Acetylcholinesterase is well known to have noncholinergic functions. Only recently, however, has the salient part been identified of the molecule responsible for these nonclassical actions, a peptide of 14 amino acids towards the C-terminus of acetylcholinesterase. The aim of this study was to test the bioactivity of this 'acetylcholinesterase-peptide' using intracellular recordings in guinea-pig hippocampal slices. In the presence of tetrodotoxin, acetylcholinesterase-peptide alone affected neither the membrane potential nor the input resistance of CA1 neurons; however, a modulatory action was observed, as a concentration-dependent decrease of N-methyl-d-aspartic acid-induced depolarization. When calcium potentials were elicited by a depolarizing current pulse, application of acetylcholinesterase-peptide increased or reduced the degree of calcium spike firing in, respectively, the presence or absence of the N-methyl-d-aspartic acid antagonist d(-)-2-amino-5-phosphonopentanoic acid. In contrast, a peptide derived from the equivalent region of butyrylcholinesterase, which also hydrolyses acetylcholine, had no effect. In conclusion, acetylcholinesterase-peptide has a selective bioactivity in the hippocampus; it could thus offer new ways of targeting mechanisms of calcium-induced neurotoxicity.