The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat

Staveren, Wilma C.G. van; Ittersum, Marjanne Markerink‐van; Steinbusch, Harry W.M.; Vente, Jan de

doi:10.1016/s0006-8993(00)03081-x

Cited by 104 publications

(75 citation statements)

References 47 publications

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“…Although only inhibitors of PDE2 and PDE4 affected NMDA receptor-mediated cyclic nucleotide signaling, other PDE families, including those examined pharmacologically in the present study, are expressed in the brains of various species (Loughney and Ferguson, 1996;Cherry and Davis, 1999;Cho et al, 2000;Perez-Torres et al, 2000;Giordano et al, 2001;van Staveren et al, 2001). At least one variant of each of these families is found in cerebral cortex and hippocampus.…”

Section: Discussionmentioning

confidence: 66%

Hydrolysis of N-Methyl-d-aspartate Receptor-Stimulated cAMP and cGMP by PDE4 and PDE2 Phosphodiesterases in Primary Neuronal Cultures of Rat Cerebral Cortex and Hippocampus

Suvarna¹,

O'Donnell²

2002

J Pharmacol Exp Ther

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Stimulation of N-methyl-D-aspartate (NMDA) receptors on neurons activates both cAMP and cGMP signaling pathways. Experiments were carried out to determine which phosphodiesterase (PDE) families are involved in the hydrolysis of the cyclic nucleotides formed via this mechanism, using primary neuronal cultures prepared from rat cerebral cortex and hippocampus. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) potentiated the ability of NMDA to increase cAMP and cGMP. However, among the family-selective inhibitors, only the PDE4 inhibitor rolipram enhanced the ability of NMDA to increase cAMP in the neurons. In contrast, only the PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) enhanced the ability of NMDA to increase cGMP. Neither adenosine nor an adenosine deaminase inhibitor mimicked the effect of EHNA; this suggests that EHNA's inhibition of PDE2, not its effects on adenosine metabolism, mediates its effects on NMDA-stimulated cGMP concentrations. The PDE inhibitoraugmented effects of NMDA on cAMP and cGMP formation were antagonized by 5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), verifying NMDA receptor mediation. In contrast, only NMDA-mediated cGMP formation was affected by altering either nitric oxide signaling or guanylyl cyclase; this suggests that NMDA-induced changes in cAMP are not secondary to altered cGMP concentrations. Overall, the present findings indicate that cAMP and cGMP formed in neurons as a result of NMDA receptor stimulation are hydrolyzed by PDE4 and PDE2, respectively. Selective inhibitors of the two PDE families will differentially affect the functional consequences of activation of these two signaling pathways by NMDA receptor stimulation.

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Section: Discussionmentioning

confidence: 66%

Hydrolysis of N-Methyl-d-aspartate Receptor-Stimulated cAMP and cGMP by PDE4 and PDE2 Phosphodiesterases in Primary Neuronal Cultures of Rat Cerebral Cortex and Hippocampus

Suvarna¹,

O'Donnell²

2002

J Pharmacol Exp Ther

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“…In addition to activating RYRs, caffeine is a phosphodiesterase inhibitor and may exert its effect by inhibiting cAMP degradation, leading to more PKA activation (van Staveren et al 2001;Yoshimura 2005). The role of cAMP and PKA in more established forms of synaptic tagging/capture has been well documented (Navakkode et al 2004 ;Young et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1

Sajikumar

Abraham

et al. 2009

Learn. Mem.

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Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic tagging/capture due to its inability to set the ''synaptic tags.'' Here, we report that priming of synapses with ryanodine receptor agonists such as ryanodine (10 mM) or caffeine (10 mM) facilitates subsequent synaptic tagging/capture, enabling an STP protocol to establish a late-LTP in response to strong tetanization of a heterosynaptic input. We identified calcium/calmodulin-dependent protein kinase II (CaMKII) as mediating the primed synaptic tag setting, which persisted for 1 h. We also identified protein kinase Mz (PKMz), presumably captured from the strongly tetanized heterosynaptic input, as a plasticity-related protein maintaining the LTP at the tagged synapses. In addition, synaptic tags in primed STP were erased or interfered with by delivering low-frequency depotentiating stimulation 5 or 10 min after its induction, thus preventing capture of newly synthesized proteins. These data reveal a novel form of metaplasticity, whereby ryanodine receptor activation lowers the threshold for subsequent synaptic tagging/capture, thus priming weakly activated synapses for heterosynaptic interactions that promote long-term functional plasticity.Long-term potentiation (LTP) and long-term depression (LTD) can be regulated by the previous history of synaptic activation. This form of plasticity regulation is termed ''metaplasticity'' (Abraham 2008).

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“…Possible site and mechanism of action of PDE5 inhibition The PDE5 inhibitors sildenafil, zaprinast and vardenafil increase cGMP accumulation in the dorsal hippocampus as assessed in vitro with radioimmunoassay and immunocytochemistry (De Vente et al 1996;Van Staveren et al 2001;Prickaerts et al 2000b). In addition, it has been found that injections of 8-bromo-cGMP into the hippocampus immediately after the first trial improved the memory performance in both the object recognition (Prickaerts et al 2002a) and passive avoidance task (Bernabeu et al 1996).…”

Section: Effects Of Both Drug Classes On Exploratory Activitymentioning

confidence: 99%

Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation

Prickaerts

Şık

Staay³

et al. 2004

Psychopharmacology

125

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Rationale: Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes.Objective: We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. Methods: The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. Results: Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. Conclusion: Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.

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The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat

Cited by 104 publications

References 47 publications

Hydrolysis of N-Methyl-d-aspartate Receptor-Stimulated cAMP and cGMP by PDE4 and PDE2 Phosphodiesterases in Primary Neuronal Cultures of Rat Cerebral Cortex and Hippocampus

Hydrolysis of N-Methyl-d-aspartate Receptor-Stimulated cAMP and cGMP by PDE4 and PDE2 Phosphodiesterases in Primary Neuronal Cultures of Rat Cerebral Cortex and Hippocampus

Priming of short-term potentiation and synaptic tagging/capture mechanisms by ryanodine receptor activation in rat hippocampal CA1

Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation

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