Prenatal stress induces vulnerability to stress together with the abnormality of central serotonin neurons in mice -Possibility of treatment by Yokukansan-

[Speaker] Kazuya Miyagawa:1
[Co-author] Atsumi Saito:1, Hiroko Miyagishi:1, Kazuhiro Saito:1, Kazuhiro Kurokawa:1, Minoru Tsuji:1, Hiroshi Takeda:1
1:Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, Japan

The ability to adapt to stress is an important defensive function of a living body, and disturbance of this stress adaptability may be related, at least in part, to the pathophysiology of stress-related psychiatric disorders. The aim of the present study was to clarify the relationship between exposure to prenatal stress and the ability to adapt to stress in mice. Naive and prenatally stressed mice were exposed to repeated restraint stress for 7 days. After the final exposure to restraint stress, the emotionality of mice was evaluated in terms of exploratory activity using an automatic hole-board apparatus. Acute emotional stress response, i.e. a decrease in head-dipping behavior, disappeared in naive mice that had been exposed to repeated restraint stress for 7 days, which confirmed the development of stress adaptation. In contrast, prenatally stressed mice did not develop this stress adaptation. Biochemical studies showed that the rate-limiting enzyme in 5-HT synthesis, tryptophan hydroxylase, was increased in raphe obtained from stress-adapted mice. In contrast, a decrease in tryptophan hydroxylase was observed in stress-maladaptive mice. In addition, the transcription factor Lmx1b, which is essential for differentiation and the maintenance of normal functions in central 5-HT neurons, was decreased in the embryonic hindbrain and adult raphe of prenatally stressed mice. These findings suggest that exposure to excessive prenatal stress may induce a vulnerability to stress and disrupt the development of 5-HT neurons. Another aim of the present study was to examine the effect of Yokukansan (YKS), a traditional Japanese herbal medicine, on the emotional abnormality induced by prenatal stress in mice. We examined the effect of treatment with YKS (1 g/kg, p.o., for 28 days at 3-6 weeks of age) on the anxiety-like behavior induced by prenatal restraint stress. The significant decrease in the percentage of time spent in open arms induced by prenatal stress was not seen under treatment with YKS. These findings indicate that the administration of YKS for 28 days was effective for improving the emotional disruption caused by exposure to excessive prenatal stress in mice.
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