fixed-ratio (FR) 5/chow feeding choice task in which they can choose between the high effort/high reward option (FR5 lever pressing for preferred food, which was Bioserve pellets) or the low effort/low reward option (consuming the concurrently available but less preferred lab chow). After initial training, rats were tested in a repeated measure design in which they received combined treatments of either a vehicle control solution, 2.0 mg/kg TBZ, or TBZ plus various doses of MPH ranging (0.5 - 4.0 mg/kg MPH) prior to testing. TBZ significantly reduced lever pressing and increased chow intake, and this effect was reversed by 2.0 mg/kg MPH. This study shows that MPH can treat motivational deficits induced by TBZ in female rats as well as male rats