The administration of mGlu5 PAM, CDPPB, and mGlu2 PAM, LY487379, enhanced MK-801- or scopolamine-induced endothelial dysfunction as manifested by increased eNOS monomer content and eNOS monomer/total protein ratio and a decreased eNOS dimer/monomer ratio in frontal cortices and hippocampi of mice brains. Here, GRM5 is linked to endothelial dysfunction.