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 DeltaFosB, 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 DeltaFosB 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 DeltaFosB 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 DeltaFosB in any of the three brain regions, and even tended to reduce DeltaFosB levels in the NAc. Two putative atypical APDs, risperidone and olanzapine, produced small but still significant increases in the levels of DeltaFosB in CP, but not NAc or PFC. Studies with selective receptor antagonists suggested that induction of DeltaFosB 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 DeltaFosB 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.

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

“…Here, consistent with previous findings from our group (Atkins et al, 1999), we demonstrate that the first-generation antipsychotic drug, haloperidol, increases DFosB expression in the medial PFC of rats. We then added to these findings by demonstrating that this increase in DFosB is associated with epigenetic modifications at the FosB gene, specifically, reduced binding of G9a, which catalyzes repressive histone methylation at bound genes.…”

“…Both first and second generation antipsychotic drugs have been shown to increase DFosB expression in several limbic brain regions including the prefrontal cortex (PFC) (Atkins et al, 1999;Hiroi and Graybiel, 1996;Kontkanen et al, 2002;Perrotti et al, 2005), which is highly implicated in the cognitive deficits associated with schizophrenia.…”

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…In designing these experiments, we targeted rodent dosing strategies relevant to antipsychotic dosing in human subjects (Mukherjee et al, 2001;Kapur et al, 1998Kapur et al, , 1999 and consistent with doses utilized in the existing rodent literature Kinkead et al, 2000;Atkins et al, 1999;Zhang et al, 2000). Therapeutic response is frequently associated with D 2 receptor occupancy of approximately 60-70% in humans, but D 2 occupancies greater than 80% are associated with increased extrapyramidal side effects.…”

Chronic Antipsychotic Drug Treatment Induces Long-lasting Expression of fos and jun Family Genes and Activator Protein 1 Complex in the Rat Prefrontal Cortex

“…Acute administration of D 2 antagonists haloperidol and ( Ϫ )-sulpiride induces the expression of c-Fos, FosB, Fra-1, c-Jun and JunD proteins, whereas treatment with acute SCH23390, a D 1 selective antagonist, results in upregulation of FosB, Fra-1 and JunD proteins (Ozaki et al 1997(Ozaki et al , 1998. Acute and chronic haloperidol treatments increase the DNA-binding activity of the AP-1 complex in the rodent caudate putamen and whole brain extracts (Nguyen et al 1992;Ozaki et al 1997Ozaki et al , 1998Atkins et al 1999), while the effects of clozapine on AP-1 complex binding activity remain more obscure.…”