On the pharmacological phenocopying of memory mutations in Drosophila: alkylxanthines accelerate memory decay.

Theophylline and 3-isobutyl-1-methylxanthine, two cyclic nucleotide phosphodiesterase inhibitors, when fed to wild-type Drosophila adults, cause the rapid decay of learning index after training in a shock-odor learning paradigm. The drugs practically do not affect the olfactory acuity of flies, hence they influence the learning/memory process itself. The time courses of memory decay resemble those of the memory mutants rutabaga and amnesiac and, to a lesser extent, dunce2 and dunceM11. Theophylline further deteriorates the learning performance of dunceM11. Biochemical characterization of the inhibition of the two major phosphodiesterase isoenzymes in Drosophila by theophylline predicts only a slight inhibition of these enzymes in vivo, in accordance with the unchanged level of cAMP in wild-type fly heads during drug feeding. 8-Phenyltheophylline, an adenosine receptor antagonist in mammals, slightly retards memory decay in the wild-type. It is suggested that alkylxanthines induce memory decay in Drosophila by interfering with cAMP dynamics at more than one point of its metabolism.