Elsevier

Neurobiology of Disease

Volume 29, Issue 2, February 2008, Pages 327-335
Neurobiology of Disease

l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation

https://doi.org/10.1016/j.nbd.2007.10.001Get rights and content

Abstract

The emergence of levodopa (l-DOPA)-induced dyskinesia and motor fluctuations represents a major clinical problem in Parkinson's disease (PD). While it has been suggested that the daily dose of l-DOPA can play a critical role, the mechanisms linking l-DOPA dosage to the occurrence of motor complications have not yet been explored. Using an experimental model of PD we have recently demonstrated that long-term l-DOPA treatment leading to the induction of abnormal involuntary movements (AIMs) alters corticostriatal bidirectional synaptic plasticity. Dyskinetic animals, in fact, lack the ability to reverse previously induced long-term potentiation (LTP). This lack of depotentiation has been associated to a defect in erasing unessential motor information. Here chronic l-DOPA treatment was administered at two different doses to hemiparkinsonian rats, and electrophysiological recordings were subsequently performed from striatal spiny neurons. Both low and high doses of l-DOPA restored normal LTP, which was disrupted following dopamine (DA) denervation. By the end of the chronic treatment, however, while the low l-DOPA dose induced AIMs only in half of the rats, the high dose caused motor complications in all the treated animals. Interestingly, the dose-related expression of motor complications was associated with a lack of synaptic depotentiation. Our study provides further experimental evidence to support a direct correlation between the daily dosage of l-DOPA and the induction of motor complications and establishes a critical pathophysiological link between the lack of synaptic depotentiation and the expression of AIMs.

Introduction

Parkinson's disease (PD) is characterized by a massive degeneration of dopaminergic nigrostriatal neurons. When the large majority of dopaminergic neurons of the substantia nigra (SN) are lost (Ruberg et al., 1995) and their projections to the striatum degenerate, the basal ganglia are no longer able to effectively promote movement and PD symptoms appear.

Levodopa therapy (l-DOPA) is considered the gold-standard treatment for this neurodegenerative disease (Olanow et al., 2006). l-DOPA is a substitutive pharmacological agent directed towards a restoration of physiological dopamine (DA) concentrations in the striatum (Calabresi et al., 2000a, Olanow et al., 2006, Picconi et al., 2003). In the early phases of the disease, l-DOPA produces robust motor effects and it is well tolerated in the majority of the patients (Wolters et al., 2000). However, with the progression of PD and accompanying DA cell loss, the brain's capacity to restore and maintain physiological levels of DA in face of pulsatile l-DOPA administration is impaired (Cenci and Lundblad, 2006). This leads to development of motor fluctuations, dyskinesia and symptomatic deterioration (Jankovic, 2002, Jankovic, 2005, Marras et al., 2004). The incidence of such motor complications is dependent on several variables such as the age at disease onset and the duration of treatment (Jankovic, 2002, Jankovic, 2005). l-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and motor fluctuations have been well analyzed from a clinical point of view and represent a dramatic event in the natural history of PD patients (Fahn, 2000, Jankovic, 2005, Riley and Lang, 1993, Vidailhet et al., 1999).

In recent years, our understanding of the effects of l-DOPA on motor control has increased greatly, and the molecular alterations caused by this treatment in different neuronal systems have begun to be unraveled (Calabresi et al., 2000c, Cenci and Lundblad, 2006, Linazasoro, 2005). l-DOPA applied in a pulsatile and non-physiological manner can result in remodeling of neuronal synapses and pathways, producing long-lasting neuronal changes (Calabresi et al., 2000b, Calabresi et al., 2000c, Calon et al., 2000a, Calon et al., 2000b, Cenci, 2007). Dyskinesia and motor fluctuations may thus be viewed as the behavioral expression of maladaptive structural and synaptic plasticity within the basal ganglia (Calabresi et al., 2000b, Graybiel, 2004, Linazasoro, 2005).

In line with this idea, in experimental parkinsonism we have demonstrated a critical link between AIMs and the loss of bidirectional synaptic plasticity at corticostriatal synapses (Picconi et al., 2003). The possibility to induce bidirectional plasticity is linked to the physiological mechanism named “depotentiation”, a phenomenon consisting in the possibility to reverse previously induced long-term potentiation (LTP) (Chen et al., 2001, Fujii et al., 2000, Huang et al., 2001, Morgan et al., 2001, Picconi et al., 2003). The lack of depotentiation of corticostriatal inputs may have profound implications in the pathophysiology of the basal ganglia circuits in PD brain. In fact, since depotentiation is implicated in the mechanisms of physiological “forgetting” (Picconi et al., 2003, Picconi et al., 2005) its absence might result in the storage of unessential motor information.

Clinical trials have demonstrated that dyskinesias are significantly more common in patients treated with high doses of l-DOPA (Fahn, 2000, Fahn, 2005) suggesting that the daily dosage of l-DOPA is a critical risk factor for the development of dyskinetic movements. However, the synaptic mechanisms underlying the relation between the development of dyskinetic movements and the daily dosage of l-DOPA therapy in PD are still unclear.

In the present study we have characterized the association between AIMs, bidirectional synaptic plasticity, and daily dosage of l-DOPA in an experimental model of PD.

Section snippets

Preparation of 6-OHDA denervated rats and l-DOPA treatment

Adult male Wistar rats (n = 150; 150–250 g) were used for all the experiments. All experiments were approved by the OHSU Institutional Animal Care and Use Committee.

6-OHDA lesion

Deeply anaesthetized rats (n = 120) were injected with 8 μg/4 μl 6-OHDA in saline 0.1% ascorbic acid in the MFB at a rate of 0.38 μl/min (for stereotaxic coordinates see Paxinos et al., 1985). Control rats were injected with vehicle (n = 30). Fifteen days later, the lesioned rats were tested with 0.05 mg/kg s.c. apomorphine and

Extent of the DA denervation in the two experimental groups

The induction of AIMs by l-DOPA is conditioned by the degree of striatal DA denervation resulting from the loss of DA neurons in the substantia nigra (for review see Cenci and Lundblad, 2006). Thus, the extent of the lesion was verified on midbrain sections using tyrosine hydroxylase (TH) immunohistochemistry. Both groups of 6-OHDA-lesioned animals (treated with either low or high doses of l-DOPA) showed a virtually complete loss of TH-positive neurons in the substantia nigra pars compacta

Discussion

The present study represents the first experimental attempt to characterize the synaptic mechanisms underlying the critical role of l-DOPA dosage in the expression of motor complications in PD. In fact, although data collected from several experimental and clinical studies have already indicated that treatment with high doses of l-DOPA is a risk factor for an early appearance of motor complications, the underlying pathophysiological mechanisms have remained unclear.

Clinical studies showed that

Acknowledgments

This study was supported by the Fondo per gli Investimenti della Ricerca di Base 2003 (FIRB2003), Ricerca Scientifica di Rilevante Interesse Nazionale 2005 (PRIN2005), Progetti Finalizzati e Strategici Ministero della Salute 2004–2006, Progetto Dopamina Istituto Superiore della Sanità and Fondazione Cassa di Risparmio Perugia (P.C.) and by the Swedish National Research Council (M.A.C.).

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