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-aspar tate (NMDA) receptor antagonists and use-dependent cation channel bloc kers attenuate METH-induced damage. The objectives of the present stud y were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glyci ne receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a almost-equal-to 70.9% depletion of striatal dopamine (DA) and almost-equal-to 62.7% depletion of dihydroxyphenylac etic acid (DOPAC) content, respectively. A significant protection agai nst METH-induced DA and DOPAC depletion was afforded by the use-depend ent channel blocker, MK-801. The competitive glycine antagonist 7-chlo rokynurenic 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) we re ineffective against METH-induced toxicity despite their abilities t o attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do n ot possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.