To elucidate the role of carbon monoxide (CO) in hippocampal long-term potentiation (LTP), the effect of an inhibitor of heme oxygenase, which produces carbon monoxide, was investigated in the dentate gyrus of anesthetized rats. Administration of zinc protoporphyrin IX (100 nmol, i.c.v.) 30 min before the tetanic stimulation of 30 pulses at 60 Hz attenuated the intensity of LTP. However, this drug did not affect the established LTP. These results suggest that CO participates in the generation of LTP in vivo.