Aminooxyacetic acid produces excitotoxic lesions in the rat striatum.
The neuropathological, biochemical, and behavioral effects of intrastriatal injection of aminooxyacetic acid (AOAA), a non-specific transaminase inhibitor, were examined in rats. AOAA, 0.1-1 mumol, produced neuronal damage when injected into the striatum of adult rats but failed to damage the striatum of 6-d-old or decorticated rats. AOAA-induced (0.25 mumol-1 mumol) striatal lesions in adult rats displayed excitotoxic characteristics and could be prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists (-)-2-amino-7-phosphono-heptanoate (AP7; 0.25 mumol) or kynurenate (KYNA; 0.5 mumol), but not by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX; 0.25 mumol). AOAA produced a dose-dependent reduction in striatal L-glutamate decarboxylase activity, as measured 14 d following intrastriatal injection, which could also be prevented by AP7 or KYNA, but not by NBQX. These findings suggest that AOAA-induced lesions are preferentially mediated by activation of the NMDA subtype of excitatory amino acid receptors. Behavioral studies revealed that the cataleptic response to haloperidol, 2 mg/kg, was decreased whereas the cataleptic response to arecoline, 15 mg/kg, and morphine, 15 mg/kg, was potentiated in AOAA lesioned animals 14 d following bilateral intrastriatal injections of AOAA, 0.25 and 1 mumol. In rats which received unilateral intrastriatal injection of AOAA, 0.1-1 mumol, apomorphine, 0.5 mg/kg, induced circling towards the lesioned side. Rats which received AP7, 0.25 mumol, or KYNA, 0.5 mumol, coadministered with AOAA, 0.25 mumol, behaved as vehicle-treated controls, while those which received NBQX, 0.25 mumol, and AOAA, 0.25 mumol, had behavioral patterns similar to those subjected to AOAA alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Urbańska
E
E
Department of Pharmacology, Medical School, Lublin, Poland.
Ikonomidou
C
C
Sieklucka
M
M
Turski
W A
WA
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002421:Caudate Nucleus / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D008854:Microscopy, Electron; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D000625:Aminooxyacetic Acid; D015763:2-Amino-5-phosphonovalerate; D005968:Glutamate Decarboxylase; D007736:Kynurenic Acid; C031231:2-amino-7-phosphonoheptanoic acid