Opposite effects of short-versus long-term administration of fluoxetine onthe concentrations of neuroactive steroids in rat plasma and brain

Rationale: Recent preclinical and clinical studies have shown that selectiv e serotonin re-uptake inhibitors modulate neurosteroid synthesis in an oppo site manner. Objectives: The action of long-term administration of fluoxeti ne was investigated on the peripheral and central concentrations of 3 alpha ,5 alpha -tetrahydroprogesterone (3 alpha ,5 alpha -TH PROG) and 3 alpha , 5 alpha -tetrahydrodeoxycorticosterone (of 3 alpha ,5 alpha -TH DOC). proge sterone, and pregnenolone in rats. We also investigated the effect of chron ic treatment with fluoxetine on the foot-shock stress-induced increase in t he plasma and brain concentrations of these steroids. Methods: Fluoxetine w as administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain. separated and pur ified by means of high-performance liquid chromatography, and quantified by means of radioimmunoassay. Results: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3 alpha ,5 alpha -TH PROG (+96% and +13%, respect ively), 3 alpha ,5 alpha -TH DOC (+129 and +31%, respectively), progesteron e (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectiv ely). In addition. the plasma concentration of corticosterone was also sign ificantly increased (+24%) after acute administration of fluoxetine. In con trast. long-term administration of fluoxetine reduced the basal concentrati ons of these various steroids (ranging from -22 to -43%), measured 48 h aft er the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the co ncentrations of steroids in both the brain and plasma of rats chronically t reated with this drug. Acute foot-shock stress increased the cortical and p lasma concentrations of steroids in rats chronically treated with fluoxetin e to extents similar to those apparent in control rats. Conclusions: A repe titive increase in the brain concentrations of neuroactive steroids may con tribute to the therapeutic action of fluoxetine.