ORIGINAL INVESTIGATION The effect of chronic phenytoin administration on single prolonged stress induced extinction retention deficits and glucocorticoid upregulation in the rat medial prefrontal cortex Sophie A. George & Mariana Rodriguez-Santiago & John Riley & Elizabeth Rodriguez & Israel Liberzon Received: 22 November 2013 /Accepted: 7 May 2014 /Published online: 31 May 2014 # Springer-Verlag Berlin Heidelberg 2014 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 excitato- ry neural transmission and glucocorticoid receptor (GR) up- regulation in the medial prefrontal cortex (mPFC) and hippo- campus (HPC) in fear memory abnormalities associated with PTSD. Objective The objective of this study is to examine the poten- tial protective effect of antiepileptic phenytoin (PHE) admin- istration 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, ex- tinction, 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 in- creased 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 neu- ral transmission via glutamate antagonism. If glutamate hy- peractivity in the days following SPS contributes to SPS- induced deficits, then these data may suggest that the gluta- matergic system constitutes a target for secondary prevention. Keywords Post-traumatic stress disorder . Anticonvulsant . Conditioned fear . Glutamate . Hypothalamic-pituitary- adrenal axis . Secondary prevention . Treatment Introduction Post-traumatic stress disorder (PTSD) is a chronic, debilitating disorder that can emerge following exposure to a traumatic event. It is the 4th most common psychiatric disorder, with lifetime prevalence in the USA at 6.8 % (Kessler et al. 2005). PTSD is characterized by a wide range of symptoms including hyperarousal, intrusive memories, and abnormalities in fear responses (APA 1994) and is associated with considerable morbidity. Only two pharmacological agents (both selective serotonin reuptake inhibitors) are FDA approved for the treatment of PTSD, and these limited options do not address the full range of symptoms nor are they equally effective in all cases (Nutt 2000). The cost of PTSD, in terms of lost productivity and lost lives, is hard to quantify, but the high prevalence, chronic nature, and resistance to treatment suggest the need for additional pharmacotherapies to improve patient outcomes. Valid animal models are critical for understanding the neurobiological processes underlying psychopathology, S. A. George (*) : M. Rodriguez-Santiago : J. Riley : E. Rodriguez : I. Liberzon Department of Psychiatry, University of Michigan, 4250 Plymouth Road, Ann Arbor, MI 48109, USA e-mail: alicegeo@med.umich.edu I. Liberzon Ann Arbor Veterans Affairs Hospital, 2215 Fuller Road, Ann Arbor, MI 49105, USA Psychopharmacology (2015) 232:47–56 DOI 10.1007/s00213-014-3635-x