Opposite effects of short- versus long-term administration of fluoxetine on the concentrations of neuroactive steroids in rat plasma and brain.
BACKGROUND
Recent preclinical and clinical studies have shown that selective serotonin re-uptake inhibitors modulate neurosteroid synthesis in an opposite manner.


OBJECTIVE
The action of long-term administration of fluoxetine was investigated on the peripheral and central concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-TH PROG) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (of 3alpha,5alpha-TH DOC), progesterone, and pregnenolone in rats. We also investigated the effect of chronic treatment with fluoxetine on the foot-shock stress-induced increase in the plasma and brain concentrations of these steroids.


METHODS
Fluoxetine was administered acutely (20 mg/kg) or chronically (10 mg/kg, once daily for 15 days). Steroids were extracted from plasma and brain, separated and purified 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 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after 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 concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats.


CONCLUSIONS
A repetitive increase in the brain concentrations of neuroactive steroids may contribute to the therapeutic action of fluoxetine.
Serra
M
M
Department of Experimental Biology, University of Cagliari, 09100 Cagliari, Italy. mserra@unica.it
Pisu
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Muggironi
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Parodo
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Papi
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Sari
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Dazzi
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Spiga
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Purdy
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Biggio
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D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004334:Drug Administration Schedule; D005473:Fluoxetine / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D011284:Pregnenolone / Q000097:blood / Q000378:metabolism; D011374:Progesterone / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013256:Steroids / Q000097:blood / Q000378:metabolism*; D013312:Stress, Physiological / Q000097:blood / Q000378:metabolism
D003345:Corticosterone; D005473:Fluoxetine; D011284:Pregnenolone; D011374:Progesterone; D017367:Selective Serotonin Reuptake Inhibitors; D013256:Steroids