title: Chronic quinolinic acid lesions in rats closely resemble Huntington's disease.
abstract: We previously found a relative sparing of somatostatin and neuropeptide Y neurons 1 week after producing striatal lesions with NMDA receptor agonists. These results are similar to postmortem findings in Huntington's disease (HD), though in this illness there are two- to threefold increases in striatal somatostatin and neuropeptide Y concentrations, which may be due to striatal atrophy. In the present study, we examined the effects of striatal excitotoxin lesions at 6 months and 1 yr, because these lesions exhibit striatal shrinkage and atrophy similar to that occurring in HD striatum. At 6 months and 1 yr, lesions with the NMDA receptor agonist quinolinic acid (QA) resulted in significant increases (up to twofold) in concentrations of somatostatin and neuropeptide Y immunoreactivity, while concentrations of GABA, substance P immunoreactivity, and ChAT activity were significantly reduced. In contrast, somatostatin and neuropeptide Y concentrations did not increase 6 months after kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) lesions. At both 6 months and 1 yr, QA lesions showed striking sparing of NADPH-diaphorase neurons as compared with both AMPA and KA lesions, neither of which showed preferential sparing of these neurons. Long-term QA lesions also resulted in significant increases in concentrations of both 5-HT and 5-hydroxyindoleacetic acid (HIAA), similar to findings in HD. Chronic QA lesions therefore closely resemble the neurochemical features of HD, because they result in increases in somatostatin and neuropeptide Y and in 5-HT and HIAA. These findings strengthen the possibility that an NMDA receptor-mediated excitotoxic process could play a role in the pathogenesis of HD.
authors.affiliation: Neurochemistry and Experimental Neuropathology Laboratories, Massachusetts General Hospital, Boston 02114.
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
authors.forename: R J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: K J
authors.initials: KJ
authors.lastname: Swartz
authors.forename: N W
authors.initials: NW
authors.lastname: Kowall
mesh_terms: D000818:Animals; D001284:Atrophy; D001679:Biogenic Amines / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005971:Glutamates / Q000378:metabolism; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000378:metabolism; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013004:Somatostatin / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001679:Biogenic Amines; D005971:Glutamates; D009478:Neuropeptide Y; D011805:Quinolinic Acids; D007051:Ibotenic Acid; D013373:Substance P; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D009252:NADPH Dehydrogenase; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid; D007608:Kainic Acid