Chronic antidepressant treatment up-regulates the cAMP cascade in limbic brain regions, suggesting that activation of this pathway contributes to the therapeutic efficacy of antidepressants. A role for cAMP signaling is supported by the finding that rolipram, a selective inhibitor of cAMP-specific phosphodiesterases type 4 (PDE4), has antidepressant efficacy in behavioral models of depression and in clinical trials. To elucidate further the role of PDE4 isozymes, we characterized the expression and regulation of PDE4A splice variants (i.e. PDE4A1, PDE4A5, PDE4A8 and PDE4A10) in rat brain by chronic antidepressant treatment. Initial in situ hybridization studies (ISH) revealed high levels of PDE4A1 mRNA in medial septum, diagonal band, olfactory system, hippocampus and cerebellum. PDE4A5 mRNA expression was restricted to the olfactory nuclei, deep cortical layers, dentate and CA1 pyramidal layers. PDE4A10 mRNA was localized in the dentate gyrus and CA1 pyramidal layers. PDE4A8 mRNA was absent in rat brain. We determined the influence of chronic fluoxetine or electroconvulsive seizure (ECS) treatments on PDE4A splice variants expression in various brain regions. ISH analysis indicated that chronic fluoxetine or ECS treatments significantly increased PDE4A1, but not PDE4A5 or PDE4A10, mRNA levels in frontal and parietal cortices. ECS increased PDE4A5 levels in the anterior cingulate and frontoparietal cortices, CA1 and dentate gyrus, whereas chronic fluoxetine or ECS treatment increased PDE4A10 levels in the hippocampus. The differential up-regulation of PDE4A splice variants suggests compensatory region-specific responses to the antidepressant-induced increase in cAMP signaling and suggests that these splice variants may be relevant as targets for antidepressant intervention.