Rolipram and Its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats

Egawa, Takashi; Mishima, Kenichi; Matsumoto, Yoshiaki; Iwasaki, Kiyo; Iwasaki, Katsunori; Fujiwara, Michihiro

doi:10.1254/jjp.75.275

Cited by 67 publications

(48 citation statements)

References 28 publications

(31 reference statements)

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“…Recent studies show that rolipram ameliorates scopolamineinduced impairment of learning and memory in rats and mice (Egawa et al 1997;Imanishi et al 1997); it also improves both working and reference memory impaired by scopolamine (Zhang and O'Donnell 2000). The results of the present study show that rolipram also reverses NMDA receptor antagonist-induced impairment of memory.…”

Section: Discussionsupporting

confidence: 71%

“…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.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Zhang

Crissman

Dorairaj

et al. 2000

Neuropsychopharmacology

148

105

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, 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 ...

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

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

Zhang

Crissman

Dorairaj

et al. 2000

Neuropsychopharmacology

148

105

View full text Add to dashboard Cite

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“…Sizeable effects temporally related to the actual drug treatment were only observed in normal mice by using much higher doses (1.25 mg/kg/day for 15 days; Nakagawa et al, 2002a, b;Fujioka et al, 2004). Concerning rats, biochemical effects on the hippocampal cAMP system and restoration of behavioral impairment in normogenic, intact animals has been only reported for substantially higher doses of Rolipram (Giorgi et al, 2004;Nagakura et al, 2002;Egawa et al, 1997). Conditioned fear, while apparently a simple form of learning, is actually a rather complex phenomenon from a neurobiological point of view.…”

Section: Discussionmentioning

confidence: 99%

Subchronic Rolipram Delivery Activates Hippocampal CREB and Arc, Enhances Retention and Slows Down Extinction of Conditioned Fear

Monti

Berteotti

Contestabile

2005

Neuropsychopharmacol

102

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Rolipram, a type IV-specific phosphodiesterase inhibitor, is known to improve memory under various learning tasks. Moreover, Rolipram treatments have been shown to increase expression and phosphorylation of a key factor for hippocampal memory consolidation, the cAMP-dependent response element-binding protein, CREB. However, the exact correlation between hippocampal CREB phosphorylation and memory improvement induced by Rolipram has not yet been determined in a CREB-dependent type of hippocampal-related learning in normogenic, intact rodents. Here, we report that subchronic Rolipram delivery by using osmotic minipumps increased the basal rat hippocampal expression and phosphorylation of CREB, as well as the expression of the cAMPdependent, memory-related protein, Arc. In parallel, the same treatment improved memory consolidation of conditioned fear. Furthermore, the increase of CREB phosphorylation and Arc expression consequent to the learning experience was enhanced in Rolipram-treated rats, compared to controls. By evaluating the time course of memory extinction over 10 days after the initial learning test, we also observed significant slowing down of the memory extinction rate in Rolipram-treated rats. This effect could be attributed to CREB phosphorylation and memory having been initially higher, as osmotic minipumps stopped to release Rolipram the first day after the initial learning test. Our data define the conditions through which the pharmacological manipulation of hippocampal CREB expression and activation result in memory amelioration in normogenic, intact animals. These results are relevant for the study of molecular correlates of memory, and may also be important in view of the efforts to design new pharmacological treatments, targeting the CREB pathway and leading to enhancement of learning and memory, even in the absence of patent neuropathology.

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“…Imanishi et al (1997) found an ameliorating effect of rolipram on learning and memory impairment in rodents. Rolipram reversed the impairment of either working or reference memory induced by the muscarinic receptor antagonist scopolamine (Egawa et al, 1997;Imanishi et al, 1997;Zhang and O'Donnell, 2000). Nonspecific PDE inhibitors, such as caffeine, improved behavioral performance under distinct conditions (Nicholson, 1990).…”

Section: Introductionmentioning

confidence: 94%

The Type IV-Specific Phosphodiesterase Inhibitor Rolipram and Its Effect on Hippocampal Long-Term Potentiation and Synaptic Tagging

Navakkode¹,

Sajikumar²,

Frey³

2004

J. Neurosci.

103

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We investigated the effects of rolipram, a selective cAMP phosphodiesterase (PDE) inhibitor, on late plastic events during functional CA1 plasticity in vitro in rat hippocampal slices. We present data showing that an early form of long-term potentiation (LTP) (early-LTP) that normally decays within 2-3 hr can be converted to a lasting LTP ( We also studied whether rolipram can interact with processes of synaptic tagging, because RLTP was also dependent on protein synthesis, similar to late-LTP. Inhibition of PDE and subsequent induction of RLTP in one synaptic population were able to transform early-LTP into late-LTP in a second, independent synaptic population of the same neurons. This supports our hypothesis that cAMP-dependent processes are directly involved in the synthesis of plasticity-related proteins.

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Rolipram and Its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats

Cited by 67 publications

References 28 publications

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

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

Subchronic Rolipram Delivery Activates Hippocampal CREB and Arc, Enhances Retention and Slows Down Extinction of Conditioned Fear

The Type IV-Specific Phosphodiesterase Inhibitor Rolipram and Its Effect on Hippocampal Long-Term Potentiation and Synaptic Tagging

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