Administration of estrogen receptor beta-specific selective estrogen receptor modulators to the hippocampus decrease anxiety and depressive behavior of ovariectomized rats

Abstract

Estradiol (E 2) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the β isoform of estrogen receptor (ER) are important for E 2's effects for anxiety and/or depressive behavior. Whether ERβ in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERβ in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERβ than ERα to the hippocampus, but not a control region/missed sites (i.e. the ventral tegmental area), should decrease anxiety and depressive behavior, compared to vehicle and that ERα-specific SERMs should not have the same effect. To investigate this, ovariectomized (ovx) rats were surgically-implanted with guide cannulae aimed at the hippocampus (target site) or ventral tegmental area (control site). Rats were administered vehicle, or 17β-E 2 (equal affinity for ERα and ERβ), SERMs with greater affinity for ERα vs. ERβ (17α-E 2 or propyl pyrazole triol), or SERMs with greater affinity for ERβ vs. ERα (coumestrol or diarylpropionitrile) to these sites (2 μg/μl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERβ-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17β-E 2 or ERβ SERMs entered more central squares in an open field, spent more time on the open arms of the plus maze, and spent less time immobile compared to rats administered vehicle. Administration of ERα-specific SERMs produced similar effects as vehicle administration. Thus, E 2's anti-anxiety and anti-depressive effects may involve ERβ in the hippocampus.