Partial dopaminergic denervation-induced impairment in stimulus discrimination acquisition in parkinsonian rats: A model for early Parkinson's disease

摘要

Parkinson's disease (PD) produces progressive nigrostriatal dopamine (DA) denervation resulting in cognitive and motor impairment. However, it is unknown whether cognitive impairments, such as instrumental learning deficits, are associated with the early stage PD-induced mild DA denervation. The current study sought to model early PD-induced instrumental learning impairments by assessing the effects of low dose (5.5 mu g), bilateral 60HDA-induced striatal DA denervation on acquisition of instrumental stimulus discrimination in rats. 60HDA (n = 20) or sham (n = 10) lesioned rats were tested for stimulus discrimination acquisition either 1 or 2 weeks post surgical lesion. Stimulus discrimination acquisition across 10 daily sessions was used to assess discriminative accuracy, or a probability measure of the shift toward reinforced responding under one stimulus condition (S-d) away from extinction, when reinforcement was withheld, under another (S-d phase). Striatal DA denervation was assayed by tyrosine hydroxylase (TH) staining intensity. Results indicated that 60HDA lesions produced significant loss of dorsal striatal TH staining intensity and marked impairment in discrimination acquisition, without inducing akinetic motor deficits. Rather 60HDA-induced impairment was associated with perseveration during extinction (S-Delta phase). These findings suggest that partial, bilateral striatal DA denervation produces instrumental learning deficits, prior to the onset of gross motor impairment, and suggest that the current model is useful for investigating mild nigrostriatal DA denervation associated with early stage clinical PD. (C) 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.