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

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.

Monoaminergic modulation of decision-making under risk of punishment in a rat model

“…For example, augmentation of dopamine availability in human subjects via administration of its precursor L-DOPA enhances preference for probabilistic over certain rewards with equivalent expected values (Rigoli et al 2016). Administration of selective dopamine receptor agonists and antagonists has a range of effects on risky decision making, depending on both the receptor subtype and behavioral task employed (Di Ciano et al 2015, St Onge and Floresco 2009, Barrus and Winstanley 2016, Rogers 2011, Zalocusky et al 2016, Milienne-Petiot et al 2017, Norbury et al 2013, van Enkhuizen et al 2013) Serotonin and norepinephrine signaling have been less well investigated than dopamine in the context of risky decision making. Systemic manipulation of serotonergic signaling via acute tryptophan depletion (which reduces brain serotonin levels), reuptake inhibitors, or direct agonists/antagonists has been shown to have a variety of effects on performance in risky decision making tasks, depending on the drug, task, and species studied (Adams et al 2017b, Macoveanu et al 2014, Macoveanu et al 2013, Long et al 2009, Zeeb et al 2009) Finally, in the few studies in which it has been assessed, noradrenergic reuptake blockade or direct agonists/antagonists have been shown to shift rats’ preference for certain vs. uncertain rewards (Yang et al 2016, Montes et al 2015)…”

Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter‐deficient mice using the 5‐choice CPT

“…One is that while the majority of people with BD tested were female, the mice tested were only male. While both male and female DAT KD mice exhibit hyperactivity and altered behaviors relative to their WT littermates, the testing of only males here limits the generalizability of our mouse findings of attention to the general population. All of our mouse cognitive testing now includes females to address this potential concern.…”

Blockade of dopamine D1-family receptors attenuates the mania-like hyperactive, risk-preferring, and high motivation behavioral profile of mice with low dopamine transporter levels

“…Fifty-six male DAT KD ( n =25) mice and their WT ( n =31) littermates aged nine months and weighing approximately 25 g were used in this study. These mice were previously tested in the same tasks and had been treated with a serotonin-dopamine modulator (brexpiprazole; Milienne-Petiot et al, 2017) after receiving a three-week washout period. The mice received this previous treatment in a within-subject design, hence all mice were treated with the same doses of this modulator.…”

“…Hence, a treatment that can reduce the risk-preference of patients with BD in the IGT may prove to be a valuable therapeutic in patients. The IGT can also be examined in rats (Rivalan et al, 2009), and mice (Milienne-Petiot et al, 2017; van Enkhuizen et al, 2014) making this a valuable cross-species task. Additionally, patients with BD exhibit increased motivation during periods of mania (Cassidy et al, 1998).…”

“…Reduction of DAT function can be achieved by pharmacological manipulations using the selective DAT inhibitor GBR12909 or by using genetic DAT knockdown (KD) mice compared to their wild-type (WT) littermates. Using these models, a BD mania-like hyperexploratory profile as measured in the BPM was observed (Milienne-Petiot et al, 2017; Perry et al, 2009), together with increased motivation to work for food reward as measured in the PRB test (Cagniard et al, 2006a; Milienne-Petiot et al, 2016), and higher risk-preference in the IGT (Milienne-Petiot et al, 2017; van Enkhuizen et al, 2014). Furthermore, we have demonstrated the pharmacological predictive validity of this model given that chronic administration of the drugs used for the treatment of BD mania, valproate and lithium, attenuate the hyperactivity of KD mice in the BPM without affecting their WT littermates (Milienne-Petiot et al, 2016; Ralph-Williams et al, 2003; van Enkhuizen et al, 2014).…”