Antidepressant- and Anxiolytic-like Effects of the Phosphodiesterase-4 Inhibitor Rolipram on Behavior Depend on Cyclic AMP Response Element Binding Protein-Mediated Neurogenesis in the Hippocampus

Abstract

Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of cAMP-response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these have not been established. In the present study, chronic administration of rolipram produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, three weeks following the end of MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB, with its antidepressant- and anxiolytic-like effects resumed. Overall, the present results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.

Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats

“…A previous study found that rolipram could increase cAMP accumulation; cAMP accumulation activates cAMP-dependent PKA and subsequently phosphorylates and activates CREB (27). Authors in a different study held the view that rolipram could reduce the distracted platform searches induced by cerebral ischemia (15). In the present study, Fig.…”

“…Therefore, we believe that targeting PDE4 may be an innovative approach to treat cognitive disorders associated with cerebral ischemia. Rolipram, as a prototypical PDE4 inhibitor, is widely used in ischemic stroke studies (15,27). A previous study found that rolipram could increase cAMP accumulation; cAMP accumulation activates cAMP-dependent PKA and subsequently phosphorylates and activates CREB (27).…”

“…Rolipram typically acts as an antidepressant-and anxiolytic-like agent (14); however, a number of studies have revealed that it may reduce the infarction area caused by cerebral ischemia (15) and also increase the phosphorylated-(p-) CREB expression level in the hippocampus (14,16). This study focused on the protective effect of rolipram on transient cerebral ischemia/reperfusion injury in rats, and aimed to investigate the hypothesis that rolipram acts through promoting angiogenesis and reducing apoptosis following cerebral ischemia.…”

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

“…Consistent with this molecular mechanism, the brain-penetrant PDE4 inhibitor rolipram shows memory-enhancing properties in preclinical and clinical models (Fleischhacker et al, 1992;Rutten et al, 2009). In addition, rolipram has beneficial effects in various neuronal systems, for example, increased expression of brainderived neurotrophic factor (Fujimaki et al, 2000) and increased proliferation of neural progenitor cells in the hippocampus (Li et al, 2009), two key effects thought to underlie the antidepressant effects of rolipram. Lastly, the elevation of cAMP in the brain is thought to have beneficial effects in models of tissue injury or neurodegeneration.…”

Effects of Repeated Treatment with Phosphodiesterase-4 Inhibitors on cAMP Signaling, Hippocampal Cell Proliferation, and Behavior in the Forced-Swim Test

“…Inhibition of neurogenesis blocks some, but not all, of the effects of antidepressants on behavior (Santarelli et al, 2003;Holick et al, 2008). Likewise, repeated treatment of mice with rolipram also increases hippocampal neurogenesis; inhibition of rolipraminduced neurogenesis reduces antidepressant-like effects on behavior (Li et al, 2009). The relationship among the ability of PDE4 inhibitors to interact with the HARBS and LARBS to alter cAMP signaling, increase neurogenesis, and produce antidepressant-like effects on behavior has not been well characterized.…”