Sluka KA, O'Donnell JM, Danielson J, Rasmussen LA. Regular physical activity prevents development of chronic pain and activation of central neurons.

Pharmacological inhibition of type 4 cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE4) produces antidepressant-like effects in animals; however, it is not known which of the four PDE4 subtypes mediates these actions. In the present study, immunoblot analysis showed loss of phosphodiesterase 4D (PDE4D) expression in the cerebral cortex and hippocampus of PDE4D knockout (PDE4D-/-) mice, but unchanged PDE4A and PDE4B expression, relative to the wild type (PDE4D+/+) and heterozygous knockout (PDE4D+/-) mice. This reduced expression was accompanied by a reduction in PDE4 activity, while non-PDE4 activity was unchanged. PDE4D-/- mice exhibited decreased immobility in tail-suspension and forced-swim tests, which is indicative of an antidepressant-like effect on behavior. Desipramine and fluoxetine produced similar antidepressant-like effects in all three genotypes, even though their behavioral baselines differed markedly. By contrast, the PDE4 inhibitor rolipram only produced antidepressant-like effects in PDE4D+/+ mice. Consistent with this, rolipram potentiated isoproterenol-induced cyclic AMP formation only in the PDE4D+/+ mice. These results suggest that PDE4D is an essential mediator of the antidepressant-like effects of rolipram, and that PDE4D-regulated cyclic adenosine monophosphate signaling may play a role in the pathophysiology and pharmacotherapy of depression.

Adult male Swiss-Webster mice were housed either singly (isolated) or with a female (nonisolated). Aggressive behavior was evoked by introducing a group-housed male mouse (intruder) into the home cage of the isolated or nonisolated mouse (resident).d-Amphetamine, methamphetamine, methylphenidate, cocaine, and L-dopa decreased attack and threat behavior by resident mice, the isolates requiring 2--4 times higher drug doses for the antiaggressive effects than the nonisolates, d-Amphetamine, methamphetamine, and methylphenidate caused intruder mice to be more frequently attacked by their non-treated resident opponents, to escape more often, to assume the defensive upright posture less, and to move about more often. L-Dopa nonspecifically de creased all elements of agonistic and nonagonistic behavior, while the amphetamines and methylphenidate suppressed attacks, increased escapes, decreased upright postures, and increased nonagonistic locomotion. By contrast, cocaine's antiaggressive effects were remarkably specific, i.e., not accompanied by changes in other behavioral elements.

, 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 ...

Rolipram may exert its effects of reversing both working and reference memory impairments via increased cyclic AMP concentrations in certain signal transduction pathways, rather than by a generalized increase in cAMP.

Chronic stress and neuronal vulnerability have recently been recognized as factors contributing to cognitive disorders. One way to modify neuronal vulnerability is through mediation of phosphodiesterase 2 (PDE2), an enzyme that exerts its action on cognitive processes via the control of intracellular second messengers, cGMP and, to a lesser extent, cAMP. This study explored the effects of a PDE2 inhibitor, Bay 60-7550, on stress-induced learning and memory dysfunction in terms of its ramification on behavioral, morphological and molecular changes. Bay 60-7550 reversed stress-induced cognitive impairment in the Morris water maze (MWM), novel object recognition and location tasks (ORT/OLT), effects prevented by treatment with 7-NI, a selective inhibitor of neuronal nitric oxide synthase (nNOS); MK801, a glutamate receptor (NMDAR) inhibitor; myr-AIP, a CaMKII inhibitor; and KT5823, a PKG inhibitor. Bay 60-7550 also ameliorated stress-induced structural remodeling in the CA1 of the hippocampus, leading to increases in dendritic branching, length, and spine density. However, the neuroplasticity initiated by Bay 60-7550 was not seen in the presence of 7-NI, MK801, myr-AIP or KT5823. PDE2 inhibition reduced stress-induced ERK activation and attenuated stress-induced decreases in transcription factors (e.g., Elk-1, TORC1, and pCREB) and plasticity-related proteins (e.g, Egr-1 and BDNF). Pre-treatment with inhibitors of NMDA, CaMKII, nNOS, PKG (or PKA), blocked the effects of Bay 60-7550 on cGMP or cAMP signaling. These findings indicate that the effect of PDE2 inhibition on stress-induced memory impairment is potentially mediated via modulation of neuroplasticity-related, NMDAR-CaMKII-cGMP/cAMP signaling.

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes that are involved in the regulation of the intracellular second messengers cyclic AMP (cAMP) and cyclic GMP (cGMP) by controlling their rates of hydrolysis. There are 11 different PDE families and each family typically has multiple isoforms and splice variants. The PDEs differ in their structures, distribution, modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown to play distinct roles in processes of emotion and related learning and memory processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or cGMP, modulate mood and related cognitive activity. This review discusses the current state and future development in the burgeoning field of PDEs in the central nervous system. It is becoming increasingly clear that PDE inhibitors have therapeutic potential for the treatment of neuropsychiatric disorders involving disturbances of mood, emotion, and cognition.

The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.