Induction of Fos protein by antipsychotic drugs in rat brain following kainic acid-induced limbic-cortical neuronal loss.

Antipsychotic drugs increase expression of the immediate early gene, c-fos, in the striatum, nucleus accumbens and prefrontal cortex of rat brain. Since intracerebro-ventricular (ICV) infusion of kainic acid (KA) produces loss of limbic-cortical neurons that project to these brain areas, we postulated that the c-fos responses to antipsychotics in these brain areas would be altered following ICV KA administration. To produce limbic-cortical lesions, rats received ICV infusions of either KA (4.5 nmol) or vehicle. Then, 25–28 days later, rats received 0.13, 0.35, or 1.5 mg/kg haloperidol, 6.3, 17.5, or 30.0 mg/kg clozapine, or saline. In both KA-lesioned and control animals, haloperidol produced greater increases in Fos protein immunoreactivity in the striatum than in limbic-cortical areas, while clozapine produced greater increases in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and clozapine administration also produced similar dose-dependent increases in Fos protein immunoreactivity in the striatum and nucleus accumbens. However, the ability of clozapine to increase Fos protein immunoreactivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathology has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos in KA-lesioned rats may be relevant to understanding clozapine’s unusual therapeutic actions in patients with schizophrenia.