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

Estradiol (E2) modulates affective and socio-sexual behavior of female rodents. E-2's functional effects may involve actions through alpha and beta isoforms of estrogen receptor (ERs). The importance of E2'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 ER beta is required for anti-anxiety and antidepressant-like effects, and ER alpha 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 17 beta-E-2 ( 10 mu g) 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 ER alpha and/ or ER beta, and were tested at hour 48. Rats infused with ER beta AS-ODNs, alone, or with ERa 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 ERb immunoreactivity in the brain than did rats administered ER beta AS-ODNs, vehicle, or scrambled AS-ODNs. Rats that were administered ER beta AS-ODNs, alone, or with ERb AS-ODNs had significantly decreased lordosis and decreased ER alpha immunoreactivity in the brain compared to rats administered ERb AS-ODNs, vehicle, or scrambled AS-ODNs. Thus, ER beta and ER alpha may be required for E-2's modulation of affective and sexual behavior, respectively.