Significance Neuropeptides represent the most diverse family of neurotransmitters with a wide distribution in the rodent brain. Cholecystokinin (CCK) is an octapeptide present in very high concentrations in the cortex, where it is expressed in several circuits. It has emerged as a useful marker, for example as an interneuron subpopulation, but its function is still unclear. Here we show that CCK, via its CCKB receptor, is essential for high-frequency stimulation-induced long-term potentiation, and that release of CCK is controlled by NMDA receptors. Thus, CCK may play an important role in memory formation.