Pharmacological characterization of the norepinephrine and dopamine reuptake inhibitor EB-1020: implications for treatment of attention-deficit hyperactivity disorder

We report on the pharmacological, behavioral, and neurochemical characterization of a novel dual norepinephrine (NE)/dopamine (DA) transporter inhibitor EB‐1020 (1R,5S)‐1‐(naphthalen‐2‐yl)‐3‐azabicyclo[3.1.0]hexane HCl). EB‐1020 preferentially inhibited monoamine reuptake in cloned cell lines transfected with human transporters with IC₅₀ values of 6 and 38, respectively, for NE and DA transporters. In microdialysis studies, EB‐1020 markedly increased NE, and DA concentrations levels in rat prefrontal cortex in vivo with peak increases of 375 and 300%, respectively with the greatest effects on NE, and also increased DA extracellular concentrations in the striatum to 400% of baseline concentrations. Behavioral studies demonstrated that EB‐1020 dose‐dependently decreased immobility in the mouse tail suspension test of depression to 13% of control levels, and did not stimulate locomotor activity in adult rats in the optimal dose range. EB‐1020 dose‐dependently inhibited locomotor hyperactivity in juvenile rats lesioned with the neurotoxin 6‐hydroxydopamine (100 μg intracisternally) as neonates; a well‐established animal model for attention‐deficit hyperactivity disorder (ADHD). These data suggest that EB‐1020 mediates its actions by stimulating NE and DA neurotransmission, which are typically impaired in ADHD. Synapse, 2012. © 2012 Wiley Periodicals, Inc.