Effects of Repeated Antidepressant Treatment on Type 4A Phosphodiesterase (PDE4A) in Rat Brain

Abstract

In a previous study, an up-regulation of rolipram-sensitive, low-K m , 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 reuptake 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 ␤-adrenergic receptor densities, suggesting these antidepressants may at some point alter intracellular signal transduction pathways in a similar manner.

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…However, while these findings appear to be consistent with FST behavior and hippocampal neurogenesis observed in PDE4BÀ/À mice, further studies are needed to determine their relationship to antidepressant activity. In addition, these results do not rule out the contributions of other PDE4 subtypes, such as PDE4A and PDE4D, given the consideration of their roles in or association with antidepressant-like behavior (Takahashi et al, 1999;Ye et al, 2000;Zhang et al, 2002). …”

Chronic Fluoxetine Bidirectionally Modulates Potentiating Effects of Serotonin on the Hippocampal Mossy Fiber Synaptic Transmission

“…The reduction of the potentiation by the higher concentration of 5-HT could be attributable to downregulation of 5-HT 4 receptors. It is also possible that upregulation of phosphodiesterases (Ye et al, 2000) contributes to the reduction of the potentiation, because the potentiating effect of 5-HT was augmented by the phosphodiesterase inhibitor (Fig. 3C).…”

Antidepressant-Induced Increase in High-Affinity Rolipram Binding Sites in Rat Brain: Dependence on Noradrenergic and Serotonergic Function

“…Furthermore, type 4 phosphodiesterase (PDE4), the primary form of phosphodiesterase hydrolyzing cAMP associated with the central ␤-adrenergic receptors (Ye and O'Donnell, 1996), has been implicated in the actions of proven antidepressants. Repeated treatment with various antidepressants or induction of electroconvulsive seizure, which has an antidepressant effect, increases the expression of PDE4A and PDE4B, but not PDE4D, in the rat frontal cortex and hippocampus (Suda et al, 1998;Takahashi et al, 1999;Ye et al, 1997Ye et al, , 2000. Furthermore, PDE4 inhibitors, such as rolipram and papaverine, have antidepressant-like effects in several behavioral models and therapeutic effects in depressed patients (Bobon et al, 1988;O'Donnell, 1993;Zhang et al, 2002).…”

“…By contrast, inhibition of guinea pig mast cell degranulation and suppression of antigen-induced T-cell proliferation are associated with the LARBS (Schmiechen et al, 1990;Barnette et al, 1995;Duplantier et al, 1996). The finding that repeated treatment with antidepressants from different pharmacological classes increases the expression of PDE4 suggests that these drugs may ultimately affect common signaling pathways (Takahashi et al, 1999;Ye et al, 1997Ye et al, , 2000. It is not known whether antidepressant treatment affects the HARBS and the LARBS differentially.…”