Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs.

Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i.p.) or melatonin (15 mg/kg, per os). Oxidative stress and inflammatory alterations, i.e. myeloperoxidase activity (MPO), reduced glutathione (GSH), lipid peroxidation (LPO) and interleukin (IL)-4 and IL-6 were measured in the prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative (social interaction deficits) schizophrenia-like symptoms. These symptoms were accompanied by increased MPO activity, decreased GSH and increased LPO in all brain areas and increments in hippocampal IL-4 and IL-6. MDT and melatonin reversed all ketamine-induced behavioral alterations. Risperidone did not reverse working memory deficits. MDT and melatonin reversed alterations in MPO activity and GSH levels. LP was reversed only by melatonin and risperidone. Risperidone could not reverse MPO alterations in the PFC and striatum. All drugs reversed the alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had lower levels of IL-6. Our findings provide further preclinical evidence that immune-inflammatory and oxidative pathways are involved in schizophrenia and that targeting these pathways is a valid treatment option in schizophrenia.

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

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.