1. ¹Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham VA Medical Center, Durham, North Carolina, USA
2. ²Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599, USA
3. ³Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina 27599, USA
4. ⁴Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA

Correspondence: Dr CE Marx, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham VA Medical Center, Mental Health Service Line (116A), 508 Fulton Street, Room C10023, Durham, NC 27705, USA. Tel: +1 919 286 0411 ext. 5112 (hospital); +1 919 286 0411 ext. 7426 (laboratory); Fax: +1 919 416 5832; E-mail: marx0001@mc.duke.edu

Received 19 December 2001; Revised 14 May 2002; Accepted 20 June 2002.

Abstract

The neuroactive steroid allopregnanolone is a potent -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.