The role of glutamate in the neurotoxic effects of methamphetamine
The role of glutamate in the neurotoxic effects of methamphetamine
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DOI：
10.1111/j.1749-6632.1996.tb17452.x
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发表时间：
1996-01-01
期刊：
影响因子：
--
通讯作者：
Koyama, T
中科院分区：
文献类型：
--
作者：
Ohmori, T;Abekawa, T;Koyama, T
Repeated administration of high doses of methamphetamine (MA) decreases neuronal concentrations of dopamine (DA), serotonin (5-HT) and their metabolites as well as the activity of their biosynthetic enzymes, tyrosine hydroxylase and tryptophan hydroxylase, respectively. Previous studies demonstrated that the toxic effect of MA on the dopaminergic and serotonergic systems is likely related to MA-induced increase in DA release and subsequent activation of DA receptor^.^*^-'O'dell et a1.* have suggested that the remarkable increase in DA release observed after repeated MA injections may be linked to striatal DA damage. Recently, glutamatargic systems were also suggested to be involved in MA-induced neurotoxicity. For instance, Sonsalla et~ 1.~~'~ showed that competitive and noncompetitive N-methyl-D-aspartate (NMDA) antagonists can prevent the decrease in tyrosine hydroxylase activity and dopamine content in the mouse striatum produced by large doses of MA. MK-801, a noncompetitive NMDA antagonist, was also shown to prevent the toxicity of MA on the striatal serotonergic system." Furthermore, Nash et a1. 12 showed that a toxic dose of MA increased extracellular concentrations of glutamate in the striatum. These results suggest a role of excitatory amino acids in MA-induced dopaminergic and serotonergic neurotoxicity in the striatum.The present study was undertaken to further elucidate the roles of dopaminergic and glutamatargic neurotransmission in MA-induced neurotoxicity. Firstly, we confirmed and extended previous findings that both competitive and noncompetitive NMDA antagonists prevented MA-induced dopaminergic and serotonergic neurotoxicity in various brain regions. Secondly, we conducted a microdialysis study to examine effects of repeated administration of a high dose of MA (5 mg/kg, sc, at 2-hr intervals, 4 injections) on extracellular concentrations of DA and glutamate not only in the striatum but also in the nucleus accumbens.
