Impulsivity and attentional dysfunction in DAT-AAA knock-in mice.

Abstract

Aberrant dopaminergic signaling is implicated in the core symptoms of attention deficit hyperactivity disorder (ADHD), including dysregulated attention, impulsivity, and hyperactivity. In a mouse model with disrupted scaffolding motif of the dopamine transporter (DAT-AAA), we previously reported extensive loss of DAT expression in striatum, resulting in locomotor hyperactivity, dysfunctional reward-driven motivation, and attenuated behavioral response to amphetamine compared to wildtype (WT) controls. Here, we investigated attention and impulsivity in DAT-AAA mice using the 5-choice serial reaction time task (5-CSRTT). Baseline task acquisition was established using a 2-s stimulus duration (SD) and fixed 5-s intertrial interval (ITI). A variable SD probe (0.2-1.8&#xa0;s with fixed 5-s ITI) was then used to challenge attentional performance and enable Theory of visual attention (TVA)-based modeling. Finally, a variable ITI schedule randomized to 5-, 10-, or 15-s ITI with fixed 2-s SD for 15 consecutive training days probed impulsive action. Training revealed higher rates of premature responding (p&#xa0;<&#xa0;0.05) in DAT-AAA mice, a finding confirmed in the variable ITI challenge (p&#xa0;<&#xa0;0.05). DAT-AAA mice demonstrated inattention (p&#xa0;<&#xa0;0.001) in the variable SD test, and TVA-based modeling revealed a specific deficit in visual processing speed (p&#xa0;<&#xa0;0.01). Finally, increased anxiety-related behavior was seen in the open field test. These preliminary findings suggest that reduced DAT expression in striatal terminals is associated with inattentive and excessive impulsive behaviors, supplementing our previously reported locomotor hyperactivity finding. The DAT-AAA mouse therefore shows face validity in terms of inattention, impulsivity, and hyperactivity, and may be a new model to study the neurobiology of ADHD.