Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c-Fos Protein Expression in Male Rats.

Abstract

Changes in gene expression associated with alcohol-induced neuroadaptations are controlled in part by post translational histone modifications. Serine 10 phosphorylation of histone H3 (H3S10ph) has been implicated in drug-induced changes in gene expression; however, ethanol (EtOH)'s effects on H3S10ph have yet to be examined in brain. Therefore, hippocampal H3S10ph was examined after acute EtOH exposure and EtOH dependence. Adult male Sprague Dawley rats received an acute exposure of EtOH (0 to 5g/kg) via gavage. Or, rats were made EtOH dependent by administering 25% w/v EtOH every 8hours for 4days following a modified Majchrowicz protocol. In both cases, rats were perfused transcardially and paraformaldehyde-fixed brains were collected and processed for immunohistochemistry to detect H3S10ph or c-fos. Acute EtOH exposure dose dependently altered the number of H3S10ph-positive (+) cells in the hippocampus. Specifically, 1g/kg EtOH increased the number of H3S10ph+ cells in all neuronal layers, while 2.5 and 5g/kg EtOH reduced the number of H3S10ph+ cells, an effect that was confined to the granule cell layer. In EtOH-dependent rats, the number of H3S10ph+ cells in the granule cell layer was reduced by 66% during intoxication; however, H3S10ph+ cells were increased in all neuronal layers during peak withdrawal. Subsequent examination of c-fos, a gene known to be regulated by H3S10ph, revealed that EtOH and withdrawal-associated changes in c-fos closely paralleled changes in H3S10ph. These results suggest that H3S10ph regulates EtOH-mediated changes in c-fos expression, effects that likely have important implications for EtOH-induced changes in hippocampal neuronal plasticity.