Sodium butyrate enhances fear extinction and rescues hippocampal acetylcholinesterase activity in a rat model of posttraumatic stress disorder.

It is believed that impaired extinction of fear memories is an underlying cause for the development of posttraumatic stress disorder (PTSD). Histone deacetylases (HDAC) are enzymes that modulate extinction by changing the chromatin structure and altering protein synthesis in the brain. Studies show that stress modifies both HDAC activity and cerebral cholinergic neurotransmission. The present work aims to evaluate the effect of sodium butyrate (NaBu), an HDAC inhibitor, on behavioral markers of extinction and biochemical changes in HDAC and acetylcholinesterase activity in the hippocampus. NaBu was administered for 7 days in a group of rats that were exposed to single prolonged stress (SPS), as a model for PTSD. Contextual fear conditioning was performed on the 8th day, and fear extinction was measured in the next 4 consecutive days. Other behavioral tests to measure anxiety, locomotor activity and working memory were performed for further interpretation of the results. Hippocampal acetylcholinesterase and HDAC activity were also measured through biochemical tests. Behavioral results showed that treatment with NaBu can reverse the SPS-induced extinction deficits. Biochemical data indicated that while SPS induced overactivity in hippocampal HDAC, it decreased acetylcholinesterase activity in the region. Both effects were reversed after NaBu treatment. It seems that at least part of extinction deficiency in SPS exposed rats is related to hypoacetylation of acetylcholinesterase in the hippocampus. Preemptive therapy with an HDAC inhibitor reverses this process and is worth further evaluation as a possible therapeutic approach in PTSD.