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. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Figure 1

AHN 2-005 improves PFC-dependent working memory performance. Shown are the mean (± SEM) percent change correct from baseline in animals treated with vehicle or varying doses of AHN 2-005. AHN 2-005 produced a dose-dependent improvement in performance in this task with significant improvement occurring at the 10 mg/kg dose. The magnitude of AHN 2-005-induced improvement in performance is comparable to that seen with systemic administration of clinically-relevant doses of psychostimulants. *P < 0.05 vs. vehicle-treatment.

Figure 2

Photomicrographs depicting placement of dialysis probes within the prefrontal cortex (PFC, Panel A), nucleus accumbens (NAc, Panel B), and the medial septal area (MSA, Panel C). For PFC, probes were placed within the medial subdivision of this region. In Panel B, dashed line indicates approximate boundary of the nucleus accumbens. For MSA, probe placement spanned the medial septum and diagonal band of Broca. Dashed line in Panel C indicates dorsal border of the medial septum. 40-μm coronal sections were stained with Neutral Red. Arrows indicate probe track. AC = anterior commissure; CC = corpus callosum; LV = lateral ventricle; M = midline.

Figure 3

Chromatograms of AHN 2-005-induced increases in DA and NE levels. Shown are chromatograms from a pre-treatment (PRE) and post-treatment (POST) sample for PFC DA (Top Panel), PFC NE (Middle Panel) and nucleus accumbens DA (NAc DA, Bottom Panel). Numbers adjacent to peaks indicate retention time and quantity (pg), respectively. 10 mg/kg AHN 2-005 increased the height of the NE and DA peaks (scale is the same in PRE vs. POST).

Figure 4

Effects of a cognition-enhancing dose of AHN 2-005 on extracellular levels of NE and DA within the PFC (Panel A), nucleus accumbens (NAc, DA only, Panel B), and medial septal area (MSA, Panel C). Shown are the mean (± SEM) DA and NE levels (per 20 μ1 sample) expressed as a percentage of baseline in 30-minute samples collected prior to (negative numbers) and following (positive numbers) injection of vehicle or 10 mg/kg AHN 2-005. AHN 2-005 elicited significant but restrained increases in extracellular DA and NE in the PFC and MSA (∼75%-100% above baseline) and larger increases in extracellular DA levels in the nucleus accumbens (∼200% above baseline). ⁺P < 0.05, ⁺⁺P < 0.01 compared to sample immediately preceding drug administration (Sample -1); *P < 0.05, **P < 0.01 compared to vehicle-treated animals.