title: Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy?
abstract: Clozapine demonstrates superior efficacy in patients with schizophrenia, but the precise mechanisms contributing to this clinical advantage are not clear. Clozapine and olanzapine increase the GABAergic neuroactive steroid (NS) allopregnanolone, and it has been hypothesized that NS induction may contribute to the therapeutic actions of these agents. Pregnenolone administration improves learning and memory in rodent models, and decreases in this NS have been associated with depressive symptoms in humans. These pregnenolone characteristics may be relevant to the actions of antipsychotics. We therefore investigated potential pregnenolone alterations in rat hippocampus and cerebral cortex following clozapine, olanzapine, and other second generation agents as a candidate NS mechanism contributing to antipsychotic efficacy. In the first set of experiments, intact, adrenalectomized, and sham-operated male rats received vehicle or clozapine (20 mg/kg) IP. In the second set, male rats received vehicle, olanzapine (5 mg/kg), quetiapine (20 mg/kg), ziprasidone (10 mg/kg) or aripiprazole (5 mg/kg) IP. Pregnenolone levels were determined by gas chromatography/mass spectrometry. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum; hippocampal levels were strongly correlated with serum levels (r=0.987). Olanzapine also elevates pregnenolone levels, but to a lesser degree than clozapine. Pregnenolone induction may contribute to the clinical actions of clozapine and olanzapine.
authors.affiliation: Duke University Medical Center, Durham NC, 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: Gary E
authors.initials: GE
authors.lastname: Duncan
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: VanDoren
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: Daniel W
authors.initials: DW
authors.lastname: Bradford
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: D000315:Adrenalectomy; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D000077152:Olanzapine; D011284:Pregnenolone / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D011284:Pregnenolone; D003024:Clozapine; D000077152:Olanzapine