Ropinirole versus l-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia

doi:10.1016/j.expneurol.2003.09.001

Experimental Neurology

Volume 185, Issue 1, January 2004, Pages 36-46

https://doi.org/10.1016/j.expneurol.2003.09.001 Get rights and content

Abstract

The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), remains the most common treatment for Parkinson's disease. However, following long-term treatment, disabling side effects, particularly l-DOPA-induced dyskinesias, are encountered. Conversely, D₂/D₃ dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect while eliciting less dyskinesia when administered de novo in Parkinson's disease patients. Parkinson's disease and l-DOPA-induced dyskinesia are both associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). Furthermore, a potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the l-DOPA-induced dyskinesia in animal models of Parkinson's disease. In this study, the behavioural response, striatal topography and levels of expression of the opioid peptide precursors PPE-A and PPE-B were assessed, following repeated vehicle, ropinirole, or l-DOPA administration in the 6-OHDA-lesioned rat model of Parkinson's disease. While repeated administration of l-DOPA significantly elevated PPE-B mRNA levels (313% cf. vehicle, 6-OHDA-lesioned rostral striatum; 189% cf. vehicle, 6-OHDA-lesioned caudal striatum) in the unilaterally 6-OHDA-lesioned rat model of Parkinson's disease, ropinirole did not. These data and previous studies suggest the involvement of enhanced opioid transmission in l-DOPA-induced dyskinesia and that part of the reason why D₂/D₃ dopamine receptor agonists have a reduced propensity to elicit dyskinesia may reside in their reduced ability to elevate opioid transmission.

Introduction

The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), remains the most common treatment for Parkinson's disease. However, repeated treatment with l-DOPA is associated with the development of serious motor complications including fluctuations, “wearing off” of efficacy, nonresponsiveness and l-DOPA-induced dyskinesia, which may prove to be as debilitating as the disease itself (Nutt, 1990). Conversely, D₂/D₃ dopamine receptor agonists, such as ropinirole, exert an anti-parkinsonian effect with a reduced propensity to elicit dyskinesia when administered de novo in Parkinson's disease patients Rascol et al., 2000, Whone et al., 2003.

Ropinirole (SK&F 101468-A) is a second-generation non-ergoline dopamine receptor agonist with D₂-like receptor selectivity and chemical structure similar to that of dopamine Coldwell et al., 1999, Tulloch, 1997. It is most potent at the D₃ dopamine receptor with lower affinity at D₂ and D₄ dopamine receptors (D₃ > D₂ > D₄) (Coldwell et al., 1999). Ropinirole does not bind to D₁-like dopamine receptors and displays no appreciable affinity for other CNS receptors, including serotonin, benzodiazepine, GABA, adrenergic, or muscarinic cholinergic receptors (Eden et al., 1991). In animal models of Parkinson's disease, ropinirole can reverse motor deficits Eden et al., 1991, Fukuzaki et al., 2000a, Fukuzaki et al., 2000b, Pearce et al., 1998 and induces less dyskinesia than l-DOPA (Pearce et al., 1998). Furthermore, ropinirole is effective when used as monotherapy in early Parkinson's disease, or as an adjunct to l-DOPA in patients with motor fluctuations Rascol et al., 2000, Whone et al., 2003 and demonstrates a reduced propensity to induce dyskinesia in patients with untreated Parkinson's disease Rascol et al., 2000, Whone et al., 2003.

Parkinson's disease and related iatrogenic dyskinesias are associated with changes in mRNA and peptide levels of the opioid peptide precursors preproenkephalin-A (PPE-A) and preproenkephalin-B (PPE-B). A potential role of abnormal opioid peptide transmission in dyskinesia is suggested due to the ability of opioid receptor antagonists to reduce the behavioural enhancement following repeated l-DOPA administration in animal models of Parkinson's disease (Henry et al., 2001). In this study, the behavioural response, topographical distribution and levels of opioid peptide precursor mRNA expression following repeated administration of ropinirole or l-DOPA in the unilaterally 6-OHDA-lesioned rat were investigated. In situ hybridisation utilising oligonucleotide probes targeted against PPE-A and PPE-B was employed to investigate the topographical distribution of mRNA expression in the striatum of 6-OHDA-lesioned rats following repeated treatment with vehicle, ropinirole, or l-DOPA.

Section snippets

Unilateral lesion of the medial forebrain bundle

Male Sprague–Dawley rats (250–300 g, Charles River, UK) were maintained under standard housing conditions with constant temperature (22 ± 1°C), humidity (relative, 30%), 12-h light/dark cycles (light period 08:00–20:00). Food (Standard pellets, B&K Universal) and water were available ad libitum. Unilateral 6-OHDA lesions were performed as previously described (Henry et al., 1999). Each animal received a unilateral injection of 2.5 μl 6-OHDA.Br (Sigma, 5 mg/ml in sterile water with 0.1% ascorbic

Assessment of lesion: [¹²⁵I]-PE2I binding

6-OHDA-lesioned rats with a greater than 90% reduction in dopamine transporter binding were included in the in situ hybridisation studies (Table 1).

