Long-term potentiation (LTP) in the hippocampus is a long-lasting enhancement of synaptic efficacy produced by a brief, high frequency repetitive stimulation of afferents. LTP has generated a great deal of interest as a candidate mechanism in learning and memory. A recent in vivo study has shown that depletion of norepinephrine (NE) or serotonin (5-hydroxytryptamine, 5-HT) reduced LTP in the dentate gyrus produced by stimulation of the perforant path. However, it was impossible to tell whether this resulted from depletion in the hippocampus, itself, or was secondary to depletion of other brain areas, and no comparison between hippocampal cell fields was done. Therefore, we have examined the effects of depletion of NE or 5-HT on LTP in the dentate and field CA1 of the isolated in vitro hippocampal slice preparation. We report here that NE depletion markedly reduces the occurrence and amplitude of LTP in the dentate, but not in field CA1. In contrast, depletion of 5-HT does not prevent occurrence of LTP in either area. Furthermore, pharmacologic data indicate that beta-receptor stimulation of adenylate cyclase is probably the mechanism of NE's action in the production of LTP in the dentate. These results suggest that endogenous hippocampal NE is more important to LTP in the dentate than is endogenous 5-HT.