Perseverative behavior underlying attentional set-shifting deficits in rats chronically treated with the neurotoxin 3-nitropropionic acid

Huntington's disease (HD) is generally considered a prototypic motor disord er, but cognitive deficits are also prominent features of the disease. Syst emic administration of the mitochondrial toxin 3-nitropropionic acid (3NP) has been proposed to be a phenotypic model of HD in rats and nonhuman prima tes. In this study, we investigated the effect of 5 days continuous subcuta neous infusion of 3NP on motor and cognitive abilities in Lewis rats. Intox icated animals developed a motor syndrome consisting of bradykinesia as wel l as gait abnormalities and dystonic hindlimbs. Results from learning tasks showed that these rats: (1) did not exhibit learning deficits per se in ou r discrimination task but showed impairments in inhibiting behavioral respo nses when a transfer of learning (to new stimuli) or a transfer of response (new position of the lever) was required; (2) showed a marked tendency to persevere in choosing the compartment they previously visited in a T maze, thus leading to a clear retardation in learning a reinforced alternation ta sk; and (3) did not show any memory deficit when a delay was introduced. Si x months later, histological analyses showed severe neurodegeneration withi n the lateral striatum accompanied by apparent cell loss in the ventral pal lidum and entopedoncular nucleus. We suggest that the 3NP rat model of basa l ganglia neurodegeneration may provide a useful model for studying certain fundamental aspects of the physiopathology of HD and for evaluating the fu nctional efficacy of new therapeutic strategies. (C) 2001 Academic Press.