Trends in Pharmacological Sciences
Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4)
Section snippets
The PDE superfamily and PDE4
PDE enzymes comprise an eleven-family group (PDE1–PDE11); there are multiple isoforms in each family, caused by multiple genes and alternative splicing 8, 9. The PDE families differ in their primary structure, ability to hydrolyze cAMP and cGMP, tissue and intracellular distribution, and sensitivity to modulators (e.g. Ca2+, calmodulin and cGMP) and pharmacological inhibitors.
The PDE4 enzyme family, which also is referred to as the low Km, cAMP-selective PDE and the rolipram-sensitive PDE,
Antidepressant effects of PDE4 inhibitors
Rolipram and other PDE4 inhibitors [e.g. Ro201724 (see Chemical names) and ICI63197] produce antidepressant-like effects in several preclinical models. They reduce the time of immobility in the forced-swim test, decrease response rate and increase reinforcement rate under a differential-reinforcement-of-low-rate schedule, reverse the effects of chronic, mild stress, normalize the behavioral deficits observed in Flinders sensitive-line and olfactory-bulbecomized rats, antagonize the effects of
PDE4 in antidepressant-sensitive signaling pathways
In general, clinically used antidepressants enhance noradrenaline-mediated and serotonin (5-HT)-mediated neurotransmission, either by inhibiting reuptake catabolism or by blocking inhibitory, presynaptic α-adrenoceptors (either autoreceptors or heteroreceptors) [25]. Thus, it was of interest to determine whether PDE4 is involved in signaling mechanisms that are associated with these two neurotransmitters (Figure 2). PDE4 was found to be either the predominant or exclusive PDE that mediates the
PDE4 subtypes in the mediation of antidepressant effects
As yet, no highly selective inhibitors of the PDE4 subtypes have been developed; available compounds are only about 10-fold selective, which limits their utility for studies in vivo. The most-studied inhibitors, such as rolipram and Ro201724, are equipotent at inhibiting the four PDE4 subtypes. Thus, it is necessary to examine the behavioral phenotype and pharmacological sensitivity of mouse lines that are deficient in a particular subtype to assess the relative roles of the PDE4 subtypes in
Inhibitor binding to conformers of PDE4
Another level of complexity in understanding the actions of PDE4 inhibitors concerns the high-affinity and low-affinity binding conformers (the HARBS and LARBS). The first indication that rolipram binding might be somewhat complex was the finding that whereas [3H]-rolipram binds with high affinity to brain membranes (Ki=1–10 nM), little high-affinity binding is detected in preparations of peripheral organs [46]. A systematic analysis of binding using a technique that assesses both high-affinity
Future directions
Much has been learned in the past several years about the mechanisms that mediate the antidepressant actions of PDE4 inhibitors. However, several areas need to be addressed more fully. First, the field would be advanced significantly by the development of highly subtype-selective PDE4 inhibitors. This has proved difficult because the catalytic site to which PDE4 inhibitors bind is highly conserved across subtypes [10]. However, as understanding of PDE4 structure and inhibitor binding increase,
Acknowledgements
Research in our laboratory was supported by research grants and an Independent Scientist Award from the National Institute of Mental Health.
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