Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity

Clozapine and haloperidol produce different induction patterns of c-fos expression in the forebrain, with haloperidol increasing Fos-like immunoreactivity (FLI) in the striatum, nucleus accumbens, lateral septal nucleus and clozapine producing such effects in the nucleus accumbens, prefrontal cortex and lateral septal nucleus. Accordingly, it was deemed possible that this approach may be useful in characterizing compounds with known or suggested antipsychotic actions. We therefore examined the effects of 17 compounds considered to be either typical, or atypical, antipsychotics on FLI in the prefrontal cortex, medial and dorsolateral striatum, nucleus accumbens and the lateral septal nucleus. Consistent with the hypothesis that the prefrontal cortex may be a target for some antipsychotic actions, FLI was elevated in this structure by clozapine, ICI 204,636, fluperlapine, RMI- 81,582, remoxipride, molindone, melperone and tiospirone. Likewise, the ability of all of the compounds, except for risperidone, to enhance FLI in the lateral septal nucleus suggests that this limbic region also may be an important locus of antipsychotic action. All of the compounds examined elevated FLI in the nucleus accumbens and medial striatum, indicating that potential antipsychotic activity is predicted most consistently on this basis. Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum. In contrast, compounds unlikely to produce EPS such as clozapine, thioridazine, risperidone, remoxipride, fluperlapine, sulpiride, melperone and RMI-81,582 either failed to increase or produced minor elevations in FLI in the dorsolateral striatum. Hence, the ability of a neuroleptic to increase FLI in the dorsolateral striatum predicted reasonably well its propensity to induce EPS. However, in order to devise a more precise classification scheme, we compared the difference between the number of neurons which displayed neuroleptic-induced FLI in the nucleus accumbens vs. that in the dorsolateral striatum after administration of each of the 17 compounds. This difference, referred to as the atypical index, was always positive for atypical antipsychotics and invariably negative for typical neuroleptics. Thus, in every instance it was possible to accurately predict the potential for EPS on the basis of whether the atypical index was positive or negative. These results suggest that Fos immunohistochemistry is a rapid and reliable method for determining the EPS liability of potential antipsychotic agents.