Abstract by Louise Bomholt Klem

Dysfunctional attention and impulsivity are present in the symptomatology of different psychiatric disorders and can negatively impact the quality of life of the afflicted patients. Continuous performance tests (CPTs) have been used in clinical research to quantify deficits in these behaviours for different patient groups, furthering the understanding of the underlying neurobiology and psychology of the disorders. Abnormal dopamine (DA) and/or noradrenaline (NA) signalling is implicated in the pathologies of some of these disorders, including attention deficit/hyperactivity disorder (ADHD). Treatment options include stimulants and non-stimulants, which increase NA/DA levels or facilitate signalling. Atomoxetine (ATX) is a non-stimulant ADHD treatment that robustly improves attention and reduces impulsivity in non-clinical research, but we currently have a limited insight into how the ATX-induced increases in NA/DA engage different receptors down-stream and mediate these behavioural changes. Research has suggested the inverted U-shaped curve of arousal-performance to explain the non-linear relationship between NA/DA levels and attentional performance.

Rodent variants of the CPTs have been used in preclinical research to conduct experiments that are not possible in a clinical setting. The novel rodent continuous performance test (rCPT) was developed to offer improved translatability to the human continuous performance tests by presenting both target (S+) and non-target stimuli (S-) in a fixed location. However, the use of the assay is currently limited by its novelty, calling for further characterisation. Recent research within our group showed non-linear effects following stimulant and non-stimulant treatments in mice, relating to the inverted U-shaped arousal-attention framework.

Both clinical and non-clinical research in related assays modify task features to engage different behaviours. Canonically, shortened stimulus durations (SDs) serve as more targeted attention challenges, while prolonged inter-trial intervals (ITIs) tax impulsivity. These paradigms often involve variable SDs (vSD) or ITIs (vITI) to add an element of temporal unpredictability, while increasing task difficulty. However, vSD and vITI studies have also reported a prominent overlap in the detected effects, calling for further characterisation of the schedule manipulations to ascertain differences between the challenged behaviours.

In our current studies, we aimed to characterise the effects of NA/DA and the receptors involved in the effects of ATX in the novel rCPT. We used the reverse effects of NA/DA receptor antagonists to estimate the behavioural effects of endogenous NA/DA levels. In another study, we used the antagonists on their own and in combination with ATX, to elucidate the involvement of the receptors towards the effects of ATX. We conducted our experiments in joint vSD and vITI studies to evaluate similarities and differences between the schedules. The effects of the antagonists were generally similar in the two schedules, except for the α2 adrenoceptor antagonist, which showed much more pronounced effects in the vSD schedule. Overall, our results showed endogenous NA exerted bidirectional control of the majority of the rCPT parameters, increasing responsiveness and impulsivity, and worsening attentional performance through α1 adrenoceptors, while exerting the opposite effects through α2 and β1/2 adrenoceptors. Endogenous DA mediated increased responsiveness and impulsivity and worsened accuracy through D1/5 Rs and D2/3 Rs, while D1/5 Rs improved discriminability, which was worsened by D2/3 Rs. Our combination studies showed prominent involvement of α2 adrenoceptors, modest involvement of β1/2 adrenoceptors, a limited role of D2/3 Rs, and no clear involvement of α1 and D1/5 Rs receptors in the effects of ATX in the vITI schedules. Some of the combinations showed modest enhancements or no clear effect on ATX in the vSD schedule. The differences between the two schedules indicated the arousal-performance curve for the more demanding vSD schedule was shifted to the left of the vITI curve. Our results do not support the canonical differentiation of schedule sensitivity towards attention or impulsivity, but support the increased difficulty of the vSD schedule. Altogether, our studies further characterised the rCPT as a suitable assay to detect changes in attention and impulsivity.