Increasing evidence indicates that the neuronal gastrin-releasing peptide-preferring bombesin receptor (GRPR) is a key molecular regulator of fear memory formation. However, the downstream signaling events remain poorly understood. The protooncogene product phosphoinositide 3-kinase (PI3K) has been implicated in regulating memory formation, as well as in mediating cellular responses to GRPR activation in glioma and neuroblastoma cells. We show here that GRPR modulation of fear memory consolidation in the rat hippocampus requires PI3K activation. Male Wistar rats received bilateral infusions of the GRPR agonist bombesin (BB) or the PI3K inhibitor LY294002 into the CA1 region of the dorsal hippocampus immediately after inhibitory avoidance (IA) conditioning. BB enhanced, whereas LY294002 impaired, IA memory retention. The BB-induced memory enhancement was blocked by coinfusion of either a GRPR antagonist or LY294002. These findings provide the first evidence suggesting that PI3K signaling is required for GRPR regulation of CNS function.