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The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex

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Abstract

Rationale

Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder. Only two pharmacological agents are approved for PTSD treatment, and they often do not address the full range of symptoms nor are they equally effective in all cases. Animal models of PTSD are critical for understanding the neurobiology involved and for identification of novel therapeutic targets. Using the rodent PTSD model, single prolonged stress (SPS), we have implicated aberrant excitatory neural transmission and glucocorticoid receptor (GR) upregulation in the medial prefrontal cortex (mPFC) and hippocampus (HPC) in fear memory abnormalities associated with PTSD.

Objective

The objective of this study is to examine the potential protective effect of antiepileptic phenytoin (PHE) administration on SPS-induced extinction retention deficits and GR expression.

Methods

Forty-eight SPS-treated male Sprague Dawley rats or controls were administered PHE (40, 20 mg/kg, vehicle) for 7 days following SPS stressors; then, fear conditioning, extinction, and extinction retention were tested.

Results

Fear conditioning and extinction were unaffected by SPS or PHE, but SPS impaired extinction retention, and both doses of PHE rescued this impairment. Similarly, SPS increased GR expression in the mPFC and dorsal HPC, and PHE prevented SPS-induced GR upregulation in the mPFC.

Conclusions

These data demonstrate that PHE administration can prevent the development of extinction retention deficits and upregulation of GR. PHE exerts inhibitory effects on voltage-gated sodium channels and decreases excitatory neural transmission via glutamate antagonism. If glutamate hyperactivity in the days following SPS contributes to SPS-induced deficits, then these data may suggest that the glutamatergic system constitutes a target for secondary prevention.

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Acknowledgments

The research in this report was funded by a Department of Defense grant W81XWH-08-1-0661 awarded to Israel Liberzon. We would like to thank Dayan Knox, Chieh Chen, Nirmala Rajaram, Lan Xiao, Heidi Winklemann, and Emma Andrews for their help in conducting the experiments described in this manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, University of Michigan, 4250 Plymouth Road, Ann Arbor, MI, 48109, USA

    Sophie A. George, Mariana Rodriguez-Santiago, John Riley, Elizabeth Rodriguez & Israel Liberzon

  2. Ann Arbor Veterans Affairs Hospital, 2215 Fuller Road, Ann Arbor, MI, 49105, USA

    Israel Liberzon

Authors
  1. Sophie A. George
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  2. Mariana Rodriguez-Santiago
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  3. John Riley
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  4. Elizabeth Rodriguez
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  5. Israel Liberzon
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Correspondence to Sophie A. George.

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George, S.A., Rodriguez-Santiago, M., Riley, J. et al. The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex. Psychopharmacology 232, 47–56 (2015). https://doi.org/10.1007/s00213-014-3635-x

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  • DOI: https://doi.org/10.1007/s00213-014-3635-x

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