A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior

Abstract

Estrogen (E2) has many effects in the central nervous system, including effects on anxiety and depression behavior. This review will address effects of E2 on behaviors related to anxiety and depression in women and animal models and include recent findings from our laboratory related to this topic. E2's antianxiety and antidepressant-like effects may depend upon many factors, including the regimen of E2 utilized and interactions with the hypothalamic-pituitary-adrenal axis. Brain targets for E2's effects on anxiety and depression include the hippocampus and amygdala. Administration of E2, compared to vehicle, subcutaneously or to the hippocampus or amygdala of ovariectomized rats decreases anxiety and depressive behavior. Intracellular estrogen receptors (ERs) may be important for E2's anxiolytic and antidepressant-like effects. Administration of an ER antagonist to the hippocampus, but not amygdala, increases anxiety and depression behavior of naturally receptive female rats. Studies utilizing ER knockout mice or selective ER modulators suggest that ER-mediated effects of E2 on anxiety and depressive behavior may require ERbeta. In addition, the behavioral effects of E2 may involve membrane actions and/or changes in cell cycle processes involved in energy expenditure. Elucidating the mechanisms by which E2 affects anxiety and depression is important in order to enhance its therapeutic potential. It is particularly important to investigate the putative receptor mechanisms and brain targets for E2 to determine whether mood-enhancing effects of E2 can occur without deleterious proliferative effects in reproductive tissues.

Figure 1

Administration of E₂ decreases anxiety and depression behavior. E₂ or vehicle alone was administered either subcutaneously or intrahippocampally. E₂ increased central open field entries (top panel) and time spent in the open arms of the plus maze (center panel). E₂ decreased the duration of immobility in the forced swim test (bottom panel). Error bars indicate one SEM. *p<0.05, E₂ vs vehicle.

Figure 2

Administration of an ER antagonist (ICI 182,780) to the hippocampus, but not the amygdala, increases anxiety and depression behavior. The antagonist applied to hippocampus decreased central open field entries (top panel) and time spent on the open arms of the plus maze (middle panel) but increased time spent immobile in the forced swim test (bottom panel). Error bars indicate one SEM. *p<0.05, antagonist vs vehicle.

Figure 3

Administration of E₂ to wild-type, but not heterozygous (+ / −ERβKO) or homozygous (−/−ERβKO) ERβ knockout mice, increases central entries in the open-field (top) and open arm duration (bottom) compared to vehicle administration. *p7lt;0.05, E₂ vs vehicle.