Abstract: Objective To investigate the effects of N-acetylcysteine (NAC ) on constitutive (agonist-independent) and agonist-stimulated mGlu1a-mediated excitotoxicity associated with mGlu1a overexpression in HEK293 cells. Methods The signaling pathways, cell viability, the surface expression of mGlu1a and the intracellular oxidative stress were detected by western blot, MTT, trypan blue-exclusion assay,Elisa, Fluorescence-based Detection of Cellular ROS and HPLC methods. Results In mGlu1a-transfected cells and mGlu1a-transfected, DHPG-induced cells, NAC inhibited the excitotoxicity of mGlu1a by different mechanisms. Under two conditions, NAC prohibited the production of ROS and modulated the intracellular glutathione redox potential. Conclusion This study further suggested that the complex effects of mGlu1a activity under different conditions might play different role in the progress of many diseases, especially in terms of the effects of increased receptor expression.