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Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats

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Abstract

Rationale

Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory.

Objective

Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain.

Methods

The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined.

Results

In the radial-arm maze, MEM1018 and MEM1091 (0.1–2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10–30 μM) and MEM1091 (10 μM) enhanced the ability of NMDA (30 μM) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar.

Conclusions

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.

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Acknowledgements

This work was supported by Memory Pharmaceuticals and research grants from the National Institute of Mental Health.

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Authors and Affiliations

  1. Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN, 38163, USA

    Han-Ting Zhang, Ying Huang, Neesha U. Suvarna, Alicia M. Crissman & James M. O’Donnell

  2. Memory Pharmaceuticals Corp., Montvale, NJ, 07645, USA

    Chengjun Deng, Allen T. Hopper, Michael De Vivo & Gregory M. Rose

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  1. Han-Ting Zhang
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  2. Ying Huang
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  3. Neesha U. Suvarna
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  4. Chengjun Deng
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  5. Alicia M. Crissman
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  6. Allen T. Hopper
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  7. Michael De Vivo
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  8. Gregory M. Rose
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  9. James M. O’Donnell
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Correspondence to Han-Ting Zhang.

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Zhang, HT., Huang, Y., Suvarna, N.U. et al. Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats. Psychopharmacology 179, 613–619 (2005). https://doi.org/10.1007/s00213-004-2085-2

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  • DOI: https://doi.org/10.1007/s00213-004-2085-2

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