Brexpiprazole reduces hyperactivity, impulsivity, and risk-preference behavior in mice with dopamine transporter knockdown-a model of mania
Milienne-Petiot, Morgane; Geyer, Mark A; Arnt, Jørn; Young, Jared W
(2017) Psychopharmacology, volume 234, issue 6, pp. 1017 - 1028
(Article)
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
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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 D2/3and 5-HT1Areceptors, 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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Keywords: Animals, Behavior, Animal, Bipolar Disorder, Choice Behavior, Disease Models, Animal, Dopamine Agonists, Dopamine Plasma Membrane Transport Proteins, Exploratory Behavior, Female, Gene Knockdown Techniques, Impulsive Behavior, Male, Mice, Mice, Inbred C57BL, Motor Activity, Phenotype, Quinolones, Receptor, Serotonin, 5-HT1A, Risk-Taking, Serotonin Agents, Thiophenes, Journal Article
ISSN: 0033-3158
Publisher: Springer Verlag
(Peer reviewed)