SYSTEMIC 3-NITROPROPIONIC ACID - BEHAVIORAL DEFICITS AND STRIATAL DAMAGE IN ADULT-RATS

Previous animal studies have demonstrated that systemic administration of 3-nitropropionic acid (3-NP) leads to neuropathological changes si milar to those seen in Huntington's disease (HD). Recently, we reporte d hypoactivity in 6- and 10-week old rats treated with systemic 3-NP ( IF, 10 mg/kg/day) once every 4 days for 28 days. Although these behavi oral results seem to differ from the observed hyperactivity in most ex citotoxic models of HD, 3-NP may provide a better model of juvenile on set and advanced HD. In the present study, older rats were similarly t reated with 3-NP to further characterize the reported age dependency o f striatal neuronal death caused by 3-NP. Hypoactivity was observed in 14- and 28-week old rats with the latter demonstrating more profound features. The present study also provided the first direct evidence of a 3-NP effect an passive avoidance behavior. Experimental and control animals showed no significant difference in daytime acquisition and r etention of a passive avoidance task. However, when the retention test s were conducted during the night time (in contrast to previous daytim e tests), 3-NP-treated animals exhibited significant retention deficit s. In addition, the neuropathological effects of 3-NP were determined by Nissl, AChE and NADPH-diaphorase histochemistry. Metabolic activity was studied using cytochrome oxidase activity as an index. Results re vealed striatal glial infiltration, loss of intrinsic striatal choline rgic neurons, but some sparing of large AChE positive neurons, minimal damage of NADPH-diaphorase-containing neurons, and very slight, if an y, alterations in cytochrome oxidase activity. In summary, the present results revealed that long-term systemic administration of 3-NP leads to a) an age-dependent hypoactivity, b) a contextual retention defici t in passive avoidance, and c) a selective destruction of striatal neu ronal populations.