We investigated the involvement of PKA and PKC signaling in a negatively reinforced operant learning paradigm in "Aplysia", learning that food is inedible (LFI). In vivo injection of PKA or PKC inhibitors blocked long-term LFI memory formation. Moreover, a persistent phase of PKA activity, although not PKC activity, was necessary for long-term memory. Surprisingly, neither PKA nor PKC activity was required for associative short-term LFI memory. Additionally, PKA and PKC were not required for the retrieval of short- or long-term memory (STM and LTM, respectively). These studies have identified key differences between the mechanisms underlying nonassociative sensitization, operant reward learning, and LFI memory in "Aplysia".