Short-term, low-dose fluoxetine prevents oestrous cycle-linked increase in anxiety-like behaviour in female rats

Background and Aims
We sought a robust behavioural test that evoked increased anxiety-like behaviour during the late diestrus phase of the estrous cycle (similar to the premenstrual period in women) and tested whether this could be prevented by acute low-dose fluoxetine.

Methods
Female Wistar rats in different stages of their cycle were exposed to 4 different tests of anxiety-like behaviour.

Results
No estrous cycle differences were detected in fear potentiated startle or conditioned freezing to an aversive context. In a light switch-off test where rats move from one compartment of a shuttle-box to the other to turn off an aversive light, females displayed enhanced responding in late diestrus. During isolation restraint stress females in late diestrus emitted 3 times more 22 kHz ultrasound vocalizations (USV) than at other cycle stages.
Using the USV test, short-term administration of low dose fluoxetine (1.75mg Kg-1, i.p.) designed to blunt the sharp fall in brain allopregnanolone concentration during late diestrus but without affecting 5-HT systems, prevented the increase in isolation stress-evoked USVs.

Conclusions
The light switch-off and isolation restraint-induced USV tests evoke unconditioned adverse emotional responses that are ethologically relevant and sensitive to estrous cycle stage. The USV test fulfils many criteria required of a model for premenstrual syndrome in women. Using the USV test short term administration of fluoxetine to increase brain allopregnanolone concentration without affecting 5-HT systems, prevented the increased USV responding in late diestrus. Short-term low dose fluoxetine treatment may have potential to alleviate development of adverse premenstrual symptoms in women.