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



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.



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.



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.



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.
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.|Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands.
Morgane
M
Milienne-Petiot
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
Mark A
MA
Geyer
Sunred Pharma Consulting, Solrod Strand, Denmark.|Synaptic Transmission, Neuroscience Drug Discovery, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, DK, Denmark.
Jørn
J
Arnt
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA. jaredyoung@ucsd.edu.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA. jaredyoung@ucsd.edu.
Jared W
JW
Young
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001714:Bipolar Disorder / Q000235:genetics / Q000523:psychology*; D002755:Choice Behavior / Q000187:drug effects*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D055785:Gene Knockdown Techniques; D007175:Impulsive Behavior / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D010641:Phenotype; D015363:Quinolones / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A; D012309:Risk-Taking; D018490:Serotonin Agents / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D015363:Quinolones; D018490:Serotonin Agents; D013876:Thiophenes; D044282:Receptor, Serotonin, 5-HT1A; C000591922:brexpiprazole
Bipolar disorder; Cognition; D2 receptor; Iowa gambling task; Risk-taking