Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 23; no. 2; pp. 198 - 204
• Main Authors: ZHANG, H.-T, CRISSMAN, A. M, DORAIRAJ, N. R, CHANDLER, L. J, O'DONNELL, J. M
• Format: Journal Article
• Language: English
• Published: New York, NY Nature Publishing 01-08-2000; Nature Publishing Group
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animal; Animals; Avoidance Learning - drug effects; Behavior; Biological and medical sciences; Cells, Cultured; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug toxicity and drugs side effects treatment; Electric Stimulation; Excitatory Amino Acid Antagonists - pharmacology; Fundamental and applied biological sciences. Psychology; Learning. Memory; Male; Maze Learning - drug effects; Medical sciences; Memory; Memory Disorders - chemically induced; Memory Disorders - drug therapy; N-Methylaspartate - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - therapeutic use; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Response rates; Rolipram - therapeutic use; Signal transduction; Toxicity: nervous system and muscle; Louisiana; United States > US; Reference memory; Memory disorder; Intraperitoneal administration; Cognitive disorder; Rat; Toxicity; Memory; Central nervous system; Cognition; Esterases; Glutamate receptor; Phosphoric diester hydrolases; Learning; Acquisition process; Antagonist; Mechanism of action; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Dizocilpine; Rodentia; Cyclic AMP; Enzyme inhibitor; Instrumental conditioning; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Neuron; Rolipram; Treatment; Animal; Hydrolases; Working memory; NMDA receptor; Avoidance; Brain (vertebrata)
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1016/S0893-133X(00)00108-1

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.