Short term, low dose fluoxetine blocks estrous cycle-linked changes in responsiveness to diazepam in female rats

Anxiety behavior in female Wistar rats was assessed at different stages of the estrous cycle using the elevated plus maze (EPM). No differences were observed at any cycle stage. Pretreatment with diazepam (1 mg kg(-1) intraperitoneal (i.p.)) 30 min before testing produced an anxiolytic effect (significant increase in percentage of time in the open arms compared to control group in the same cycle phase) in animals in proestrus, estrus, and early diestrus but had no effect in rats in late diestrus. Locomotor activity (total arm entries) was unchanged at any cycle phase. When rats in the late diestrus phase were pretreated with the selective serotonin reuptake inhibitor fluoxetine (1.75 mg kg(-1) i.p. on the afternoon of early diestrus and again in the morning of late diestrus) diazepam produced an anxiolytic effect (increase percentage time in the open arms). This dose is sufficient to raise brain allopregnanolone concentration without affecting 5-hydroxytryptamine (5-HT) systems. We propose that insensitivity to diazepam in late diestrus is due to increased expression of benzodiazepine insensitive α4 subunit-containing gamma-aminobutyric acid A (GABAA) receptors triggered by a sharp decrease in brain allopregnanolone concentration. Pretreatment with fluoxetine to raise brain allopregnanolone concentration during late diestrus prevents the withdrawal effect.