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

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 beta isoform of estrogen receptor (ER) are important for E(2)'s effects for anxiety and/or depressive behavior. Whether ERbeta in the hippocampus is a target for these effects was investigated in the present study. We hypothesized that if actions at ERbeta in the hippocampus are important for the anti-anxiety and anti-depressive effects, then administration of selective ER modulator (SERMs) with greater affinity for ERbeta than ERalpha 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 ERalpha-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 17beta-E(2) (equal affinity for ERalpha and ERbeta), SERMs with greater affinity for ERalpha vs. ERbeta (17alpha-E(2) or propyl pyrazole triol), or SERMs with greater affinity for ERbeta vs. ERalpha (coumestrol or diarylpropionitrile) to these sites (2 microg/microl/side) before testing in anxiety (open field, elevated plus maze) or depression (forced swim) tasks. ERbeta-selective SERMs to the hippocampus, but not the ventral tegmental area, decreased anxiety and depressive behavior. Rats administered 17beta-E(2) or ERbeta 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 ERalpha-specific SERMs produced similar effects as vehicle administration. Thus, E(2)'s anti-anxiety and anti-depressive effects may involve ERbeta in the hippocampus.