Modulation by serotonin of glutamate-induced lethality in mice.
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.
Kamei
J
J
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Igarashi
H
H
Kasuya
Y
Y
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000494:pharmacology; D010852:Picrotoxin / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology*; D012970:Sodium Glutamate / Q000633:toxicity*; D013331:Strychnine / Q000633:toxicity; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014364:Tryptophan / Q000494:pharmacology; D019805:alpha-Methyltyrosine
D006916:5-Hydroxytryptophan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010134:Fenclonine; D008781:Methyltyrosines; D016202:N-Methylaspartate; D010433:Pentylenetetrazole; D010852:Picrotoxin; D010879:Piperazines; D012110:Reserpine; D012701:Serotonin; D012970:Sodium Glutamate; D013331:Strychnine; D013764:Tetrahydronaphthalenes; D014364:Tryptophan; D019805:alpha-Methyltyrosine; C018406:1-(3-trifluoromethylphenyl)piperazine