QUANTIFIABLE BRADYKINESIA, GAIT ABNORMALITIES AND HUNTINGTONS-DISEASE-LIKE STRIATAL LESIONS IN RATS CHRONICALLY TREATED WITH 3-NITROPROPIONIC ACID

Impairment in energy metabolism is thought to be involved in the aetio logy of Huntington's disease. In line with this hypothesis, chronic sy stemic administration of the mitochondrial toxin 3-nitropropionic acid to rats and monkeys produces selective striatal lesions similar to Hu ntington's disease. The present study examined whether rats treated wi th varying regimen of 3-nitropropionic acid could present motor abnorm alities reminiscent of Huntington's disease symptomatology, correlated with Huntington's disease specific striatal symptomatology. Subacute 3-nitropropionic acid treatment (15 mg/kg per day intraperitoneally fo r 10 days) produced dramatic motor symptoms associated with extensive neuronal loss and gliosis in the lateral striatum as well as severe hi ppocampal degeneration in 50% of the cases. In contrast, chronic 3-nit ropropionic acid treatment (10 mg/kg per day subcutaneously for one mo nth) led to more subtle excitotoxic-like lesions, selective for the do rsolateral striatum and more closely resembling Huntington's disease s triatal pathology. Animals with these Huntington's disease-like lesion s showed spontaneous motor symptoms including mild dystonia, bradykine sia and gait abnormalities, which were barely detectable on visual ins pection but could be readily identified and quantified by computerized video analysis. In these chronic animals, the degree of striatal neur onal loss was significantly correlated with the severity of spontaneou s motor abnormalities, as is the case in Huntington's disease. The pre sent study demonstrates that chronic low-dose 3-nitropropionic acid tr eatment in rats results in a valuable model of both the histological f eatures and motor deficits which occur in Huntington's disease. Despit e the interanimal variability in terms of response to 3-nitropropionic acid treatment, this rat model may be particularly useful for evaluat ing the functional benefits of new therapeutic strategies for Huntingt on's disease, particularly those aiming to reduce the severity of moto r symptoms. (C) 1997 IBRO.