Corticotrophin-releasing hormone (CRH), the primary regulator of the neuroendocrine responses to stress, has been shown to modulate synaptic efficacy and the process of learning and memory in hippocampus. However, effects of CRH on N-methyl-D-aspartate (NMDA) receptor, the key receptor for synaptic plasticity, remain unclear. In primary cultured hippocampal neurons, using the technique of whole-cell patch-clamp recordings, we found that CRH (1 pmol/l - 10 nmol/l) inhibited NMDA-induced currents in a dose-dependent manner. This effect was reversed by the CRH receptor type 1 (CRH-R1) antagonist, antalarmin, but not by the CRH-R2 antagonist astressin-2B, suggesting that CRH-R1 mediated the inhibitory effect of CRH. Investigations on the signaling pathways of CRH showed that CRH dose-dependently induced phosphorylated PLC-3 expression and increased intracellular cAMP content in these cells. Blocking phospholipase C (PLC) activity with U73122 prevented CRH-induced depression of NMDA current, whereas blocking protein kinase A (H89) and adenylate cyclase (SQ 22536) failed to affect the CRH-induced depression of NMDA current. Application of IP₃ receptor antagonist, Ca²⁺ chelators or protein kinase C (PKC) inhibitors also mainly blocked CRH-induced depression of NMDA currents, suggesting involvement of PLC/IP₃R/Ca²⁺and PLC/PKC signaling pathways in CRH downregulation of NMDA receptors. Our results suggest that CRH may exert neuromodulatory actions on hippocampus through regulating NMDA receptor function.