title: MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.
abstract: 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.
authors.affiliation: Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: R T
authors.initials: RT
authors.lastname: Layer
authors.forename: L R
authors.initials: LR
authors.lastname: Bland
authors.forename: P
authors.initials: P
authors.lastname: Skolnick
mesh_terms: 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
chemical_list: 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