¹Dept. of Drug Design and Pharmacology, Dept. of Drug Design and Pharmacology, Copenhagen, Denmark

Background: This talk will explore contemporary neurobiological hypotheses of ADHD with a focus on two converging frameworks: arousal dysregulation and deficient reward processing. Central to the arousal account is the Yerkes–Dodson relationship, which proposes an inverted‑U association between arousal and attentional performance. Individuals with ADHD may show fluctuating catecholamine signaling within frontostriatal and frontoparietal circuits, arising from reduced tonic catecholamine levels combined with exaggerated phasic responses. These fluctuations may contribute to unstable arousal and the characteristic variability in attention and task engagement.
The reward‑processing perspective highlights altered delay discounting and heightened sensitivity to immediate reinforcement. This motivational instability is also hypothesized to arise from reduced tonic dopamine levels combined with exaggerated phasic responses, producing a behavioural bias toward short‑term rewards. Such mechanisms may help explain the increased impulsivity observed in ADHD and the elevated risk of substance misuse and addictive behaviours in affected individuals.

Aims & Objectives: The talk will integrate these frameworks by discussing how unstable arousal and reward signaling jointly shape attentional control, motivational consistency, and impulsive decision‑making. Stimulant medication may stabilize catecholamine levels – enhancing tonic levels and dampening phasic responses – which may shift individuals toward a more optimal region of the arousal–performance curve.

Method: The presentation includes example data from the continuous performance test, a translational cognitive test method employed in both healthy humans and mice. All test subjects were treated with both vehicle/placebo and active treatment at different doses of stimulant ADHD medication, according to a diagram-balanced Latin-Square Design. In addition, individual baseline performance measures were taken outside of the Latin-Square Design. Data were analysed with a repeated measures mixed effect model, with treatment, time, and baseline performance as fixed effects.

Results: In both healthy humans and mice, we found that stimulant medication significantly improved attentional performance at a group level. Further, a significant dose-by-baseline interaction revealed that improvement was baseline-dependent. Specifically, a more pronounced performance-enhancing effect in subjects with low baseline performers compared to high-performers.

Discussion & Conclusions: This demonstrates translational behavioural patterns consistent with the Yerkes–Dodson function and illustrates how arousal modulation shapes performance across species.

A stabilizing effect of stimulant also has implications for the shared reward processing deficit in ADHD and substance use disorder: While stimulants increase mesolimbic dopamine, clinical evidence indicates that appropriately monitored treatment is associated with reduced, not increased, risk of addiction.

Together, these perspectives aim to provide a cohesive neurobiological account of ADHD that links neurobiology and pharmacology with cognitive variability, motivational dynamics, and clinical outcomes.