The dunce locus of Drosophila melanogaster codes for a low Km, cAMP phosphodiesterase. The correct function of this gene is required for normal learning and memory activity in flies, because dunce mutants fail in tests of behavioral conditioning. These observations have indicated that cAMP regulation is an important aspect of the biochemistry underlying learning and memory processes in insects. To determine whether the locus is functionally conserved in mammals, we have expressed dunce gene homologs from the rat in a yeast expression system. We find that the rat homologs encode low Km, cAMP phosphodiesterases similar to that coded for by the Drosophila dunce+ gene and, more importantly, that the mammalian enzymes are inhibited by rolipram and RO 20-1724, drugs with antidepressant properties. Surprisingly, the dunce-encoded phosphodiesterase was not inhibited by rolipram or RO 20-1724. These findings suggest that the phosphodiesterases, through their regulation of cAMP levels, influence learning and memory in insects and mood in mammals.