OLANZAPINE-INDUCED FOS EXPRESSION IN THE RAT FOREBRAIN - CROSS-TOLERANCE WITH HALOPERIDOL AND CLOZAPINE

Acute administration of the atypical antipsychotic drug olanzapine (5 mg kg(-1) i.p.) increased the number of Fos-positive cells moderately in the prefrontal cortex and the striatum; more pronounced were the ef fects in the nucleus accumbens, the lateral septum, the hypothalamic p araventricular nucleus and the amygdala. The acutely-induced Fos respo nses of olanzapine were significantly reduced in all brain areas inves tigated after a 3-week treatment period, indicating the development of tolerance. Through evaluation of cross-tolerance we investigated whet her the effects of olanzapine, haloperidol and clozapine on Fos expres sion and on plasma corticosterone are mediated by the same or by diffe rent mechanisms. Cross-tolerance between olanzapine and either haloper idol or clozapine was assessed by the administration of a challenge do se of olanzapine to rats, that were pretreated for 3 weeks with either the same drug, with saline (1 mi kg(-1) day(-1)), haloperidol (1 mg k g(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)). A competitive dose of olanzapine in long-term haloperidol-treated rats showed cross-tole rance in the rostral part of the cingulate cortex, the dorsomedial and the dorsolateral striatum, the nucleus accumbens and the lateral sept um. Cross-tolerance between olanzapine and clozapine, however, was lim ited to limbic nuclei, including the prefrontal cortex, the lateral se ptum, the hypothalamic paraventricular nucleus and the amygdala, with minor effects in the mid- and caudal parts of the cingulate cortex. in teresting are the common effects in the lateral septum, possibly an im portant target for antipsychotic efficacy. Olanzapine administration i nduced elevated levels of plasma corticosterone and cross-tolerance wa s seen in haloperidol- and clozapine-pretreated rats. (C) 1998 Elsevie r Science B.V. All rights reserved.