Possible involvement of histone acetylation in the resistance and adaptation to stress in mice

Abstract

Recent reports have implied that aberrant biochemical processes in the brain frequently accompany subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. Furthermore, certain antidepressants or mood stabilizers have been reported to have the ability to modulate epigenetic parameters. We previously reported that pretreatment of mice with 5-HT1A receptor agonists 24 h before testing suppressed the decrease in emotional behaviors induced by exposure to acute restraint stress. Based on this finding, the aim of the present study was to examine the association between the development of emotional resistance to stress stimuli and the modulation of an epigenetic parameter, particularly histone acetylation. We found that acetylated histone H3 was increased in the hippocampus of mice that had developed resistance to emotional stress by pretreatment with the 5-HT_1A receptor agonist flesinoxan (1 mg/kg, i.p.) 24 h before testing. On the other hand, pretreatment with benzodiazepine anxiolytic diazepam (1 mg/kg, i.p.) did not have similar effects. Interestingly, similar to flesinoxan, the histone deacetylase inhibitor trichostatin A (TSA; 1650 μM/4 μL, i.c.v.) also protected against the emotional changes induced by acute restraint stress, as well as histone H3 acetylation. Another aim of the present study was to examine the effect of TSA on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. From the first day of stress exposure, mice were treated with TSA 2 hr before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using an automatic hole-board apparatus. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. The decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA (1650 μM/4 μL, i.c.v.). These findings suggest that HDAC inhibitor may have a beneficial effect on stress adaptation and alleviate the emotional abnormality under conditions of excessive stress.