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Role of Cortical Catecholamines in the Paradoxical Action of Psychostimulants
Author(s) -
Harris Sharonda,
Green Sara
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb90
Subject(s) - dopamine , methylphenidate , amphetamine , atomoxetine , stimulant , neuroscience , guanfacine , dopamine transporter , psychology , dextroamphetamine , neurotransmitter , striatum , monoamine neurotransmitter , attention deficit hyperactivity disorder , medicine , clonidine , receptor , dopaminergic , psychiatry , serotonin , central nervous system
Attention deficit hyperactivity disorder (ADHD) affects young children and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. The primary line of treatment for ADHD are the psychostimulant class of drugs including amphetamine (Adderall) and methylphenidate (Ritalin). Several theories have been postulated on the paradoxical calming effect of psychostimulants on ADHD patients, but even after decades of research, their exact mechanism of action is unknown. Clinical studies have shown reduced levels of dopamine (DA) receptor and DA transporters (DAT) in ADHD patients, presumably due to elevated caudate DA levels. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the parallel actions of other monoamine neurotransmitters. On the other hand, newer non‐stimulant classes of drugs such as atomoxetine and Intuniv suggest that targeting the norepinephrine (NE) system might explain the paradoxical calming effect. Again, the molecular and cellular mechanisms of action for these drugs or neurotransmitters in ADHD therapy is unknown. Previous work has shown that DA levels in the PFC have a reciprocal effect on striatal DA levels and locomotion. Our preliminary data suggest that PFC D2+ pyramidal neurons project to the striatum and midbrain dopamine neurons and that infusion of D2 agonists in the PFC inhibits locomotion. We hypothesize that PFC DA through the action of PFC D2+ pyramidal neurons regulates striatal DA release and locomotion. To test our hypothesis we use ex vivo neurotransmitter release from mouse PFC slices, microdialysis and locomotor measurements, in NET and DAT knockout mice. Our preliminary data suggest that NET and SERT blockers not only increase extracellular levels of NE and 5HT, but also DA. These data suggest a possible role for cortical catecholamines in regulating the paradoxical effects of psychostimulants. Our future studies will not only shed light on the mechanism of psychostimulant action in ADHD therapy, but will facilitate development of newer therapies based on mechanistic evidence. Support or Funding Information Brain Behavior Research Foundation 27765 to N. Urs This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .