Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate.

Exposure to stressful events early in life may have permanent deleterious consequences on nervous system function and increase the susceptibility to psychiatric conditions later in life. Maternal deprivation, commonly used as a source of neonatal stress, impairs memory in adult rats and reduces hippocampal brain-derived neurotrophic factor (BDNF) levels. Inflammatory cytokines, such as interleukins (IL) and tumor necrosis factor-α (TNF-α) have been shown to be increased in the peripheral blood of patients with psychiatric disorders. The aim of the present study was to investigate the effects of maternal separation on the levels of IL-10 and TNF-α, and BDNF in the hippocampus and prefrontal cortex of adult rats. We also evaluated the potential ameliorating properties of topiramate and valproic acid on memory deficits and cytokine and BDNF changes associated with maternal deprivation. The results indicated that, in addition to inducing memory deficits, maternal deprivation increased the levels of IL-10 in the hippocampus, and TNF-α in the hippocampus and in the cortex, and decreased hippocampal levels of BDNF, in adult life. Neither valproic acid nor topiramate were able to ameliorate memory deficits or the reduction in BDNF induced by maternal separation. The highest dose of topiramate was able to reduce IL-10 in the hippocampus and TNF-α in the prefrontal cortex, while valproate only reduced IL-10 levels in the hippocampus. These findings may have implications for a better understanding of the mechanisms associated with alterations observed in adult life induced by early stressful events, and for the proposal of novel therapeutic strategies.

Early life stress exacerbates cognitive dysfunction induced by d-amphetamine: amelioration by valproic acid.

It has been demonstrated that experiences taking place early in life have a profound influence on brain development, interacting with the genetic background and determining differences in the vulnerability to the onset of bipolar disorder when the individual is exposed to a second adverse event later in life. Here, we investigated the effects of exposure to an early adverse life event (maternal deprivation) and to a later adverse life event [D-amphetamine (AMPH)] on cognition in an animal model of mania. We have previously demonstrated that that repeated AMPH exposure produces severe and persistent cognitive impairment, which was more pronounced when the animals were maternal deprived, suggesting that the early adverse life event could be potentiating the effects of the exposure to the second adverse life event later in life. Here, we show that valproic acid ameliorated the cognitive deficits induced by AMPH, but it was not effective when the animals were exposed to both stressors: maternal deprivation and AMPH treatment.