title: [Novel therapeutic approach for the treatment of post-traumatic stress disorder (PTSD): facilitating fear extinction].
abstract: Pharmacological agents enhancing fear extinction may be promising tools for the treatment of PTSD. Histone acetylation is involved in memory formation, and histone deacetylase (HDAC) inhibitors increase histone acetylation and subsequently enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitated fear extinction, using a contextual fear conditioning (FC) paradigm. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR). The levels of acetylated histone and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus 2 h after administration of vorinostat. We investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The levels of acetylated histone and the binding of p-CREB to its binding site at the promoter of the NR2B gene were increased. These findings suggest that vorinostat in conjunction with exposure therapy can be a promising new avenue for the treatment of PTSD.
authors.affiliation: Department of psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan. yosukefujita1009@yahoo.co.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morinobu
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D000077337:Vorinostat; D000123:Acetyltransferases