An intact mesocortical dopaminergic (DA) input to the prefrontal cortex (PFC) has been reported to be necessary for long-term potentiation (LTP) to occur at hippocampal-prefrontal cortex synapses. Here, we investigated the role of D1 and D2 receptors in this NMDA receptor-dependent LTP. Local infusion of the D1 agonist SKF81297 at an optimal dose induced a sustained enhancement of hippocampal-PFC LTP, whereas the D1 antagonist SCH23390 caused a dose-related impairment of its induction. The D1 agonist effect was mimicked by infusion of a low dose of the adenylyl cyclase activator forskolin, whereas LTP was severely attenuated with a protein kinase A inhibitor, Rp-cAMPS. To further assess the complex interplay between DA and NMDA receptors, changes in extracellular DA levels in the PFC were estimated during LTP, and a significant increase was observed immediately after tetanus. Taken together, these data suggest that D1 but not D2 receptors are crucial for the DA control of the NMDA receptor-mediated synaptic response on a specific excitatory input to the PFC. The interactions of these receptors may play a crucial role in the storage and transfer of hippocampal information in the PFC.