A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder.
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'.
Psychology Department, University of Wisconsin, 1202 W. Johnson St., Madison, WI 53706, USA.
Brooke E
BE
Schmeichel
Frank P
FP
Zemlan
Craig W
CW
Berridge
D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D001590:Benztropine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009638:Norepinephrine / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; C504727:N-allyl-(bisfluorophenyl)methoxytropane; D018697:Nootropic Agents; D001590:Benztropine; D004298:Dopamine; D009638:Norepinephrine