MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclopepten-5,10-imine maleate), a non-competitive NMDA receptor antagonist (0.01-1 micrograms), injected intracerebroventricularly (i.c.v.) dose dependently increased the baseline levels of plasma interleukin-6 in mice. In the 1-h immobilization-stressed animals, MK-801 (1 micrograms) administered i.c.v. produced an additive increase of plasma interleukin-6. NMDA (N-methyl-D-aspartate) (3, 10 ng) administered i.c.v. attenuated dose dependently the 1-h immobilization stress-induced rise in plasma interleukin-6 level. Neither 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) (0.01-0.5 micrograms) nor alpha-methyl-4-carboxyphenylglycine (MCPG) (1-20 micrograms), antagonists of non-NMDA and metabotropic glutamate receptors, respectively, i.c.v. administered, affected the basal and stress-induced plasma interleukin-6 levels. These data indicate that NMDA receptors may be involved in the suppressive regulation of the plasma interleukin-6 levels.