A Japanese herbal medicine attenuates anxiety-like behavior through GABAA receptor and brain-derived neurotrophic factor expression in a rat model of premenstrual syndrome

Abstract Inochinohaha White (IHW) is a Japanese herbal medicine for treating women with anxiety associated with premenstrual syndrome (PMS). In this study, we examined the effects of IHW on anxiety-like behavior in rats undergoing progesterone withdrawal (PWD), a model for PMS. Female rats were injected daily with progesterone for 21 days. Water and ethanol extracts of IHW (WE-IHW and EE-IHW, respectively) were administered orally 15 days after the initiation of progesterone injections. Anxiety-like behavior in an elevated plus maze was evaluated 48 h after the final injection of progesterone. PWD induced anxiety-like behavior, and EE-IHW (300 mg/kg), but not WE-IHW, significantly attenuated this behavior. Administration of the GABA agonists, diazepam or muscimol, significantly attenuated PWD-induced anxiety-like behavior. To investigate the underlying mechanisms of IHW action, we analyzed GABAA receptor expression in the amygdala of these rats. EE-IHW ameliorated the PWD-induced decrease in GABAA receptor β2-subunit mRNA, although β2-subunit protein was unchanged. Brain-derived neurotrophic factor (BDNF) has been reported to have anxiolytic effects and enhance GABAergic synaptic transmission. We found that EE-IHW increased BDNF levels in a dose-dependent manner. Our results suggest that EE-IHW attenuates PWD-induced anxiety-like behavior by increasing GABAA receptor-mediated signaling via increases in β2-subunit and BDNF in the amygdala.