Abstract
Non-motor symptoms, including psychiatric disorders, are increasingly recognized as a major challenge in the treatment of Parkinson's disease (PD). These ailments, which often appear in the early stage of the disease, affect a large number of patients and are only partly resolved by conventional antiparkinsonian medications, such as L-DOPA. Here, we investigated non-motor symptoms of PD in a mouse model based on bilateral injection of the toxin 6-hydroxydopamine (6-OHDA) in the dorsal striatum. This model presented only subtle gait modifications, which did not affect horizontal motor activity in the open-field test. Bilateral 6-OHDA lesion also impaired olfactory discrimination, in line with the anosmia typically observed in early stage parkinsonism. The effect of 6-OHDA was then examined for mood-related dysfunctions. Lesioned mice showed increased immobility in the forced swim test and tail suspension test, two behavioral paradigms of depression. Moreover, the lesion exerted anxiogenic effects, as shown by reduced time spent in the open arms, in the elevated plus maze test, and by increased thigmotaxis in the open-field test. L-DOPA did not modify depressive- and anxiety-like behaviors, which were instead counteracted by the dopamine D2/D3 receptor agonist, pramipexole. Reboxetine, a noradrenaline reuptake inhibitor, was also able to revert the depressive and anxiogenic effects produced by the lesion with 6-OHDA. Interestingly, pre-treatment with desipramine prior to injection of 6-OHDA, which is commonly used to preserve noradrenaline neurons, did not modify the effect of the lesion on depressive- and anxiety-like behaviors. Thus, in the present model, mood-related conditions are independent of the reduction of noradrenaline caused by 6-OHDA. Based on these findings we propose that the anti-depressive and anxiolytic action of reboxetine is mediated by promoting dopamine transmission through blockade of dopamine uptake from residual noradrenergic terminals.
Highlights
Parkinson’s disease (PD) is classically defined by the progressive degeneration of the dopaminergic nigro-striatal pathway and by the emergence of rigidity, tremor, and bradykinesia (Braak et al, 2003; Jankovic, 2008)
6-OHDA-lesioned mice were analyzed for step cycle regularity, which indicates the frequency of correct step cycles during movement (Redondo-Castro et al, 2013)
In this study we show that a partial bilateral lesion of the dorsal striatum with 6-OHDA results in a subtle impairment of gait dynamics, accompanied by olfactory deficit, depression- and anxiety-like behavior
Summary
Parkinson’s disease (PD) is classically defined by the progressive degeneration of the dopaminergic nigro-striatal pathway and by the emergence of rigidity, tremor, and bradykinesia (Braak et al, 2003; Jankovic, 2008). L-DOPA remains the gold standard therapy for the motor symptoms of PD, its efficacy on mood-related dysfunctions is limited and its chronic administration correlates with the emergence of depression and anxiety (Damasio et al, 1971; Marsh and Markham, 1973; Vazquez et al, 1993; Choi et al, 2000; Kim et al, 2009; Negre-Pages et al, 2010; Eskow Jaunarajs et al, 2011). The use of L-DOPA is complicated by the development of motor side effects such as dyskinesia (Obeso et al, 2000). In this context, drugs acting preferentially on dopamine D2 receptors (D2Rs) and D3 receptors (D3Rs) represent a potential alternative (Hametner et al, 2012). The D2R/D3R agonist, pramipexole, has been shown to reduce depression and anxiety in clinical trials (Leentjens et al, 2009; Barone et al, 2010)
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