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Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania

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Abstract

Rationale

Bipolar disorder (BD) is a unique mood disorder defined by periods of depression and mania. The defining diagnosis of BD is the presence of mania/hypomania, with symptoms including hyperactivity and risk-taking. Since current treatments do not ameliorate cognitive deficits such as risky decision-making, and impulsivity that can negatively affect a patient’s quality of life, better treatments are needed.

Objectives

Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D2/3 and 5-HT1A receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania.

Methods

The effects of brexpiprazole on DAT knockdown and wild-type littermate mice were examined in the behavioral pattern monitor (BPM) and Iowa gambling task (IGT) to quantify activity/exploration and impulsivity/risk-taking behavior respectively.

Results

DAT knockdown mice exhibited hyper-exploratory behavior in the BPM and made fewer safe choices in the IGT. Brexpiprazole attenuated the mania-like hyper-exploratory phenotype and increased safe choices in risk-preferring DAT knockdown mice. Brexpiprazole also reduced safe choices in safe-preferring mice irrespective of genotype. Finally, brexpiprazole reduced premature (impulsive-like) responses in both groups of mice.

Conclusions

Consistent with earlier reports, DAT knockdown mice exhibited hyper-exploratory, risk-preferring, and impulsive-like profiles consistent with patients with BD mania in these tasks. These behaviors were attenuated after brexpiprazole treatment. These data therefore indicate that brexpiprazole could be a novel treatment for BD mania and/or risk-taking/impulsivity disorders, since it remediates some relevant behavioral abnormalities in this mouse model.

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Abbreviations

IGT:

Iowa gambling task

DAT:

Dopamine transporter

BD:

Bipolar disorder

WT:

Wild type

KD:

Knockdown

BPM:

Behavioral pattern monitor

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Acknowledgements

We thank Mr. Luis F. Garcia, Dr. Jordy van Enkhuizen, and Ms. Mahalah Buell for their support.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA

    Morgane Milienne-Petiot, Mark A. Geyer & Jared W. Young

  2. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands

    Morgane Milienne-Petiot

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

    Mark A. Geyer & Jared W. Young

  4. Sunred Pharma Consulting, Solrod Strand, Denmark

    Jørn Arnt

  5. Synaptic Transmission, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, DK, Denmark

    Jørn Arnt

Authors
  1. Morgane Milienne-Petiot
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  2. Mark A. Geyer
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  3. Jørn Arnt
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  4. Jared W. Young
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Corresponding author

Correspondence to Jared W. Young.

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All behavioral testing procedures were approved by the UCSD Institutional Animal Care and Use Committee, California, USA. The UCSD animal facility meets all federal and state requirements for animal care and was approved by the American Association for Accreditation of Laboratory Animal Care. This work was supported by grant funding from H. Lundbeck A/S, Valby, Denmark and by the National Institute of Mental Health (R01 MH071916).

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Milienne-Petiot, M., Geyer, M.A., Arnt, J. et al. Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown—a model of mania. Psychopharmacology 234, 1017–1028 (2017). https://doi.org/10.1007/s00213-017-4543-7

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  • DOI: https://doi.org/10.1007/s00213-017-4543-7

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