Protective effects of MK‐801 on methamphetamine‐induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: An immunohistochemical study

Cunfeng Pu, Charles V. Vorhees

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Abstract

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. © 1995 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)97-104
Number of pages8
JournalSynapse
Volume19
Issue number2
DOIs
StatePublished - Jan 1 1995

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Corpus Striatum
Methamphetamine
Neostriatum
Serotonin
Nerve Degeneration
Excitatory Amino Acids
Prosencephalon
Tyrosine
Dopamine
Immunohistochemistry
Injections
Brain
Enzymes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience

Cite this

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title = "Protective effects of MK‐801 on methamphetamine‐induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: An immunohistochemical study",
abstract = "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. {\circledC} 1995 Wiley‐Liss, Inc.",
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AB - 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. © 1995 Wiley‐Liss, Inc.

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