EFFECTS OF OLANZAPINE ON REGIONAL C-FOS EXPRESSION IN RAT FOREBRAIN

Compared to typical antipsychotic drugs, clozapine produces a unique p attern of Fos-like immunoreactive neurons in the rat forebrain. It has been proposed, therefore, that this approach may be useful in identif ying other agents with clozapine's therapeutic profile. In the present study, toe examined the ability of olanzapine to increase the number of Fos-like immunoreactive neurons in the striatum, nucleus accumbens, lateral septal nucleus, and prefrontal cortex. Olanzapine (5, 10 mg/k g) produced dose-dependent increases in the number of Fos-positive neu rons in the nucleus accumbens and lateral septal nucleus, important co mponents of the limbic system that may mediate some of the therapeutic actions of neuroleptics. Olanzapine also produced dose-dependent incr eases in the number of Fos-positive neurons in the dorsolateral striat um, an effect that correlates with the ability of neuroleptics to prod uce extrapyramidal side-effects. The effects of olanzapine on regional c-fos expression are not therefore identical to clozapine, which is w ithout effect in the dorsolateralstriatum. However, olanzapine-induced increases in the dorsolateral striatum were considerably smaller than those generated in the nucleus accumbens suggesting that at low, pote ntially therapeutic doses olanzapine may not generate significant extr apyramidal side effects. Olanzapine also increased the number of Fos-p ositive neurons in medical prefrontal cortex, an action unique to cloz apine and a few other atypical antipsychotics. These findings are cons istent with the hypothesis that olanzapine is an atypical antipsychoti c in the sense that it does not produce significant extrapyramidal sid e-effects at low therapeutic doses. However extrapyramidal side-effect s at higher doses can be predicted by these results. Finally, olanzapi ne's actions in the medial prefrontal cortex may be predictive of a cl ozapine-like profile with respect to actions on negative symptoms in s chizophrenia. Additional clinical experience with olanzapine and other new antipsychotics is required to test the validity of these hypothes es.