Amphetamine increases activity but not exploration in humans and mice.

Abstract

Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as bipolar disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n = 25), 10mg d-amphetamine (n = 18), or 20mg amphetamine (n = 23). Eighty mice were administered one of four doses of d-amphetamine or vehicle. Humans and mice were tested in the behavioral pattern monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases.