MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.
Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.
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Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
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Skolnick
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D018009:Receptors, Glycine / Q000187:drug effects; D013331:Strychnine / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D018009:Receptors, Glycine; D015102:3,4-Dihydroxyphenylacetic Acid; C023863:1-aminocyclopropane-1-carboxylic acid; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid; D013331:Strychnine; C057013:7-chlorokynurenic acid; D004298:Dopamine