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 24h period post-GBR12909 to better characterize this model. Our second aim was to determine the preventive effects of lithium (Li) or VAL 2h post-GBR12909. For this, adult male mice received GBR12909 or saline being evaluated at 2, 4, 8, 12 or 24h 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 24h. Rearing behavior increased only at 2h. GSH levels decreased in the hippocampus and striatum at the time points of 2, 4, 8 and 12h. Increased lipid peroxidation was detected at the time-points of 2 and 12h in all brain areas studied. At the time-point of 2h 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 2h 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.