title: Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder.
abstract: BACKGROUND
  Given that impairment of fear extinction plays a pivotal role in the pathophysiology of posttraumatic stress disorder (PTSD), drugs that facilitate fear extinction may be useful as novel treatments for PTSD. Histone deacetylase (HDAC) inhibitors have recently been shown to enhance fear extinction in animal studies.
  
  
  OBJECTIVE
  Using a single prolonged stress (SPS) paradigm, an animal model of PTSD, we examined whether the HDAC inhibitor vorinostat can facilitate fear extinction in rats, and elucidated the mechanism by which vorinostat enhanced fear extinction, focusing on the N-methyl-D-aspartate (NMDA) receptor signals in the hippocampus.
  
  
  METHODS
  Seven days after SPS, rats received contextual fear conditioning, followed by 2-day extinction training. Vorinostat was intraperitoneally injected immediately after second extinction training session. Contextual fear response was assessed 24 h after vorinostat injection. Hippocampal tissues were dissected 2 h after vorinostat injection. The levels of mRNA and protein tested were measured by RT-PCR or western blotting, respectively.
  
  
  RESULTS
  Systemic administration of vorinostat with extinction training significantly enhanced fear extinction in SPS rats as compared with the controls. Furthermore, vorinostat enhanced the hippocampal levels of NR2B and calcium/calmodulin kinase II (CaMKII) α and β proteins, accompanied by increases in the levels of acetylated histone H3 and H4.
  
  
  CONCLUSIONS
  These findings suggest that vorinostat ameliorated the impaired fear extinction in SPS rats, and this effect was associated with an increase in histone acetylation and thereby enhancement of NR2B and CaMKII in the hippocampus. Our results may provide new insight into the molecular and therapeutic mechanisms of PTSD.
authors.affiliation: Department of Psychiatry and Neurosciences, Applied Life Sciences Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morinobu
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Shiro
authors.initials: S
authors.lastname: Takei
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D000077337:Vorinostat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2