Clozapine-induced Fos-protein expression in rat forebrain regions: differential effects of adrenalectomy and corticosterone supplement

Unlike classical antipsychotic drugs, clozapine activates the hypothalamo-p ituitary-adrenal axis and induces a specific regional pattern of Fos-protei n expression in the rat forebrain. Whether corticosterone plays a role in t he clozapine-induced Fos response is the subject of this study. Some rats w ere adrenalectomized and in a number, including intact animals, a corticost erone pellet (100 mg s.c.) was implanted; after 1 week, a single dose of cl ozapine (20 mg kg(-1) i.p.) was administered. The clozapine-induced Fos res ponse was not affected by adrenalectomy, apart from the nucleus accumbens s hell, the subfornical organ and the supraoptic nucleus; then was an increas ed response in the nucleus accumbens shell, while other regions showed less Fos immunoreactivity. Implantation of the corticosterone pellet in both sh am-operated and adrenalectomized animals, reduced the clozapine-induced Fos responses strongly in the hypothalamic paraventricular nucleus, the subfor nical organ and possibly in the prefrontal cortex; in the supraoptic nucleu s, this effect was seen only in intact animals. The effect of clozapine on plasma corticosterone levels was also diminished by supplemental corticoste rone treatment. These results imply that the effects of clozapine are parti ally dependent upon hypothalamo-pituitary-adrenal axis integrity and activa tion. The efficacy of clozapine in the treatment of polydipsia and hyponatr emia in chronic psychiatric patients may involve clozapine-mediated activat ion of the cellular activity in the subfornical organ. (C) 2001 Elsevier Sc ience B.V. All rights reserved.