biostudies-literatureHarris SSNational Alliance for Research on Schizophrenia and Depression3129https://www.ebi.ac.uk/biostudies/studies/S-EPMC8873208biostudies-literatureUnknown12(1)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), bScientific reportsA role for cortical dopamine in the paradoxical calming effects of psychostimulants.PMC887320827765Harris SSGreen SMKumar MUrs NMfalseA role for cortical dopamine in the paradoxical calming effects of psychostimulants.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), b2022-01-01T00:00:00Z2022 Feb2025-06-01T12:03:34.361Z2025-06-01T12:03:34.361ZS-EPMC88732083521048910.1038/s41598-022-07029-2