Differential effects of exogenous and endogenous estrogen on anxiety as measured by elevated T-maze in relation to the serotonergic system

The effects of estrogen on anxiety-like behaviors have been widely studied but the mechanisms responsible are still inconclusive. The purpose of the current study was to compare the effects of transient high levels of endogenous estrogen and chronic exogenous estrogen treatment on the anxiety-like behaviors using the elevated T-maze (ETM) test. In addition, serotonin (5-HT) and its metabolite (5-HIAA), serotonin reuptake transporter (SERT) and tryptophan hydroxylase enzyme (TPH) were measured at the end of the study and correlated to the task performances. Female sham-operated rats in proestrous phase (Sham-Pro) and ovariectomized rats treated with or without 17β-estradiol (10 μg/kg, s.c.; Ovx + E2 or Ovx) for 4 weeks were used. In the ETM test, the Ovx + E2 group had reduced inhibitory avoidance responses compared to others, suggesting that exogenous E2 replacement is anxiolytic, while escape latency was prolonged in the Sham-Pro group suggesting endogenous E2 is panicolytic. Further, the serotonin turnover rate (5-HIAA/5-HT ratio) in the hippocampus and nucleus accumbens was highest in the Ovx + E2 group. While the TPH protein in the midbrain of Ovx rats was significantly higher than others, the SERT levels were not significantly different among groups in all measured brain areas. In conclusion, Ovx rats with chronic estrogen administration and Sham-Pro rats with naturally high levels of estrogen, demonstrated anxiolytic behavior by exhibiting different forms of anxiety that related to the changes in the function of serotonergic system.