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Original Article |
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Neuropsychopharmacology (2000) 23 198-204.10.1038/sj.npp.1395516
Inhibition of Cyclic AMP Phosphodiesterase (PDE4) Reverses Memory Deficits Associated with NMDA Receptor Antagonism
Han-Ting Zhang1 PhD, MD, Alicia M Crissman1 BS, Nandakumar R Dorairaj1 MS, L Judson Chandler2 Ph.D and James M O'Donnell1 Ph.D |
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1Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, LA 71130, USA
2Departments of Physiology/Neuroscience and Psychiatry, Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC 29425, USA
Correspondence: Dr Han-Ting Zhang, Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport, LA 71130, USA, Tel.: 318-675-6632, Fax: 318-675-7857, Email: hzhang@lsumc.edu
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ABSTRACT
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Rolipram, 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] = 11.10; p < .0001 and F[4,64] = 2.53; p < .05, respectively) at doses of 0.01-0.1 mg/kg in the radial-arm maze task. Similar antagonism by rolipram of the effects of MK-801 was observed on inhibitory avoidance behavior (F[3,35] = 190.8; p < .0001). In vitro evidence suggests that an increase in cAMP concentrations may mediate the observed behavioral effects of rolipram. In the absence of PDE4 inhibition, NMDA did not increase cAMP concentrations in primary cultures of rat cerebral cortical neurons. However, when PDE4 was inhibited with rolipram, NMDA markedly elevated cAMP. These observations suggest that PDE4 is an integral component of the NMDA receptor-mediated signal transduction pathway involved in memory processes. Inhibitors of PDE4 may act on this pathway to produce their effects on memory and may represent a new class of cognitive enhancers.
Keywords: Rolipram; MK-801; Cyclic AMP; Phosphodiesterase; NMDA receptor; Memory |
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