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Chronic administration of carbamazepine down-regulates AP-2 DNA-binding activity and AP-2alpha protein expression in rat frontal cortex.

Rao JS, Bazinet RP, Rapoport SI, Lee HJ

Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. jrao@mail.nih.gov

BACKGROUND: Despite being approved for treating bipolar disorder, carbamazepine's (CBZ) mechanism of action is not fully understood. Carbamazepine and lithium, when administered chronically to rats, decrease brain messenger ribonucleic acid (mRNA), protein, and activity levels of the arachidonic acid-selective cytosolic phospholipase A2 (cPLA2). The ability of lithium to decrease cPLA2 mRNA was ascribed to its ability to down-regulate the cPLA2 transcription factor, AP-2. The present study was undertaken to see whether chronic CBZ treatment also would down-regulate the AP-2 transcription factor. METHODS: Male CDF-344 rats received (intraperitoneally for 30 days) 25 mg/kg per day or vehicle. Transcription factors regulating cPLA2 were measured by gelshift assay in the frontal cortex. RESULTS: Chronic CBZ decreased AP-2 transcription factor-binding activity, cyclic adenosine monophosphate (cAMP)--dependent protein kinase A (PKA) activity, nuclear phospho AP-2, and the protein but not mRNA level of AP-2alpha in rat frontal cortex. There was no significant change in activator protein (AP) 1, nuclear factor kappa B (NF-kappaB), glucocorticoid response element, or polyoma enhancer activator 3 (PEA3). CONCLUSIONS: These results support the hypothesis that, like lithium, CBZ's down-regulation of AP-2 transcription factor activity may be responsible for down-regulating cPLA2 gene transcription. Chronically administered CBZ appears to decrease AP-2 DNA-binding activity by decreasing cAMP-dependent PKA activity, phosphorylation of AP-2 protein, and the protein level of its AP-2alpha subunit in rat frontal cortex.

Published 15 January 2007 in Biol Psychiatry, 61(2): 154-61.
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