GBR 12909 administration as an animal model of bipolar mania: time course of behavioral, brain oxidative alterations and effect of mood stabilizing drugs

Abstract

Polymorphisms in the human dopamine transporter (DAT) are associated with bipolar endophenotype. Based on this, the acute inhibition of DAT using GBR12909 causes behavioral alterations that are prevented by valproate (VAL), being related to a mania-like model. Herein our first aim was to analyze behavioral and brain oxidative alterations during a 24 h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2 h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24 h post-administration. Hyperlocomotion, levels of reduced glutathione (GSH) and lipid peroxidation in brain areas were assessed at all these time-points. GBR12909 caused hyperlocomotion at 2 and 24 h. Rearing behavior increased only at 2 h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12 h. Increased lipid peroxidation was detected at the time-points of 2 and 12 h in all brain areas studied. At the time-point of 2 h post-GBR12909 Li prevented the hyperlocomotion and rearing alterations, while VAL prevented only rearing alterations. Both drugs prevented pro-oxidative changes. In conclusion, we observed that the main behavioral and oxidative alterations took place at the time-period of 2 h post-GBR12909, what points to this time-period as the best for the assessment of alterations in this model. Furthermore, the present study expands the predictive validity of the model by the determination of the preventive effects of Li.

The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania

“…Specifically, mice treated with the selective DAT inhibitor GBR12909 (GBR) or with a genetic knockdown (KD) of DAT exhibited hyperactivity, increased specific exploration, and straighter movement through space consistent with BD mania patients in the cross-species behavioral pattern monitor (BPM) (Perry et al, 2009; Young et al, 2010a, b). Chronic administration of the standard BD treatments valproate and lithium, at clinically therapeutic levels, to DAT KD and GBR-treated mice attenuated the hyperactivity of mice, without affecting their specific exploration, or straight-line movement (Queiroz et al, 2015; van Enkhuizen et al, 2013a; van Enkhuizen et al, 2015a, b). These effects were similar to treatment-induced reduction of activity of mania patients (Minassian et al, 2011).…”

Animal models for bipolar disorder: from bedside to the cage

“…Several different psychostimulants were administrated to induce mania-like behavior. Apart from cocaine, the used substances were amphetamine (Frey et al 2006), lisdexamfetamine dimesylate (Macêdo et al 2013), and fenproporex in rats (Rezin et al 2014), and alpha-lipoid acid (Macêdo et al 2012) and GBR12909 in mice (Queiroz et al 2015). All these substances resulted in mania-like behavior, which could be attenuated by mood stabilizers like valproate or lithium (Sharma et al 2016).…”

Adolescent GBR12909 exposure induces oxidative stress, disrupts parvalbumin-positive interneurons, and leads to hyperactivity and impulsivity in adult mice

“…Thus, the effect of GBR12909 on 8-oxo-dG levels appears to be specific to PV+ interneurons in the present study, although future studies should assess other subtypes of GABA interneurons more specifically. Previous studies have shown that GBR12909 decreased GSH levels and lipid peroxidation in PFC, striatum, and hippocampus acutely and up to 24h in PFC and hippocampus (Querioz et al 2015), indicating that GBR12909 is capable of creating redox imbalance in brain. The current study also showed that PV immunoreactivity in PFC decreased in adult mice exposed to GBR12909 during adolescence (Fig 3b).…”

“…2007) and induces oxidative stress (e.g. reduced GSH and increased lipid peroxidation) in frontal cortex (Queiroz et al 2015). Additionally, cocaine produces greater c-fos activation in cortical regions compared to subcortical regions in adolescent rats (Cao et al.…”

“…GBR12909 is a high affinity, long-acting DA transporter (DAT) inhibitor (Heikkila et al 1984), which induces a hyperdopaminergic state when administered systemically and is known to produce oxidative stress by producing reactive oxygen species (ROS) via the catabolism of DA (Meiser et al 2013; Grima et al 2003). Acute administration of GBR12909 decreased levels of GSH and increased lipid peroxidation in the hippocampus and PFC of mice up to 24h after injection (Queiroz et al 2015). Hence, we exposed adolescent mice to GBR12909.…”