Antidepressant-like Profile and Reduced Sensitivity to Rolipram in Mice Deficient in the PDE4D Phosphodiesterase Enzyme

Abstract

Pharmacological inhibition of type 4 cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE4) produces antidepressant-like effects in animals; however, it is not known which of the four PDE4 subtypes mediates these actions. In the present study, immunoblot analysis showed loss of phosphodiesterase 4D (PDE4D) expression in the cerebral cortex and hippocampus of PDE4D knockout (PDE4D-/-) mice, but unchanged PDE4A and PDE4B expression, relative to the wild type (PDE4D+/+) and heterozygous knockout (PDE4D+/-) mice. This reduced expression was accompanied by a reduction in PDE4 activity, while non-PDE4 activity was unchanged. PDE4D-/- mice exhibited decreased immobility in tail-suspension and forced-swim tests, which is indicative of an antidepressant-like effect on behavior. Desipramine and fluoxetine produced similar antidepressant-like effects in all three genotypes, even though their behavioral baselines differed markedly. By contrast, the PDE4 inhibitor rolipram only produced antidepressant-like effects in PDE4D+/+ mice. Consistent with this, rolipram potentiated isoproterenol-induced cyclic AMP formation only in the PDE4D+/+ mice. These results suggest that PDE4D is an essential mediator of the antidepressant-like effects of rolipram, and that PDE4D-regulated cyclic adenosine monophosphate signaling may play a role in the pathophysiology and pharmacotherapy of depression.

A whole genome association study of neuroticism using DNA pooling

“…A PDE4-specific inhibitor rolipram has antidepressant effects on animals and patients with major depression. [61][62][63] PDE4D knockout mice show antidepressant-like behavior, which is further increased by the antidepressants desipramine and fluoxetine but not by rolipram. This suggests that the PDE4D subtype is an essential mediator of the antidepressant effects of rolipram.…”

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

“…The other half of the above supernatants from the cerebral cortex, amygdala, and hippocampus were used for PDE assay, as described previously (Zhang et al, 2002). PDE activity was determined by the detection of the [ 3 H]cAMP converting rate, using unlabeled cAMP (1 mM) as the substrate, in the absence (total PDE activity) and presence (non-PDE4 activity) of 10 mM rolipram; PDE4 activity was determined by subtracting non-PDE4 activity from the total PDE activity.…”

“…The TST was performed as described previously (Zhang et al, 2002). Each mouse was suspended using adhesive tape placed approximately 1 cm from the tip of its tail.…”

“…Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000). Inhibition of PDE4 also increases adult neurogenesis (Nakagawa et al, 2002), which is believed to be involved in antidepressant activity (Dranovsky and Hen, 2006;Malberg and Duman, 2003;Santarelli et al, 2003).…”

“…While the lack of selective inhibitors of PDE4 isoforms has made it particularly difficult in understanding the roles of PDE4 subfamilies, gene mutation and RNA interference (RNAi) have been shown to be feasible approaches to identifying functions of PDE4 subfamilies and even their variants (Lehnart et al, 2005;Lynch et al, 2005;Terrin et al, 2006;Zhang et al, 2002). Using genetic deletion mutants of specific PDE4 subtypes (Hansen et al, 2000;Jin et al, 2005b), it has been shown that PDE4D is important for antidepressant activity (Zhang et al, 2002). Mice deficient in PDE4D display antidepressant-like behavior in tests sensitive to antidepressants; the antidepressant-like effect of rolipram is abolished in these mice, which do not show any changes in a test sensitive to anxiolytic treatment.…”