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 (K A) produces loss of limbic-cortical neurons that project to these brai n areas, we postulated that the c-fos responses to antipsychotics in t hese 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, o r saline. In both KA-lesioned and control animals, haloperidol produce d greater increases in Fos protein immunoreactivity in the striatum th an in limbic-cortical areas, while clozapine produced greater increase s in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and cl ozapine 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 immunoreact ivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathol ogy has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos i n KA-lesioned rats may be relevant to understanding clozapine's unusua l therapeutic actions in patients with schizophrenia.