Chronic valproate attenuates some, but not all, facets of mania-like behaviour in mice

Bipolar disorder (BD) mania is a psychiatric disorder with multifaceted symptoms. Development of targeted treatments for BD mania may benefit from animal models that mimic multiple symptoms, as opposed to hyperactivity alone. Using the reverse-translated multivariate exploratory paradigm, the behavioural pattern monitor (BPM), we reported that patients with BD mania exhibit hyperactivity as well as increased specific exploration and more linear movements through space. This abnormal profile is also observed in mice with reduced function of the dopamine transporter (DAT) through either constitutive genetic [knockdown (KD)] or acute pharmacological (GBR12909) means. Here, we assessed the pharmacological predictive validity of these models by administering the BD-treatment valproic acid (VPA) for 28 d. After 1.5% VPA- or regular-chow treatment for 28 d, C57BL/6J mice received GBR12909 (9 mg/kg) or saline and were tested in the BPM. Similarly, DAT KD and wild type (WT) littermates were treated with VPA-chow and tested in the BPM. GBR12909-treated and DAT KD mice on regular chow were hyperactive, exhibited increased specific exploration and moved in straighter patterns compared to saline-treated and WT mice respectively. Chronic 1.5% VPA-chow treatment resulted in therapeutic concentrations of VPA and ameliorated hyperactivity in both models, while specific exploration and behavioural organization remained unaffected. Hence, the mania-like profile of mice with reduced functional DAT was partially attenuated by chronic VPA treatment, consistent with the incomplete symptomatic effect of VPA treatment in BD patients. Both DAT models may help to identify therapeutics that impact the full spectrum of BD mania.