Estradiol and orexin-2 saporin actions on multiple forms of behavioral arousal in female mice

Estrogens modulate almost all aspects of female behavioral arousal; however, apart from that of sexual behavior, the neurobiology of female arousal remains unclear. Because orexins-hypocretins are neurotransmitters known to be important for behavioral arousal, the authors hypothesized that orexins may be a target for estrogen. Gonadectomized female mice received an intracerebral injection of either phosphate-buffered saline, the neurotoxin saporin (SAP), or the orexin-2-saporin conjugate (OXSAP) in the lateral hypothalamus. SAP- and OXSAP-treated mice were also divided into groups receiving either estradiol capsules or oil capsules. Mice were tested in 3 behavioral tests measuring different modes of arousal: sensory responsiveness, running wheel activity, and fearfulness. OXSAP mice showed decreases in sensory responsiveness and fearfulness concomitant with a reduction in orexin cell number. Estradiol affected all behaviors tested but decreased fearfulness only when combined with OXSAP treatment. These data indicate that estrogens modulate orexins' effects on fearfulness.