In a previous study, an up-regulation of rolipram-sensitive, low-Km, cyclic AMP phosphodiesterase (PDE4) subtype PDE4A in rat cerebral cortex following repeated treatment of desipramine was observed. To determine whether this effect is shared by antidepressants from different pharmacological classes, PDE4A expression was examined using immunoblot analyses following repeated treatment with the norepinephrine re-uptake inhibitor desipramine, the monoamine oxidase inhibitor phenelzine, the atypical antidepressant trazodone, and the serotonin reuptake inhibitor fluoxetine. Desipramine, phenelzine, and fluoxetine all increased the intensities of the PDE4A bands in hippocampal preparations; trazodone did not. In preparations of cerebral cortex, the intensities of the PDE4A bands were increased following desipramine treatment, not changed following phenelzine or fluoxetine treatment, and decreased following trazodone treatment. It appears that repeated treatment with antidepressant drugs from different pharmacological classes produces similar effects on the expressions of PDE4A variants in hippocampus. This effect is not correlated with the changes in beta-adrenergic receptor densities, suggesting these antidepressants may at some point alter intracellular signal transduction pathways in a similar manner.