The cAMP signaling cascade has been implicated in several stages of memory formation. We have examined activation of this cascade by serotonin (5-HT) in the sensory neurons of Aplysia. We find that different patterns of 5-HT exposure induce three distinct modes of PKA activation. First, a single 5 min pulse induces transient (5 min) PKA activation that requires neither transcription nor translation. Second, 4-5 pulses induce intermediate-term persistent activation (3 hr duration) that requires translation but not transcription. Third, 5 pulses of 5-HT, as well as continuous (90 min) exposure, induce long-term persistent activation 20 hr later, which requires both transcription and translation. Thus, in the sensory neurons, different patterns of 5-HT give rise to three independent phases of PKA activation that differ in their induction requirements, their temporal profiles, and their molecular mechanisms.