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Amphetamine increases activity but not exploration in humans and mice

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Abstract

Rationale

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.

Objectives

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.

Methods

Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n = 25), 10 mg d-amphetamine (n = 18), or 20 mg 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.

Results

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.

Conclusions

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.

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Acknowledgments

This study was supported by funding from the National Institute of Mental Health (R01 MH071916), as well as by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. The authors do not have a financial relationship with the funding organizations, and had full control of all primary data. The authors thank Dr. Harriet De Wit for her assistance in designing this study, Dr. Martin Paulus for his consultation on data analysis, and Dustin Kreitner, Elise Winbrock, and Karen Kloezeman for their contributions to data collection and analysis.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 200 West Arbor Drive, La Jolla, Mailcode 8620, San Diego, CA, 92103-8620, USA

    Arpi Minassian, Jared W. Young, Zackary A. Cope, Brook L. Henry, Mark A. Geyer & William Perry

  2. Center of Excellence for Stress and Mental Health (CESAMH), Veteran’s Administration, San Diego, CA, USA

    Arpi Minassian

  3. VA San Diego Healthcare System, San Diego, CA, USA

    Jared W. Young & Mark A. Geyer

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  1. Arpi Minassian
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Correspondence to Arpi Minassian.

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The University of California San Diego (UCSD) School of Medicine’s institutional review board approved the study.

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Minassian, A., Young, J.W., Cope, Z.A. et al. Amphetamine increases activity but not exploration in humans and mice. Psychopharmacology 233, 225–233 (2016). https://doi.org/10.1007/s00213-015-4098-4

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  • DOI: https://doi.org/10.1007/s00213-015-4098-4

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