PROTECTIVE EFFECTS OF MK-801 ON METHAMPHETAMINE-INDUCED DEPLETION OF DOPAMINERGIC AND SEROTONERGIC TERMINALS AND STRIATAL ASTROCYTIC RESPONSE - AN IMMUNOHISTOCHEMICAL STUDY

It has been shown previously that methamphetamine induces dopaminergic nerve terminal degeneration, serotonin depletion and striatal reactiv e astrogliosis, and that the noncompetitive N-methyl-D-aspartate (NMDA ) antagonist MK-801 can block methamphetamine (MA)-induced depletion o f 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 alterati ons of dopaminergic and serotonergic terminals and striatal astrocytic responses. Adult male rats were treated with methamphetamine (4 injec tions of 10 mg/kg at 2 hour intervals) in conjunction with MK-801 whic h was administered 15 min before each methamphetamine administration a t doses of 1 mg/kg or 2 mg/kg. Brains were examined three days followi ng 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 NMD A 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 th ree of nine MA-MK-801-treated animals. This indicates that the protect ive effects of MK-801 on MA-induced dopaminergic terminal degeneration varies among animals with complete protection in most animals and par tial protection in the others using the present doses and dosing regim en. (C) 1995 Wiley-Liss, Inc.