OBJECTIVE To investigate the relationship between the neurochemical and behavioral effects of inhibitors of cyclic nucleotide phosphodiesterases 2(PDE2) and PDE4 in the hope of identifying promising therapeutic targets and indications. METHODS Depression-and anxiety-like behaviors were evaluated by forced swimming,tail suspending and elevated plus maze tests. The memory enhancing effects were evaluated by Morris water maze test. RESULTS Inhibition of PDE4 results in antidepressant-like and memory-enhancing effects,in part due to increased cyclicAMP signaling.While targeting PDE4 subtypes(PDE4A-D) pharmacologically has proven challenging due to a highly conserved inhibitor-binding site in the catalytic region of the enzyme,some promise is offered by recently identified negative allosteric modulators of PDE4,which can act in a subtype-specific manner.While PDE2 has not been studied as extensively,it has been shown to be coded for by a single mammalian gene and to be highly expressed in the brain. Its inhibition results in anxiolytic-and antidepressant-like effects as wells as reducing oxidative stress and affording some degree of neuroprotection;these actions appear to be due to increased cyclicGMP signaling,even though PDE2 catalyzes the hydrolysis of both cyclicAMP and cyclicGMP. CONCLUSION Inhibitors targeting specific family of PDE may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions,while drug discovery efforts focusing on PDE2 are not as advanced as those for PDE4,some selective inhibitors are being developed and evaluated.
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