Region-specific induction of Delta FosB by repeated administration of typical versus atypical antipsychotic drugs

Whereas acute administration of many types of stimuli induces c-Fos and rel ated proteins in brain, recent work has shown that chronic perturbations ca use the region-specific accumulation of novel Fos-like proteins of 35-37 kD . These proteins, termed chronic FRAs (Fos-related antigens), have recently been shown to be isoforms of Delta FosB, which accumulate in brain due to their enhanced stability. In the present study, we sought to extend earlier findings that documented the effects of acute administration of antipsycho tic drugs (APDs) on induction of Fos-like proteins by investigating the abi lity of typical and aytpical APDs, after chronic administration, to induce these Delta FosB isoforms in several brain regions implicated in the clinic al actions of these agents. By Western blotting we found that chronic admin istration of the typical APD, haloperidol, dramatically induces Delta FosB in caudate-putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accu mbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of t he prototype atypical APD clozapine failed to significantly increase levels of Delta FosB in any of the three brain regions, and even tended to reduce Delta FosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of Delta FosB in CP, but not NAc or PFC. Studies with selective receptor anta gonists suggested that induction of Delta FosB in CP and NAc is most depend ent on antagonism of D-2-D-3 dopamine receptors, with antagonism of D-1-lik e receptors most involved in the PFC. Immunohistochemical analysis confirme d the greater induction of Delta FosB in CP by typical versus atypical APDs , with no significant induction seen in PFC with either class of APD. Toget her, these findings demonstrate that repeated administration of APDs result s in the induction of long-lasting Fos-like transcription factors that-coul d mediate some of the persistent and region-specific changes in brain funct ion associated with chronic drug exposure. (C) 1999 Wiley-Liss, Inc.