Stress is thought to be a risk factor for psychiatric disorders, such as major depression. Previously, we reported that mice exposed to repeat excessive restraint stress show emotional abnormality. Moreover, this emotional abnormality was alleviated by chronic treatment with flesinoxan, a serotonin (5-HT)_1A receptor agonist. The present study was designed to investigate the levels of expression of 5-HT_1A receptor protein and mRNA in the midbrain and hippocampus of stress-maladaptive mice. Male ICR mice were chronically exposed to maladaptable stress, i.e. repeated restraint stress for 240 min/day for 14 days. After the final exposure to stress, brains of mice were rapidly removed and the midbrain and hippocampus were dissected. The expression levels of 5-HT_1A receptor protein and mRNA were increased in the midbrain, but not the hippocampus, of stressed mice. 5-HT_1A receptor expression is regulated by several transcription inhibitors such as Nuclear deformed epidermal regulatory factor (NUDR) and Five prime repressor under dual repressor binding protein (Freud-1). Real time PCR analysis revealed that the expression level of Freud-1 was decreased in the midbrain of stressed mice, although no significant change in the level of expression of NUDR was observed. These results suggest that increased expression of 5-HT_1A receptor due to decrease in expression of Freud-1 in the midbrain may play a pivotal role in the emotional abnormality of stress-maladaptive mice.