Noradrenaline reuptake inhibition increases control of impulsive action by activating D1-like receptors in the infralimbic cortex

Abstract

Higher impulsivity is a risk factor for criminal involvement, substance abuse, and suicide. However, only a few drugs are clinically available for the treatment of deficient impulse control. We recently proposed a strategy for identifying potential drugs to treat such disorders by investigating clinically available drugs that increase extracellular dopamine levels in the medial prefrontal cortex and stimulate dopamine D₁-like receptors without increasing extracellular dopamine levels in the ventral striatum. To determine whether this strategy is promising, we examined the effects of duloxetine, a serotonin-noradrenaline reuptake inhibitor that might meet these criteria, on impulsive action in adult male Wistar/ST rats using a 3-choice serial reaction time task. The effects of duloxetine on extracellular dopamine levels in the medial prefrontal cortex and nucleus accumbens, a part of the ventral striatum were evaluated using in vivo microdialysis, as the noradrenaline transporter transports dopamine in some brain regions. Our results showed that the administration of duloxetine reduced impulsive actions and increased extracellular dopamine levels in the mPFC but not in the nucleus accumbens. Microinjection of a selective D₁-like receptor antagonist into the infralimbic cortex blocked the suppression of impulsive action by duloxetine. In addition, we demonstrated that the microinjection also blocked the suppression of impulsive action by atomoxetine, a noradrenaline reuptake inhibitor and an established anti-impulsive drug. These results support our proposed strategy for identifying and developing anti-impulsivity drugs.

Keywords: Behavioral inhibition; Dopamine; Impulsive behavior; Impulsivity; Microdialysis; SNRI.