Abstract
Despite being the most effective treatment for Parkinson’s disease, L-DOPA causes a development of dyskinetic movements in the majority of treated patients. L-DOPA-induced dyskinesia is attributed to a dysregulated dopamine transmission within the basal ganglia, but serotonergic and noradrenergic systems are believed to play an important modulatory role. In this study, we have addressed the role of the locus coeruleus nucleus (LC) in a rat model of L-DOPA-induced dyskinesia. Single-unit extracellular recordings in vivo and behavioural and immunohistochemical approaches were applied in rats rendered dyskinetic by the destruction of the nigrostriatal dopamine neurons followed by chronic treatment with L-DOPA. The results showed that L-DOPA treatment reversed the change induced by 6-hydroxydopamine lesions on LC neuronal activity. The severity of the abnormal involuntary movements induced by L-DOPA correlated with the basal firing parameters of LC neuronal activity. Systemic administration of the LC-selective noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine did not modify axial, limb, and orolingual dyskinesia, whereas chemical destruction of the LC with ibotenic acid significantly increased the abnormal involuntary movement scores. These results are the first to demonstrate altered LC neuronal activity in 6-OHDA lesioned rats treated with L-DOPA, and indicate that an intact noradrenergic system may limit the severity of this movement disorder.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative process that causes the most common movement disorder of basal ganglia origin [1]
There is evidence implicating the noradrenergic system in L-DOPA-induced dyskinesias (LID): (1) LDOPA may be transformed into noradrenaline [8], and radioligand binding data demonstrate that dopamine produced from L-DOPA and some L-DOPA metabolites bind with high affinity D1 and D2 dopamine receptors, and to a2A and a2C-adrenoceptors [9]; (2) post-mortem studies have revealed a substantial loss of noradrenergic neurons [10,11], a decrease in noradrenaline levels in the brain [12,13] and reduced levels of the noradrenaline transporter in several noradrenergic areas in the brains of PD patients [14]; (3) studies using a2-adrenoceptor antagonists, such as idazoxan, yohimbine and fipamezole, show a significant reduction in dyskinesia in 6-hydroxydopamine (6OHDA)-lesioned rats [15], 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates [16,17,18,19] and PD patients [20]
We examined the effects of locus coeruleus nucleus (LC) damage on the severity of LID and we recorded single unit extracellular activities from LC neurons
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative process that causes the most common movement disorder of basal ganglia origin [1]. Long-term administration of L-DOPA induces abnormal involuntary movements known as L-DOPA-induced dyskinesias (LID). These motor complications are discomforting and potentially disabling, and affect up to 40% of PD patients within 5 years of treatment [3]. A1adrenoceptors contribute to L-DOPA-induced hyperactivity in MPTP-lesioned macaques [21]
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