title: Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions.
abstract: Olanzapine and fluoxetine elevate the GABAergic neuroactive steroid allopregnanolone to physiologically relevant concentrations in rodent cerebral cortex. It is unknown if these agents also alter pregnenolone or deoxycorticosterone. Since olanzapine and fluoxetine in combination have clinical utility and may demonstrate synergistic effects, we investigated neuroactive steroid alterations following olanzapine, fluoxetine or coadministration. Male rats received IP vehicle, olanzapine, fluoxetine or the combination of both agents in higher-dose (0, 10, 20 or 10/20 mg/kg, respectively) and lower-dose (0, 5, 10 or 5/10 mg/kg, respectively) experiments. Pregnenolone and allopregnanolone levels in hippocampus were determined by gas chromatography/mass spectrometry. Peripheral deoxycorticosterone and other steroid levels were determined by radioimmunoassay. Olanzapine, fluoxetine or the combination increased hippocampal pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-dose conditions. No synergistic effects on pregnenolone or allopregnanolone were observed following olanzapine and fluoxetine coadministration compared to either compound alone. Pregnenolone and its sulfate enhance learning and memory in rodent models, and therefore pregnenolone elevations may be relevant to cognitive changes in psychotic and affective disorders. Since pregnenolone decreases have been linked to depression, it is possible that olanzapine- and fluoxetine-induced pregnenolone elevations may contribute to the antidepressant actions of these agents.
authors.affiliation: Duke University Medical Center, Durham NC, New York, NY, USA. marx0001@mc.duke.edu
authors.forename: Christine E
authors.initials: CE
authors.lastname: Marx
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Shampine
authors.forename: Rahul T
authors.initials: RT
authors.lastname: Khisti
authors.forename: William T
authors.initials: WT
authors.lastname: Trost
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bradford
authors.forename: A Chistina
authors.initials: AC
authors.lastname: Grobin
authors.forename: Mark W
authors.initials: MW
authors.lastname: Massing
authors.forename: Roger D
authors.initials: RD
authors.lastname: Madison
authors.forename: Marian I
authors.initials: MI
authors.lastname: Butterfield
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000378:metabolism; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000077152:Olanzapine; D011280:Pregnanolone / Q000378:metabolism*; D011284:Pregnenolone / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003345:Corticosterone; D003900:Desoxycorticosterone; D005473:Fluoxetine; D000077152:Olanzapine; D011280:Pregnanolone; D011284:Pregnenolone; D017367:Selective Serotonin Reuptake Inhibitors; C009413:tetrahydrodeoxycorticosterone