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Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder

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Abstract

Rationale

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.

Objectives

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.

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Funding and grants

This work was supported by a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan, a Health Science Research Grant for Research on Brain Science from the Ministry of Health and Welfare of Japan, and a grant from Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology (JST).

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All authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. 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

    Yasutaka Matsumoto, Shigeru Morinobu, Shigeto Yamamoto, Tomoya Matsumoto, Shiro Takei, Yosuke Fujita & Shigeto Yamawaki

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  1. Yasutaka Matsumoto
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  2. Shigeru Morinobu
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  3. Shigeto Yamamoto
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  4. Tomoya Matsumoto
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  5. Shiro Takei
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  6. Yosuke Fujita
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  7. Shigeto Yamawaki
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Correspondence to Shigeru Morinobu.

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Matsumoto, Y., Morinobu, S., Yamamoto, S. et al. Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder. Psychopharmacology 229, 51–62 (2013). https://doi.org/10.1007/s00213-013-3078-9

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