Inhibition of Cyclic AMP Phosphodiesterase (PDE4) Reverses Memory Deficits Associated with NMDA Receptor Antagonism

Abstract

, a selective inhibitor of type 4 cyclic AMP phosphodiesterase (PDE4), completely reversed the amnesic effects of MK-801 on working and reference memory (F[4,64] ϭ 11.10; p Ͻ .0001 and F[4,64] N-methyl-D-aspartate (NMDA) receptors are widely distributed in the brain; their density is highest in the hippocampal CA1 subregion (Monaghan and Cotman 1985; Monyeret al. 1994;Boyer et al. 1998). It has been shown that NMDA receptors in this area are very important in the regulation of synaptic plasticity and the process of learning and memory, especially long-term memory (Kesner and Dakis 1995;Morris et al. 1986;Nguyen and Kandel 1996;Kawabe et al. 1998). Meanwhile, NMDA elicits an increase in cAMP in the hippocampal CA1 area that is antagonized by the competitive antagonist DL-2-amino-5-phosphonovaleric acid (AP5) or removal of extracellular Ca 2 ϩ (Chetkovich et al. 1991). Antagonism of NMDA receptors not only blocks NMDA-induced increases in cAMP, but also impairs learning and memory (Morris et al. 1986;Nguyen and Kandel 1996;Kawabe et al. 1998;Chetkovich et al. 1991;Meehan 1996). These results indicate that cAMP is involved in the NMDA receptor antagonist-induced impairment of learning and memory.Rolipram, a selective inhibitor of type 4 cAMP-specific phosphodiesterase (PDE4), produces an increase in brain cAMP levels via the inhibition of its degradation Rolipram Antagonizes MK-801-Induced Memory Deficits 199 (Schneider 1984;Ilien et al. 1982). Behavioral studies show that rolipram inhibits locomotor activity and rearing induced by methaphetamine and produces biphasic effects on schedule-controlled behavior, increasing response rate at lower doses and decreasing response rate at higher doses (Iyo et al. 1995;O'Donnell and Frith 1999). It elicits a morphine-withdrawal-like behavioral syndrome characterized by head twitches, forepaw shaking, grooming and hypoactivity, which are related to a high level of cAMP (Wachtel 1982;Wachtel 1983). Rolipram also exhibits antidepressant-like effects in animal models and in patients with depressive disorders (O'Donnell and Frith 1999;Hebenstreit et al. 1989;O'Donnell 1993).Recently, rolipram has been shown to reverse the impairment of either working memory or reference memory induced by the muscarinic receptor antagonist scopolamine (Egawa et al. 1997;Imanishi et al. 1997;Zhang and O'Donnell 2000). Furthermore, PDE4 has been shown to be involved in NMDA receptor-mediated signal transduction mechanisms. Chronic treatment with rolipram up-regulates NMDA receptors in the rat hippocampus ; rolipram also attenuates the expression of the heat shock protein HSP-70 induced by the NMDA receptor antagonist MK-801 (Hashimoto et al. 1997). Thus, although there is no direct evidence linking the effect of rolipram to NMDA receptors, the results described above suggest that rolipram will reverse the amnesic effect of the NMDA receptor antagonist MK-801. Such a finding would suggest an important role for PDE4 and cAMP in signal transduction mechanisms for NMDA receptors that are involved in ...

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

“…Our studies have not exhaustively examined the involvement of PDE polymorphisms in MDD or antidepressant treatment response; therefore, we cannot reject the role of any PDE gene in the genetic or pharmacogenetic of MDD. The contributions of other SNPs in the PDE family of genes should also be further scrutinized, especially in the PDE4 gene family, because PDE4D-regulated cAMP signaling may play a role in the pathophysiology and pharmacotherapy of depression (24,25). Although we examined 17 SNPs in this gene of the PDE4 family, we have not found an association with diagnosis of MDD or drug response.…”

“…Several lines of investigation suggest that PDE4, a cAMPspecific enzyme, should be considered a prime target for therapeutic intervention in a range of CNS disorders, including depression and impaired cognition (23)(24)(25). The selective inhibitor of PDE4 rolipram has been shown to produce antidepressant-like and memory-enhancing effects in animals (23,(25)(26)(27). Behavioral phenotype and pharmacological data of knockout mice support the concept that PDE4D might be involved in the mediation of depressive symptoms and antidepressant response (28).…”

The DISC locus in psychiatric illness

“…102 The PDE4 inhibitors MEM1018 and MEM1091 influence NMDA receptor-dependent memory, 103 and other selective PDE4 inhibitors including rolipram have been shown to influence memory and cognition in several studies. [103][104][105][106][107][108][109][110] Moreover, translation of specific PDE4 isoforms is regulated during long-term potentiation 111 and in NMDA-receptor-mediated memory functions. 112 PDE4s also influence myelination, 113 and rolipram has been shown to reduce demyelination and CNS inflammation, 114 and to promote axon regrowth and myelination in vivo.…”

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

“…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).…”