Antisense oligodeoxynucleotides for estrogen receptor-β and α attenuate estradiol's modulation of affective and sexual behavior, respectively

Estradiol (E2) modulates affective and socio-sexual behavior of female rodents. E2's functional effects may involve actions through α and β isoforms of estrogen receptor (ERs). The importance of E 2's actions at these isoforms for anxiety (open field, elevated plus maze), depression (forced swim test), and sexual behavior (lordosis) was investigated using an antisense oligonucleotide (AS-ODN) strategy. If ERβ is required for anti-anxiety and antidepressant-like effects, and ERα is required for sexual receptivity, of E2, then intracerebroventricular administration of AS-ODNs against these ERs should attenuate these effects and reduce immunoreactivity of ERs in brain regions that mediate these behaviors, such as the hippocampus and ventral medial hypothalamus (VMH). Ovariectomized rats were primed with 17β-E2 (10 μg) 48 h before testing (hour 0). At hours 0, 24, and 47.5, rats were infused with saline vehicle, scrambled control AS-ODNs, or AS-ODNs targeted against ERα and/or ERβ, and were tested at hour 48. Rats infused with ERβ AS-ODNs, alone, or with ERα AS-ODNs had significantly decreased open field central entries, decreased plus maze open arm time and entries, increased time spent immobile, and decreased time spent swimming in the forced swim test, and decreased ERβ immunoreactivity in the brain than did rats administered ERα AS-ODNs, vehicle, or scrambled AS-ODNs. Rats that were administered ERα AS-ODNs, alone, or with ERβ AS-ODNs had significantly decreased lordosis and decreased ERα immunoreactivity in the brain compared to rats administered ERβ AS-ODNs, vehicle, or scrambled AS-ODNs. Thus, ERβ and ERα may be required for E2's modulation of affective and sexual behavior, respectively. © 2008 Nature Publishing Group All rights reserved.Peer Reviewe