Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine

The effects of acute and chronic administration of fluoxetine on the basal and stress-induced increases in cerebrocortical and plasma concentrations of allopregnanolone (3?,5?-tetrahydroprogesterone; 3?,5?-TH PROG) and tetrahydrodeoxycorticosterone (3?,5?-TH DOC) were compared with those of mirtazapine, an antidepressant that (unlike fluoxetine) is not a selective serotonin reuptake inhibitor. A single injection (20 mg/kg i.p.) of fluoxetine or mirtazapine resulted in significant increases in the cerebrocortical and plasma concentrations of 3?,5?-TH PROG and 3,5?-TH DOC. In contrast, long-term administration (10 mg/kg i.p., once daily for 2 weeks) of fluoxetine, but not that of mirtazapine, induced marked decreases in the cortical and plasma concentrations of these neuroactive steroids. Chronic treatment with fluoxetine, however, did not inhibit the increases in the cortical and plasma concentrations of 3?,5?-TH PROG and 3?,5?-TH DOC induced by acute foot-shock stress. In contrast, chronic treatment with mirtazapine prevented or significantly reduced the stress-induced increases in neurosteroid concentrations in the cerebral cortex and plasma, respectively. These results show that mirtazapine, similar to fluoxetine, initially increases the cortical concentration of neuroactive steroids; however, chronic administration of this drug modulates the plasma and brain availability of these hormones in a manner distinct from that of fluoxetine.