Justin A McClain1, Kimberly Nixon1. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky.
Abstract
BACKGROUND: 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. METHODS: Adult male Sprague Dawley rats received an acute exposure of EtOH (0 to 5 g/kg) via gavage. Or, rats were made EtOH dependent by administering 25% w/v EtOH every 8 hours for 4 days 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. RESULTS: Acute EtOH exposure dose dependently altered the number of H3S10ph-positive (+) cells in the hippocampus. Specifically, 1 g/kg EtOH increased the number of H3S10ph+ cells in all neuronal layers, while 2.5 and 5 g/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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: Adult male Sprague Dawley rats received an acute exposure of EtOH (0 to 5 g/kg) via gavage. Or, rats were made EtOH dependent by administering 25% w/v EtOH every 8 hours for 4 days 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. RESULTS: Acute EtOH exposure dose dependently altered the number of H3S10ph-positive (+) cells in the hippocampus. Specifically, 1 g/kg EtOH increased the number of H3S10ph+ cells in all neuronal layers, while 2.5 and 5 g/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. CONCLUSIONS: 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.
Authors: Ana Soloaga; Stuart Thomson; Giselle R Wiggin; Navita Rampersaud; Mark H Dyson; Catherine A Hazzalin; Louis C Mahadevan; J Simon C Arthur Journal: EMBO J Date: 2003-06-02 Impact factor: 11.598
Authors: María Pascual; Bruno R Do Couto; Silvia Alfonso-Loeches; Maria A Aguilar; Marta Rodriguez-Arias; Consuelo Guerri Journal: Neuropharmacology Date: 2012-02-11 Impact factor: 5.250