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

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.

Effects of Atomoxetine on Motor and Cognitive Behaviors and Brain Electrophysiological Activity of Dopamine Transporter Knockout Rats

“…Despite the amount of research conducted on underlying mechanisms of ADHD, many aspects are still unclear, given the vast degree of interplay between monoaminergic systems. There is evidence that cortical dopamine, norepinephrine and serotonin play the central role in the pathology of the disorder [ 14 , 67 , 68 ], while recent findings suggest that the paradoxical calming effect of psychostimulants in ADHD, as well as in DAT-KO mice, is mediated predominantly by dopamine [ 13 ]. Deficits in DA transmission have been considered the main cause of other disorders, such as schizophrenia (SZ).…”

“…NET blockade has been shown to inhibit hyperactivity in DAT-KO mice [ 13 , 49 ] by nisoxetine and desipramine, see also [ 26 ]. In our study, atomoxetine failed to produce a similar result in DAT-KO rats.…”

“…Symptoms include hyperactivity, impulsivity, inattention, lack of motivation and learning difficulties [ 8 , 9 ]. In ADHD, changes in DA and NE are thought to play a crucial role in the pathology of the disorder [ 10 , 11 , 12 ], although the contribution of serotonin system to at least some behavioral manifestations cannot be excluded [ 13 , 14 ]. One of the approved medications with proven clinical efficacy in reducing ADHD symptoms is atomoxetine (ATX, atomoxetine, LY139603) [ 15 , 16 , 17 ].…”

Attention-deficit/hyperactive disorder updates

“…Additionally, several studies have shown that the dopamine receptor density in several brain regions of ADHD patients is lower compared to healthy individuals ( Jönsson et al, 1999 ; Medin et al, 2013 ). Notably, it has been revealed that it is the elevation of the frontal cortical dopamine levels and not norepinephrine or serotonin that acts as a convergent mechanism for the paradoxical effects of ADHD psychostimulants therapies ( Harris et al, 2022 ). ADHD is associated with higher mortality and lowered estimated life expectancy by adulthood and some of the dopaminergic SNP has been reported to relate to 5- and 2-year reductions in estimated life expectancy ( Barkley et al, 2019 ).…”

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

“…As psychostimulants (first-line ADHD treatment; e.g., MPH, amphetamine) ( Banaschewski et al, 2018 ), demonstrate large effect sizes, the dopaminergic deficit theory has been studied for many years ( Gonon, 2009 ). However, the paradoxical calming effects of psychostimulants in ADHD have still not been fully understood ( Robbins and Sahakian, 1979 ; Harris et al, 2022 ). Recently, the excitatory/inhibitory imbalance theory has gained interest ( Selten et al, 2018 ), in which GABAergic and parvalbumin-interneurons are hypothesized to play a role in some of the circuits ( Bakhtiari et al, 2012 ; Morello et al, 2020 ; Sousa et al, 2022 ).…”