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 effects in the nucleus accumbens, the lateral septum, the hypothalamic paraventricular nucleus and the amygdala. The acutely-induced Fos responses of olanzapine were significantly reduced in all brain areas investigated after a 3-week treatment period, indicating the development of tolerance. Through evaluation of cross-tolerance we investigated whether the effects of olanzapine, haloperidol and clozapine on Fos expression and on plasma corticosterone are mediated by the same or by different mechanisms. Cross-tolerance between olanzapine and either haloperidol or clozapine was assessed by the administration of a challenge dose of olanzapine to rats, that were pretreated for 3 weeks with either the same drug, with saline (1 ml kg(-1) day(-1), haloperidol (1 mg kg(-1) day(-1) or clozapine (20 mg kg(-1) day(-1). A competitive dose of olanzapine in long-term haloperidol-treated rats showed cross-tolerance in the rostral part of the cingulate cortex, the dorsomedial and the dorsolateral striatum, the nucleus accumbens and the lateral septum. Cross-tolerance between olanzapine and clozapine, however, was limited to limbic nuclei, including the prefrontal cortex, the lateral septum, the hypothalamic paraventricular nucleus and the amygdala, with minor effects in the mid- and caudal parts of the cingulate cortex. Interesting are the common effects in the lateral septum, possibly an important target for antipsychotic efficacy. Olanzapine administration induced elevated levels of plasma corticosterone and cross-tolerance was seen in haloperidol- and clozapine-pretreated rats.