The effects repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and CDP840, which differ in their interactions with high- and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cyclic AMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1, 3 mg/kg), piclamilast (0.3, 1 mg/kg), or CDP840 (10, 30 mg/kg) for sixteen days increased cyclic AMP and phosphorylation of cyclic AMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cyclic AMP and pCREB in hippocampus and prefrontal cortex, but the dose- and time-dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, likely due to its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cyclic AMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.
- cyclic AMP
- cyclic AMP response element binding protein
- Received January 12, 2011.
- Revision received May 10, 2011.
- Accepted May 11, 2011.
- The American Society for Pharmacology and Experimental Therapeutics