Translational Pharmacology of a Putative Measure of Motor Impulsivity in Larval Zebrafish

Background: Impulsivity is poorly planned, premature or inap- propriate behaviour, and deficits in impulse control are linked to a number of neuropsychiatric disorders. There are a number of theories relating to the neural basis of impulsivity, but the precise molecular mechanisms of im- pulse control are not clearly understood. Motor impulsivity has been ob- served in adult zebrafish, but in order to increase throughput it would be beneficial if early markers could be identified in larvae. One such method was recently shown to have some potential efficacy in zebrafish larvae, re- lating to an ADHD morphant (lphn3.1) showing increases in motor 'peaks' during free swimming behaviour. Objective: The aim of this study was to carry out a pharmacological evaluation of motor 'peaks' as a measure of motor impulsivity in larval zebrafish, as well as evaluate the behav- iour of mutant lines that might be predicted to show variation in motor impulsivity. Method: 6dpf zebrafish larvae were filmed for 90-seconds following incubation in amisul- pride (a DRD2/3 antagonist), nicotine, apomorphine (a non-specific dopamine agonist), atomoxetine (a norepinephrine reuptake inhibitor), and methylphenidate (a combined dopa- mine/norepinephrine agonist). We also filmed 6dpf larvae homozygous and heterozygous for mutations in pink1, disc1, and ache. In all larvae, we analysed distance moved and motor 'peaks', calculated as number of 3-second bins in which the larva traveled > 10mm. Results: Atomoxetine and methylphenidate, which reduce impulsivity in humans and other mammalian models, reduced motor peaks while having no effect on overall distance traveled. Apomorphine increased locomotor peaks in a bimodal manner. disc1 homozygous mutants showed lower peaks than wild-type siblings. Finally, although nicotine increased distance traveled, there were no effects on motor peaks. Conclusion: The results suggest that analysis of motor peaks may be a promising method for the early detection of impulsivity-related phenotypes.