Inhibitory control and response latency differences between C57BL/6J and DBA/2J mice in a Go/No-Go and 5-choice serial reaction time task and strain-specific responsivity to amphetamine

Abstract

Among the best-replicated and most heritable endophenotypes of attention-deficit/hyperactivity disorder (ADHD) are deficits in attention, inhibitory response control and larger intra-individual variability in response latencies. Here, we explored the presence of these heritable ADHD endophenotypes in two commonly used inbred mouse strains, C57BL/6J and DBA/2J, and investigated whether treatment with the stimulant amphetamine affected these phenotypes. Both in an operant Go/No-Go task and 5-choice serial reaction time (5-CSRT) task, DBA/2J mice showed reduced inhibitory response control compared with C57BL/6J mice. Mean correct response latencies of DBA/2J mice were slower in both tasks. Analysis of the distribution of correct response latencies suggested similar processing speed, but DBA/2J mice displayed larger intra-individual variability. Amphetamine did not affect inhibition in the Go/No-Go task but increased omission errors. In contrast, in the 5-CSRT task, amphetamine did not affect omission errors but impaired inhibitory response control, specifically in C57BL/6J mice. The dopamine uptake inhibitor, GBR 12909, mimicked this effect and decreased accurate choice, specifically in C57BL/6J mice, indicating that dopamine modulates inhibitory response control and attention in the murine 5-CSRT task. Amphetamine did not affect response distributions in either task. Furthermore, we extended previous reports on differences in the brain dopamine system of DBA/2J and C57BL/6J mice, by showing differential gene expression levels of three dopamine receptors (Drd1, Drd4 and Drd5) in the mPFC. In conclusion, genetic differences between DBA/2J and C57BL/6J mice translate into multiple ADHD-related phenotypes, indicating that these strains are valuable resources to understand genetic mechanisms underlying ADHD-relevant phenotypes.