Behavioural responses following drug treatment

Following repeated l-DOPA treatment, 6-OHDA-lesioned rats displayed stereotypic behaviour, compulsive grooming, rotations were in circles of small diameter (nose-to-tail circling). Following repeated ropinirole treatment, 6-OHDA-lesioned rats did not display stereotypies, rotations were of wider diameter and behaviour was more naturalistic. These

Discussion

The major finding described in this study is that l-DOPA induces increases in PPE-B expression, whereas ropinirole does not, despite both compounds having similar anti-parkinsonian actions following repeated treatment, in the 6-OHDA-lesioned rat model of Parkinson's disease.

Conclusion

Ropinirole has a reduced propensity to induce dyskinesia compared to l-DOPA in Parkinson's disease patients Rascol et al., 2000, Whone et al., 2003. While repeated administration of l-DOPA elevated opioid peptide precursor mRNA levels in the 6-OHDA-lesioned rat model of Parkinson's disease, the D₂/D₃ dopamine receptor agonist ropinirole did not. The absence of an elevation of opioid precursors, in particular PPE-B, by ropinirole administration, may underlie its reduced propensity to induce

Acknowledgements

The authors thank GSK for providing ropinirole. The technical assistance of Bill Moser is gratefully appreciated. Thanks are also due to Dr Michael Hill for critical reading of this manuscript. This study was funded by the Parkinson's Disease Society (UK).

