Milnacipran enhances the control of impulsive action by activating D₁-like receptors in the infralimbic cortex.

Rationale: Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives: Our goal was to identify whether D(1)- and/or D(2)-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods: The rats were bilaterally injected with SCH23390, a selective D(1)-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D(2)-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results: Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions: This is the first report that demonstrates a critical role for D(1)-like receptors of the IL in milnacipran-enhanced control of impulsive action.