CONTRASTING EFFECTS OF CHRONIC CLOZAPINE, SEROQUEL(TM) (ICI-204,636) AND HALOPERIDOL ADMINISTRATION ON DELTA-FOSB-LIKE IMMUNOREACTIVITY IN THE RODENT FOREBRAIN

We have recently demonstrated that specific neuroanatomical patterns o f Fos-like immunoreactivity are predictive of atypical antipsychotic a ctivity. However, the fact that neuroleptics must be administered chro nically in order to generate both extrapyramidal side effects and an o ptimal therapeutic response calls into question the relevance of acute changes in Fos-like immunoreactivity for these slowly developing even ts. Fos-like immunoreactivity cannot be used to identify neurons activ ated by chronic neuroleptic administration because the increase in Fos -like immunoreactivity produced by an acute antipsychotic injection is dramatically reduced following repeated neuroleptic administration. I n contrast, expression of the immediate-early gene product Delta FosB is persistently elevated in the striatum by chronic haloperidol admini stration. This suggests that Delta FosB-like immunoreactivity may be u sed to identify neurons activated by chronic antipsychotic administrat ion. Since typical and atypical neuroleptics elevate Fos-like immunore activity in different regions of the forebrain acutely, the purpose of the present study was to determine whether typical (haloperidol) and atypical (clozapine, ICI 204,636) antipsychotics produce distinct patt erns of elevated Delta FosB-like immunoreactivity in the forebrain aft er chronic administration. Administration of haloperidol (2 mg/kg/day) to rats for 19 days induced a homogeneous elevation of neurons which displayed Delta FosB-like immunoreactivity in the ventral, medial and dorsolateral aspects of the striatum. Chronic haloperidol administrati on did not enhance Delta FosB-like immunoreactivity in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapin e (20 mg/kg/day) and ICI 204,636 (20 mg/kg/day) for 19 days elevated D elta FosB-like immunoreactivity not only in the ventral striatum but a lso in the prefrontal cortex and lateral septal nucleus. However, thes e compounds had weak effects on Delta FosB-like immunoreactivity in th e dorsolateral striatum. These results suggest that a preferential act ion on limbic structures such as the prefrontal cortex, ventral striat um and lateral septal nucleus may account for the ability of chronic c lozapine and ICI 204,636 administration to reduce the symptoms of schi zophrenia without generating extrapyramidal side effects.