title: Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice.
abstract: BACKGROUND
  Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a "paradoxical" calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood.
  
  
  OBJECTIVE
  This study was conducted to investigate the effects of psychostimulants and noradrenergic and serotonergic drugs on cognition in DAT-KO mice and normal (WT) littermates.
  
  
  METHODS
  We used a recently developed behavioral apparatus, the automated H-maze. The H-maze involves the consecutive learning of three different rules: delayed alternation, nonalternation, and reversal tasks.
  
  
  RESULTS
  Treatment of WT animals with the psychostimulants replicated the behavior observed in untreated DAT-KO mice while "paradoxically" restoring cognitive performances in DAT-KO mice. Further investigation of the potential involvement of other monoamine systems in the regulation of cognitive functions showed that the norepinephrine transporter blocker atomoxetine restored cognitive performances in DAT-KO mice without affecting hyperactivity. In contrast, the nonselective serotonin receptor agonist 5CT, which antagonizes hyperactivity in DAT-KO mice, had no effect on cognitive functions.
  
  
  CONCLUSIONS
  Taken together, these data allow dissociation of the locomotor and cognitive effects of ADHD drugs and suggest that the combination of DAT-KO mice with the automated H-maze can constitute a powerful experimental paradigm for the preclinical development of therapeutic approaches for ADHD.
authors.affiliation: Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval, Pavillon Ferdinand-Vandry, 1050, avenue de la Médecine, Québec City, QC, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Del'Guidice
authors.forename: Morgane
authors.initials: M
authors.lastname: Lemasson
authors.forename: Adeline
authors.initials: A
authors.lastname: Etiévant
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Luiz Alexandre V
authors.initials: LA
authors.lastname: Magno
authors.forename: Guy
authors.initials: G
authors.lastname: Escoffier
authors.forename: François S
authors.initials: FS
authors.lastname: Roman
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000235:genetics / Q000523:psychology*; D018782:Maze Learning / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D012903:Smell / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D011437:Propylamines; D018490:Serotonin Agents; D012701:Serotonin; D008694:Methamphetamine; D000069445:Atomoxetine Hydrochloride; D000661:Amphetamine; D009638:Norepinephrine
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