Objective:To examine the regulatory effect of corticotrophin-releasing hormone (CRH) on glutamate-mediated current (IGLU) in cultured hippocampal neurons and to study the related mechanism. Methods: Immunofluorescence analysis was used to investigate whether the cultured hippocampal neurons express CRH receptors, and the whole-cell patch-clamp technique was used to examine the direct modulation of CRH on IGLU and the possible intracellular signal pathway. Results: Two minutes’ exposure to CRH obviously depressed IGLU in the neurons in a dose-dependent manner. CRH receptor antagonist α-helical CRH or CRH receptor type 1 (CRHR1) antagonist antalarmin completely blocked CRH-induced depression of IGLU; whereas, CRH receptor type 2 (CRHR2) antagonist astressin-2B failed to block the effects of CRH. Application of the PKC inhibitor G6976 totally blocked the CRH-induced decrease of IGLU. Conclusion: CRH can inhibit IGLU in primary cultured hippocampal neurons, which is mediated by CRHR1 and may involve the PKC signal pathway.