title: Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model.
abstract: Prefrontal cortical dopamine plays an important role in cognitive control, specifically in attention and response inhibition; the core deficits in ADHD. We have previously shown that methylphenidate and atomoxetine differentially improve these deficits dependent on baseline performance. The present study extends this work to investigate the effects of putative therapeutic targets in our model. A selective dopamine D4 receptor agonist (A-412997) and the catechol-O-methyl-transferase (COMT) inhibitor; tolcapone, were investigated in the combined subtype of adult ADHD (ADHD-C). Adult female rats were trained to criterion in the 5C-CPT (5-Choice Continuous Performance Task) and then separated into subgroups according to baseline levels of sustained attention, vigilance, and response disinhibition. The subgroups included: high-attentive (HA) and low-attentive with high response disinhibition (ADHD-C). The ADHD-C subgroup was selected to represent the combined subtype of adult ADHD. Effects of tolcapone (3.0, 10.0, 15.0mg/kg) and A-412997 (0.1, 0.3, 1.0µmol/kg) were tested by increasing the variable inter-trial-interval (ITI) duration in the 5C-CPT. Tolcapone (15mg/kg) significantly increased sustained attention, vigilance and response inhibition in ADHD-C animals, and impaired attention in HA animals. A-412997 (1.0µmol/kg) significantly increased vigilance and response inhibition in ADHD-C animals only, with no effect in HA animals. This is the first study to use the translational 5C-CPT to model the adult ADHD-C subtype in rats and to study new targets in this model. Both tolcapone and A-412997 increased vigilance and response inhibition in the ADHD-C subgroup. D4 and COMT are emerging as important potential therapeutic targets in adult ADHD that warrant further investigation.
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK. Electronic address: anneka.tomlinson@gtc.ox.ac.uk.
authors: Anneka
authors: A
authors: Tomlinson
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK.
authors: Ben
authors: B
authors: Grayson
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK.
authors: Samuel
authors: S
authors: Marsh
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK.
authors: Andrew
authors: A
authors: Hayward
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK.
authors: Kay M
authors: KM
authors: Marshall
authors: Manchester Pharmacy School, University of Manchester, Oxford Rd, Manchester M13 9PT, UK. Electronic address: joanna.neill@manchester.ac.uk.
authors: Joanna C
authors: JC
authors: Neill
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001288:Attention / Q000187:drug effects; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D001577:Benzophenones / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors / Q000627:therapeutic use*; D002755:Choice Behavior / Q000187:drug effects*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007266:Inhibition, Psychological; D009596:Nitrophenols / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D000077867:Tolcapone
chemical_list: C506999:2-(3',4',5',6'-tetrahydro-2'H-(2,4') bipyridinyl-1'-yl)-N-m-tolyl-acetamide; D000081:Acetamides; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D018491:Dopamine Agonists; D009596:Nitrophenols; D011725:Pyridines; D000077867:Tolcapone
keywords: 5C-CPT; ADHD; COMT; D4; Dopamine; Translational