title: Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.
abstract: The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27705, USA. marx0001@mc.duke.edu
authors.forename: Christine E
authors.initials: CE
authors.lastname: Marx
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: VanDoren
authors.forename: Gary E
authors.initials: GE
authors.lastname: Duncan
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; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011280:Pregnanolone / Q000378:metabolism*; D011374:Progesterone / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D014150:Antipsychotic Agents; D012739:Gonadal Steroid Hormones; D001569:Benzodiazepines; D010890:Pirenzepine; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine; D003345:Corticosterone