To investigate the effect of serotonin depletion on the intracerebroventricularly (i.c.v.) administered MK-801-induced plasma interleukin-6 (IL-6) levels, we pretreated mice with parachlorophenylalanine (PCPA, 300 mg/kg, i.p.) 3 d before an i.c.v. injection of MK-801 (1 microg). The i.c.v. MK-801-induced rise of plasma IL-6 level was markedly enhanced in the PCPA-pretreated mice. However, serotonin depletion by PCPA pretreatment did not affect the i.c.v. MK-801-induced increase in plasma corticosterone level. These results suggest that serotonergic system is involved in the suppressive regulation of MK-801-induced plasma IL-6 level.