Synergistic effects of chronic exposure to subthreshold concentrations of quinolinic acid and malonate in the rat striatum.

Adult rats received chronic intrastriatal dialytic exposure to quinolinic acid (QUIN), malonate, or a combination of QUIN and malonate. The combination of subthreshold concentrations of QUIN (4 mM) and malonate (400 mM) produced lesions larger than did either QUIN or malonate alone. The neurotoxic effect of QUIN combined with malonate was subsequently blocked by co-administration of the NMDA receptor antagonist MK-801 (1 mM). These findings indicate that malonate synergistically enhances NMDA receptor mediated excitotoxicity.

Chronic intrastriatal administration of quinolinic acid produces transient nocturnal hypermotility in the rat.

Adult male Sprague-Dawley rats were exposed to 15 mM quinolinic acid solution or vehicle via bilateral intrastriatal dialytic administration for a period of 3 weeks. Animals were tested twice weekly for spontaneous behaviors and nocturnal activity during the 3-week dialysis period and for the 3 weeks following cessation of the dialysis period treatment. Nocturnal activity increased significantly (p < 0.005) during the first week of quinolinic acid exposure compared to vehicle exposed animals. The increase in nocturnal activity subsequently diminished to near control levels by the end of the 3-week dialysis period. During the 3-week period following cessation of dialysis, no significant differences were seen between quinolinic acid and vehicle-exposed animals. In addition, no differences were noted between quinolinic acid and vehicle-exposed animals in spontaneous behaviors either in the 3-week dialysis period or the 3-week period following cessation of dialysis. The results of this study are in agreement with other recent findings of transient nocturnal hyperactivity following striatal damage in rats. One possible explanation for the transient nature of this behavioral change is a transient effect of excitotoxicity in the striatum. During initial exposure to excitotoxins, nocturnal hypermotility could result from premorbid changes in neural function. With continued exposure, this behavioral effect may then diminish as a result of subsequent widespread striatal cell death.

Chronic administration of malonic acid produces selective neural degeneration and transient changes in calbindin immunoreactivity in rat striatum.

Adult rats received chronic dialytic delivery devices that exposed the striatum to a 100 mM, 400 mM, or 4 M solution of the reversible succinate dehydrogenase inhibitor malonic acid (MA). Three weeks of exposure to 100 or 400 mM MA produced no significant reduction in striatal cytochrome oxidase staining, whereas striata chronically exposed to 1 and 4 M MA showed a significant and dose-related reduction in cytochrome oxidase staining. In striata exposed to 1 M MA, analysis of regions radial to the necrotic core revealed significant reduction of nissl cell staining with relative sparing of NADPH-diaphorase-containing neurons. Although 100 and 400 mM MA failed to produce lesions, both of these concentrations significantly decreased the number of striatal calbindin (CALB) immunoreactive perikarya. The reduction in CALB immunoreactivity was partly reversed in animals allowed to survive 4 weeks after cessation of exposure to 400 mM MA. These results indicate that, like striatal lesions produced by quinolinic acid, lesions produced by chronic exposure to MA possess a Huntington's disease-like pattern of selective neurodegeneration. In addition, exposure to subthreshold MA concentrations (100 and 400 mM) produce widespread transient changes in striatal CALB that may be associated with a premorbid state of neuronal dysfunction.

Chronic intrastriatal quinolinic acid produces reversible changes in perikaryal calbindin and parvalbumin immunoreactivity.

We recently reported the use of a chronic dialytic delivery system for intrastriatal administration of quinolinic acid in the rat. This system produces neurodegeneration with some characteristics similar to post mortem brain tissue from Huntington's disease patients, including reduced cytochrome oxidase staining, a decreased number of Nissl-stained neurons, and relative sparing of striatal NADPH-diaphorase containing neurons. The present findings show that chronic dialytic delivery of quinolinic acid also produces a Huntington's disease-like pattern of reduced calbindin and parvalbumin perikaryal immunoreactivity that is reversed in rats allowed four to eight weeks' recovery after cessation of quinolinic acid. Furthermore, cytochrome oxidase staining and the number of Nissl-stained cells were unchanged in the region of transient calbindin and parvalbumin immunoreactive perikaryal staining alterations. These results suggest that changes in calbindin and parvalbumin perikaryal immunoreactivity provide a relatively sensitive measure of quinolinic acid induced neurotoxicity. The reversible nature of reduced perikaryal immunoreactivity suggests a premorbid state of neurotoxicity, possibly marked by cellular redistribution of calbindin and parvalbumin.