This study investigated the role of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the induction of long-term potentiation (LTP) in the hippocampal-prefrontal cortex pathway in vivo. Field potentials evoked by electrical stimulation of the CA1/subicular region were recorded in the prelimbic area of the prefrontal cortex under continuous perfusion of artificial cerebrospinal fluid in anaesthetized rats. High-frequency stimulation of the CA1/subicular region induced LTP of the evoked response in the prelimbic area of the prefrontal cortex. LTP was completely blocked when the selective NMDA receptor antagonist D-(-)2-amino-5-phosphonopentanoic acid (D-AP5; 200 microM), was perfused during the tetanus. Perfusion of D-AP5 did not affect normal transmission or pre-established LTP. These results demonstrate that induction of LTP in the hippocampal-prefrontal cortex pathway is an NMDA receptor-dependent process.