Here, we tested whether acute treatment with brexpiprazole, a serotonin-dopamine activity modulator with partial agonist activity at D<sub>2/3</sub> and 5-HT<sub>1A</sub> receptors, would attenuate the BD mania-relevant behaviors of the dopamine transporter (DAT) knockdown mouse model of mania.
Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression.
Selective genetic or pharmacologic inhibition of the dopamine transporter matched the mania phenotype better than the effects of amphetamine, which has been the criterion standard for animal models of mania.
The dopamine transporter gene (SLC6A3) is a compelling candidate for pediatric bipolar disorder because (a) it has been associated with ADHD, (b) bipolar comorbidity with ADHD has been hypothesized to be an etiologically distinct familial subtype (c) blockade of the dopamine transporter with psychostimulants can induce mania in susceptible individuals and (d) previous studies have implicated the gene in bipolar disorder in adults.