To determine the involvement of serotonergic mechanisms in glutamate-induced excitotoxicity, the effects on glutamate-induced lethality of drugs that modify serotonergic transmission were studied in mice. Monosodium glutamate (MSG; 6-10 g/kg, i.p.) produced a dose-related increase in lethality in mice. Pretreatment with reserpine (2.5 mg/kg, i.p., 5 hr) resulted in an increase in MSG-induced lethality. p-Chlorophenylalanine (PCPA; 300 mg/kg, i.p. 24 hr) specifically produced a reduction of more than 60% in the level of 5-HT in the brain. PCPA-treated mice were also more sensitive to the lethal effects of MSG. alpha-Methyl-p-tyrosine (300 mg/kg, i.p. 5 hr) produced a significant reduction in the levels of norepinephrine and dopamine in the brain, but the sensitivity to the lethal effects of MSG was unchanged. L-Tryptophan (300 and 500 mg/kg, i.p.) and 5-hydroxy-L-tryptophan (5-HTP; 3-30 mg/kg, i.p.), precursors of serotonin (5-HT), protected mice to a significant extent against MSG-induced lethality, in a dose-related manner. 1-(m-Trifluoromethylphenyl) piperazine (TFMPP; 50 mg/kg, i.p.), an agonist of 5-HT1 receptor, was also associated with protection against MSG-induced lethality. This protective effect was not observed in PCPA- or methysergide-treated mice. These results suggested that 5-HT in the brain may play an inhibitory role in MSG-induced excitotoxicity.