Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid

Combinatory therapy is widely used in psychiatry owing to the possibility that drugs with different mechanisms of action may synergize to improve functions deteriorated in schizophrenia, bipolar disorders, and major depression. While combinatory strategies rely on receptor and synaptic mechanisms, it should also be considered that two drugs may also "interact" on the long-term to determine more robust changes in neuronal plasticity, which represents a downstream target important for functional recovery. The aim of the study is to investigate neuroadaptive changes set in motion by chronic concomitant administration of the novel antipsychotic lurasidone and the mood stabilizer valproate. Animals were chronically treated with lurasidone, valproate, or the combination of the two drugs and killed 24 h after the last injection to evaluate alterations of different measures of neuronal plasticity such as the neurotrophin brain-derived neurotrophic factor (BDNF), the immediate early gene Activity-regulated cytoskeletal associated protein, and the epigenetic regulators HDAC 1, 2, and 5 in dorsal and ventral hippocampus. The results suggest that coadministration of lurasidone and valproate produces, when compared to the single drugs, a larger increase in the expression of BDNF in the ventral hippocampus, through the regulation of specific neurotrophin transcripts. We also found that the histone deacetylases were regulated by the drug combination, suggesting that some of the transcriptional changes may be sustained by epigenetic mechanisms. Our results suggest that the beneficial effects associated with combinatory treatment between a second-generation antipsychotic and a mood stabilizer could result from the ability to modulate neuroplastic molecules, whose expression and function is deteriorated in different psychiatric conditions.