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 dioestrus phase of the oestrous cycle (similar to the premenstrual period in women) and tested whether this could be prevented by acute low-dose fluoxetine (FLX). Methods: Female Wistar rats in different stages of their cycle were exposed to four different tests of anxiety-like behaviour. Results: No oestrous 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 dioestrus. During isolation restraint stress females in late dioestrus emitted three times more 22kHz ultrasound vocalisations (USV) than at other cycle stages. Using the USV test, short-term administration of low-dose FLX (1.75mgkg(-1), i.p.) designed to blunt the sharp fall in brain allopregnanolone concentration during late dioestrus 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 oestrous 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 FLX to increase brain allopregnanolone concentration without affecting 5-HT systems prevented the increased USV responding in late dioestrus. Short-term low-dose FLX treatment may have potential to alleviate development of adverse premenstrual symptoms in women.