Region‐specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs

Abstract

Whereas acute administration of many types of stimuli induces c-Fos and related proteins in brain, recent work has shown that chronic perturbations cause 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 ΔFosB, 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 antipsychotic drugs (APDs) on induction of Fos-like proteins by investigating the ability of typical and aytpical APDs, after chronic administration, to induce these ΔFosB isoforms in several brain regions implicated in the clinical actions of these agents. By Western blotting we found that chronic administration of the typical APD, haloperidol, dramatically induces ΔFosB in caudate–putamen (CP), a brain region associated with the extrapyramidal side effects of this drug. A smaller induction was seen in the nucleus accumbens (NAc) and prefrontal cortex (PFC), brain regions associated with the antipsychotic effects of the drug. In contrast, chronic administration of the prototype atypical APD clozapine failed to significantly increase levels of ΔFosB in any of the three brain regions, and even tended to reduce ΔFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of ΔFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of ΔFosB in CP and NAc is most dependent on antagonism of D2–D3 dopamine receptors, with antagonism of D1-like receptors most involved in the PFC. Immunohistochemical analysis confirmed the greater induction of ΔFosB in CP by typical versus atypical APDs, with no significant induction seen in PFC with either class of APD. Together, these findings demonstrate that repeated administration of APDs results in the induction of long-lasting Fos-like transcription factors that could mediate some of the persistent and region-specific changes in brain function associated with chronic drug exposure. Synapse 33:118–128, 1999. © 1999 Wiley-Liss, Inc.