A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder

Neuropharmacology. 2013 Jan;64(1):321-8. doi: 10.1016/j.neuropharm.2012.07.005. Epub 2012 Jul 11.


Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / physiopathology
  • Behavior, Animal / drug effects
  • Benztropine / administration & dosage
  • Benztropine / adverse effects
  • Benztropine / analogs & derivatives
  • Benztropine / therapeutic use
  • Cognition / drug effects*
  • Cognition Disorders / etiology
  • Cognition Disorders / prevention & control*
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / adverse effects
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Dose-Response Relationship, Drug
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • Male
  • Memory, Short-Term / drug effects
  • Neurons / drug effects*
  • Neurons / metabolism
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / adverse effects
  • Nootropic Agents / therapeutic use*
  • Norepinephrine / metabolism
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism
  • Spatial Behavior / drug effects


  • Dopamine Uptake Inhibitors
  • N-allyl-(bisfluorophenyl)methoxytropane
  • Nootropic Agents
  • Benztropine
  • Dopamine
  • Norepinephrine