We studied the distributions of four different cyclic AMP-specific phosphodiesterase isoform mRNAs (APDE1-4) and compared them with that of 63 kDa calmodulin-stimulated phosphodiesterase (CPDE) in the rat brain by in situ hybridization histochemistry using specific radiolabeled oligonucleotides. The distribution patterns were unique for all the APDE isoforms examined here. Although no significant signals for APDE1 could be detected anywhere in the rat brain, all other isoforms were expressed ubiquitously but unevenly and showed overlapping distribution patterns. Among all the APDE isoforms studied here, APDE3 showed the strongest and the most extensive expression. Its distribution pattern implies that it may modulate different cellular processes associated with learning and memory. Compared to APDE3, the levels of expression of APDE2 and APDE4 were weaker, the latter showing the weakest expression. Our study suggests that different isoforms of APDE are expressed together in the same class of neurons implying complex interactions among different signaling pathways, thereby mediating distinct and specific functions.