Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an...

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.