A role for cortical dopamine in the paradoxical calming effects of psychostimulants

Sharonda S. Harris,Mayank Kumar,Sara M. Green,Nikhil M. Urs

doi:10.1038/s41598-022-07029-2

Abstract

Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.

Highlights

Previous reports have shown that NE transporter (NET)-KO mice have reduced locomotor activity[5], whereas hyperactivity in DATKO is reduced by shown that administration of the 5-HT transporter (SERT) inhibition[1]
We apply an integrated approach, using ex vivo efflux techniques, monoamine transporter genetic knockouts, and behavior, to understand the molecular and anatomical mechanisms that regulate the phenomenon of paradoxical calming effects of psychostimulants in Attention deficit hyperactivity disorder (ADHD) therapy
We showed that the NET inhibitor desipramine, but not the SERT inhibitor fluoxetine, elevates NE and DA levels from prefrontal cortex (PFC) tissue slices

Summary

Introduction

We sought to test the effects of NET or SERT inhibition on locomotor activity in DAT-KO mice. Systemic administration of the NET inhibitor, desipramine (25 mg/kg, i.p.), or the SERT inhibitor, fluoxetine (20 mg/kg, s.c.), significantly decreased hyperactivity in DAT-KO mice, compared to vehicle (saline) injected controls (Fig. 1). We first tested Amph-induced efflux in PFC tissue slices from WT, DAT-KO, and NET-KO mice.

Results

Conclusion