Anxiety-like behavior and GABAergic system in ovariectomized rats exposed to chronic mild stress

Stress or low level of estrogen could promote anxiety and depression; thus, it is of interest to investigate the combined effect of mild stress and the lack of estrogen on mental disorders by utilizing an animal model. This study was conducted to assess anxiety- and depressive- like behaviors in ovariectomized (Ovx) rats exposed to chronic mild stress (CMS) and determine the alteration in gamma-aminobutyric acid (GABA)-related transmission. Ovx rats were randomly assigned into four groups: (1) estrogen replacement (E2-NoCMS), (2) estrogen replacement and exposure to CMS (E2-CMS), (3) vehicle (VEH-NoCMS), and (4) vehicle and exposure to CMS (VEH-CMS). Following 4-week CMS, VEH groups (VEH-NoCMS and VEH-CMS) showed a similar level of anxiety-like behavior in elevated T-maze, whereas E2-CMS, VEH-NoCMS and VEH-CMS showed anxiety-like behavior in open field. The depressive-like behavior in the force swimming test tended to be affected by estrogen deprivation than CMS. The alteration of the GABAergic system as determined from the GABA level and mRNA expression of GABA-related transmission (i.e., glutamic acid decarboxylase, GABA transporter and GABA_A subunits) showed that the GABA level in the amygdala and frontal cortex was affected by CMS. For mRNA expression, the mRNA profile in the amygdala and hippocampus of VEH-NoCMS and E2-CMS was the same but different from those of VEH-NoCMS and E2-CMS. In addition, compared with E2-NoCMS, the mRNA profile in the frontal cortex was similar in VEH-NoCMS, E2-CMS, and VEH-CMS. These findings indicated that the underlying mechanism of the GABAergic system was differently modified, although VEH-NoCMS and VEH-CMS showed anxiety-like behavior. The findings of this study may provide a comprehensive understanding of the modulation of the GABAergic system during estrogen deprivation under CMS, as observed in menopausal women who were daily exposed to stress.