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

Abstract

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.

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

“…In both monkey ) and human (Ciliax et al, 1999) dlPFC, DA fibers express DA transporters, although there are far fewer than in the striatum. Small alterations in the carboxyl-terminal tail of the DA transporters can make it less specific for DA (Lee et al, 1996) and this may explain why DA and norepinephrine (NE) transporters in the PFC appear to take up both catecholamines (Schmeichel et al, 2013). In monkey dlPFC, DA axons establish symmetric synapses with the soma, dendritic shafts, and spines of pyramidal cells, the latter participating in synaptic triads where both a DA symmetric synapse and a glutamate-like asymmetric synapse converge onto a single spine .…”

Catecholamine mechanisms in the prefrontal cortex: proven strategies for enhancing higher cognitive function

“…Consistent with this, NET inhibitors effective in ADHD increase both NE and DA in the PFC without altering striatal DA (Figure 4; [50 ,51]). Conversely, when administered at a cognition-enhancing dose, a selective DAT inhibitor also increases both extracellular DA and NE in the PFC (Figure 4; [52]). In this case, the drug is posited to indirectly affect NE levels via drug-induced increases in extracellular DA that compete with NE at the NET.…”

Neurocircuitry Underlying the Preferential Sensitivity of Prefrontal Catecholamines to Low-Dose Psychostimulants

“…Consequently, in regions with minimal DAT (eg, PFC), drugs that block the NET increase both NE and DA while having no significant impact on DA levels in regions with high DAT density and low NET density (eg, NAc;Bymaster et al, 2002;Carboni et al, 1990). Conversely, recent studies demonstrate that a highly selective DAT inhibitor also elevates both DA and NE in the PFC (Schmeichel et al, 2012). These observations suggest that NE and DA binding to the NET in the PFC is competitive, with elevations in extracellular levels of one transmitter resulting in elevations of the other.…”

“…For example, in the PFC the NE transporter (NET) has a prominent role in DA clearance from the extracellular space (Carboni et al, 2006(Carboni et al, , 1990Moron et al, 2002;Valentini et al, 2004). Evidence suggests that NE and DA binding to the NET is competitive, with increases in either NE or DA within the PFC elevating extracellular levels of the other transmitter (Bymaster et al, 2002;Schmeichel et al, 2012;Valentini et al, 2004). Such a feed-forward process could contribute to the enhanced sensitivity of PFC catecholamines to low-dose psychostimulants.…”