Interactions between environmental stimulation and antipsychotic drug effects on forebrain c-Fos activation

The immediate-early gene product Fos is differentially induced in the rat brain by the antipsychotic drugs haloperidol and clozapine. It is often claimed that although both drugs induce Fos in the nucleus accumbens, haloperidol but not clozapine increases Fos-like immunoreactivity in the striatum, whereas clozapine but not haloperidol increases Fos-like immunoreactivity in prefrontal cortex. Investigations of antipsychotic drug effects on Fos have typically administered high doses with pronounced sedative effects to behaviorally naive animals. In the present study, we compared the effects of low doses of haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) on Fos-like immunoreactivity in rats which were either behaviorally naive, exposed to a novel environment or tested for two-way active avoidance. We determined that haloperidol increased Fos in the striatum and nucleus accumbens regardless of testing condition whereas clozapine markedly reduced the induction of Fos by behavioral testing in these regions; moreover, haloperidol dramatically increased prefrontal cortical Fos expression in animals placed in a novel environment, but not in testing-naive controls. From these results we suggest that antipsychotic drug-induced patterns of Fos expression in the rat are highly dependent on animals' concurrent behavioral status, perhaps reflecting neuroanatomically specific interactions between antipsychotic drugs and environmental stressors which also may occur in the schizophrenic condition.