Effect of the additional noradrenergic neurodegeneration to 6-OHDA-lesioned rats in levodopa-induced dyskinesias and in cognitive disturbances

Abstract

Parkinson's disease is a motor and cognitive disorder characterised by a progressive loss of the substantia nigra pars compacta (SNc) dopaminergic neurons as well as of the locus coeruleus (LC) noradrenergic neurons. It has been suggested that LC neurodegeneration might influence levodopa-induced motor disturbances and cognitive performance. We investigated the influence of dopaminergic and noradrenergic lesions on levodopa-induced dyskinesias and on working memory in rats. Two groups of animals were used: (1) rats with a dopaminergic lesion induced by a unilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA), and (2) rats with a combined lesion of the dopaminergic and noradrenergic systems induced by 6-OHDA and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), respectively. Dyskinesias were evaluated on days 1, 8, 15 and 22 of chronic levodopa treatment (6 mg/kg, twice at day, i.p.). Working memory was evaluated by a radial-arm maze (1) before lesions, (2) before levodopa administration and (3) after 22 days of levodopa treatment. Total, axial, limb and orofacial dyskinesias not differed significantly between both groups. Working memory tasks worsened in both lesioned groups reaching significance in terms of time of performance (P < 0.05). The number of repeated entries in the same arm (errors) was only significant in the double-lesioned group (P < 0.05). This behaviour was not different from the one observed after chronic levodopa treatment. These results suggest that levodopa-induced dyskinesias in the 6-OHDA-lesioned rats were not affected by the additional noradrenergic lesion, whereas this last condition was sufficient to worse the cognitive performance deficit produced by the dopaminergic lesion.