Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents

Abstract

The neuroactive steroid allopregnanolone is a potent g-aminobutyric acid type A (GABAA) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioralmodels. We therefore postulated thatolanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidolwould have minimaleffects. Male ratsreceived intraperitonealolanzapine (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. Cerebralcorticalallopregnanolone and peripheralprogesterone and corticosterone levels were determined.Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebralcorticalallopregnanolone levels, butneither risperidone nor haloperidolhad significant effects. Olanzapine and clozapine also increased serum progesterone andcorticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanoloneinduction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in thisneuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing toantipsychotic effcacy. © 2003 American College of Neuropsychopharmacology.