It has been shown previously that methamphetamine induces dopaminergic nerve terminal degeneration, serotonin depletion and striatal reactive astrogliosis, and that the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 can block methamphetamine (MA)-induced depletion of dopamine and serotonin and reduction in activity of their synthetic enzymes. In this study, immunohistochemistry was used to evaluate the effect of MK-801 on methamphetamine-induced neuropathological alterations of dopaminergic and serotonergic terminals and striatal astrocytic responses. Adult male rats were treated with methamphetamine (4 injections of 10 mg/kg at 2 hour intervals) in conjunction with MK-801 which was administered 15 min before each methamphetamine administration at doses of 1 mg/kg or 2 mg/kg. Brains were examined three days following treatment. MK-801 administration prevented methamphetamine-induced depletion of 5-hydroxytryptophan (5-HT) terminals in the forebrain and depletion of tyrosine hydroxylase-positive dopaminergic terminals and astrocytic response in the neostriatum in most animals. These results support the concept that excitatory amino acids acting through an NMDA receptor are involved in methamphetamine-induced neuronal damage on dopaminergic and serotonergic terminal fields. A minor depletion of TH-positive terminals and astrogliosis in the neostriatum was seen in three of nine MA-MK-801-treated animals. This indicates that the protective effects of MK-801 on MA-induced dopaminergic terminal degeneration varies among animals with complete protection in most animals and partial protection in the others using the present doses and dosing regimen.