Partial bilateral dopaminergic denervation to dorsal striatum and levodopa effects on simple operant discrimination learning in parkinsonian rats.

摘要

Knowledge of pathogenic mechanisms contributing to cognitive function in Parkinson's disease has advanced rapidly during the past decade. The major aim of the current study was to investigate potential effects of partial dopaminergic denervation on skilled operant learning in parkinsonian rats in order to model cognitive deficits associated with early stage Parkinson's disease. Experiment 1 investigated the effects of partial (5.5 microg) bilateral 6-hydroxydopamine (6-OHDA) lesions to the dorsal striatum in acquisition of a simple operant discrimination task one and two weeks following surgery. Animals were tested for 10 once-daily sessions and assessed on performance in the discrimination operant task and rates of responding. Biochemical assays were then conducted on striatal TH positive terminal immunostaining intensity in the dorsal striatum. Experiment 2 investigated levodopa (LD)-replacement therapy in ameliorating the impairment in simple discrimination acquisition two weeks after 6-OHDA surgery. Animals in Experiment 2 received either vehicle (PBS) or levodopa (5 mg/kg, i.p.; 10 mg/kg, i.p.) prior to starting the task. Results indicated that 6-OHDA-lesioned animals were impaired in the acquisition of a simple operant discrimination task after both one and two weeks following the surgery, compared to sham-lesioned animals. This was not associated with alterations in rate of responding during the task, suggesting that motor function was spared by the lesions. Biochemical data suggested a mild reduction in striatal TH positive immunostaining intensity. Results from Experiment 2 indicated that LD treatment for 6-OHDA-induced parkinsonian animals provided partial benefit in attenuating deficits in discrimination acquisition. These results have implications that partial dopamine deficiency in the dorsal striatum at early stage in PD pathogenesis contributes to cognitive impairments in skilled learning. Findings from the present study also suggest novel approaches to safer and more effective ways to diagnose and manage cognitive dysfunction in early stage PD and other dopamine disease states.