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l-Dopa is the most effective drug used for Parkinson's disease (PD), but after long-term treatment, the vast majority of PD patients develop abnormal involuntary movements (AIMs) termed l-Dopa-induced dyskinesia (LID). Cannabinoid receptors in the basal ganglia can modulate motor functions, but their role in the treatment of LID is controversial. Therefore, the aim of this study is to evaluate the motor behavior and mRNA expression of the cannabinoid receptor-1 (CB₁R), encoded by the Cnr1 gene, in the striatum and globus pallidus of a 6-hydroxydopamine rat model of PD. The evaluated rats had 6-hydroxydopamine-induced injury, LID, and LID treated with arachidonyl-2′-chloroethylamide (ACEA), a cannabinoid receptor agonist. Contralateral turns and AIMs were recorded to assess motor behavior. Gene expression was quantified by reverse transcription coupled with quantitative polymerase chain reaction using TaqMan probes. Behavioral evaluations demonstrated that dyskinetic rats treated with ACEA had a significant reduction in AIMs compared to the dyskinetic group. The expression of CB₁R mRNA was significantly decreased in the 6-hydroxydopamine-injured and dyskinetic rats, compared to intact rats. The striata of dyskinetic rats treated with ACEA exhibited highly significant increases in CB₁R mRNA expression. Contrary to results in the striatum, a lower CB₁R expression was observed in globus pallidus from dyskinetic ACEA-treated group. In summary, significant differences in mRNA expression of CB₁R were found between the evaluated groups of rats, suggesting the occurrence of compensatory mechanisms that may result in the ACEA-mediated reduction of dyskinesias in a rat model of PD.
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The dopamine (DA) precursor, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), is the most effective treatment for Parkinson's disease (PD), but causes dyskinesias (abnormal involuntary movements) in the vast majority of patients. There is a wide consensus that l-DOPA-induced dyskinesia (LID) depends on both pre- and postsynaptic disturbances of the nigrostriatal DA transmission. Presynaptically, LID is associated with abnormal DA release and defective DA clearance, which converge to cause large swings in brain DA levels concomitant with the medication. Postsynaptically, LID is associated with a dysregulation of intracellular signaling and gene expression downstream of the D1 DA receptor. These phenomena are particularly well studied in the striatum and are thus the main topic of this chapter. In addition, the chapter reviews studies that have revealed associations between LID and different types of abnormalities in glutamatergic and GABAergic transmission within cortico-basal ganglia circuits.
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Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.
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Regulators of G-protein signalling (RGS) proteins are implicated in striatal G-protein coupled receptor (GPCR) sensitisation in the pathophysiology of l-DOPA-induced abnormal involuntary movements (AIMs), also known as dyskinesia (LID), in Parkinson's disease (PD). In this study, we investigated RGS protein subtype 4 in the expression of AIMs in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID. The effects of RGS4 antisense brain infusion on the behavioural and molecular correlates of l-DOPA priming in 6-OHDA-lesioned rats were assessed. In situ hybridisation revealed that repeated l-DOPA/benserazide treatment caused an elevation of RGS4 mRNA levels in the striatum, predominantly in the lateral regions. The increased expression of RGS4 mRNA in the rostral striatum was found to positively correlate with the behavioural (AIM scores) and molecular (pre-proenkephalin B, PPE-B expression) markers of LID. We found that suppressing the elevation of RGS4 mRNA in the striatum by continuous infusion of RGS4 antisense oligonucleotides, via implanted osmotic mini-pumps, during l-DOPA priming, reduced the induction of AIMs. Moreover, ex vivo analyses of the rostral dorsolateral striatum showed that RGS4 antisense infusion attenuated l-DOPA-induced elevations of PPE-B mRNA and dopamine-stimulated [³⁵S]GTPγS binding, a marker used for measuring dopamine receptor super-sensitivity. Taken together, these data suggest that (i) RGS4 proteins play an important pathophysiological role in the development and expression of LID and (ii) suppressing the elevation of RGS4 mRNA levels in l-DOPA priming attenuates the associated pathological changes in LID, dampening its physiological expression. Thus, modulating RGS4 proteins could prove beneficial in the treatment of dyskinesia in PD.
Performance of movement in hemiparkinsonian rats influences the modifications induced by dopamine agonists in striatal efferent dynorphinergic neurons
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In line with the crucial role played by the striatum in motor function, lesions of the dopaminergic nigrostriatal pathway and administration of dopaminergic agonists have been shown to induce adaptive long-term changes in glutamic acid decarboxylase 67 (GAD67), dynorphin, enkephalin, and early gene mRNAs in this brain area. These changes have been linked to motor impairment in Parkinson's disease (PD), as well as to motor complications induced by treatments with L-3,4-dihydroxyphenylalanine (L-DOPA) or dopamine receptor agonists (Carta et al., 2001, 2005, 2010; Cenci et al., 2009; Gerfen et al., 2002; Ravenscroft et al., 2004; Soghomonian et al., 1992; Van de Witte et al., 2002). Previous studies of our and other groups have described how the first ever administration of a dopamine agonist sensitizes unilaterally 6-hydroxydopamine-(6-OHDA)-lesioned hemiparkinsonian rats to the subsequent challenge with the same or a different dopamine agonist (priming model) (Morelli et al., 1989, 1993; Pollack et al., 1997; van de Witte et al., 1998).
A previous study of our group demonstrated that movement performance induced by dopamine agonist drugs in hemiparkinsonian rats unilaterally lesioned with 6-hydroxydopamine (6-OHDA), governs the occurrence of a sensitized motor response to a subsequent dopaminergic challenge (priming model). In the present study, we examined the influence of movement performance (rotational behavior) on the molecular events induced by priming in the striatum. To this end, unilaterally 6-OHDA-lesioned rats were primed with apomorphine (0.2 mg/kg) in immobilized or freely moving conditions (priming induction) and 3 days later the D₁ receptor agonist SKF 38393 was administered (priming expression). Evaluation of striatal mRNA for enkephalin and dynorphin, markers of the indirect and direct striatonigral pathways, and of GAD67 showed an increase in dynorphin in primed SKF 38393-treated rats, no matter whether immobilized or freely moving during priming induction, whilst enkephalin and GAD67 did not show any changes. In contrast, evaluation of mRNA for the early gene zif-268 in the striatum showed a generalized increase after administration of SKF 38393, in both primed and unprimed rats. However, examination of zif-268 mRNA at the single-cell level, showed that only dynorphin(+) neurons of primed not immobilized rats displayed a significantly higher number of zif-268-positive silver grains in response to the SKF 38393 challenge. This selective activation of zif-268 in dynorphinergic striatonigral efferent neurons demonstrates that movement performance in response to dopaminergic drug administration under conditions of dopamine denervation is critical for the emergence of neurochemical modifications in selected striatal efferent neurons. Furthermore, these results may provide information on the first initial molecular events taking place in the complex processes that lead to dyskinetic movements in Parkinson's disease.
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Dyskinesia seen in the off-state, referred as graft-induced dyskinesia (GID), has emerged as a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. Although the mechanism underlying the appearance of GID is unknown, in a recent clinical study the partial 5-HT_1A agonist buspirone was found to markedly reduce GID in three grafted patients, who showed significant serotonin (5-HT) hyperinnervation in the grafted striatum in positron emission tomography scanning (Politis et al., 2010, 2011). Prompted by these findings, this study was performed to investigate the involvement of serotonin neurons in the appearance of GID in the rat 6-hydroxydopamine model.
L-DOPA-primed rats received transplants of DA neurons only, DA plus 5-HT neurons or 5-HT neurons only into the lesioned striatum. In DA cell-grafted rats, with or without 5-HT neurons, but not in 5-HT grafts, GID was observed consistently after administration of amphetamine (1.5 mg/kg, i.p.) indicating that grafted DA neurons are required to induce GID. Strikingly, a low dose of buspirone produced a complete suppression of GID. In addition, activation of 5-HT_1A and 5-HT_1B receptors by 8-OH-DPAT and CP 94253, known to inhibit the activity of 5-HT neurons, significantly reduced GID, whereas induction of neurotransmitter release by fenfluramine administration significantly increased GID, indicating an involvement of the 5-HT system in the modulation of GID. To investigate the involvement of the host 5-HT system in GID, the endogenous 5-HT terminals were removed by intracerebral injection of 5,7-dihydroxytryptamine, but this treatment did not affect GID expression. However, 5-HT terminal destruction suppressed the anti-GID effect of 5-HT_1A and 5-HT_1B agonists, demonstrating that the 5-HT₁ agonist combination exerted its anti-GID effect through the activation of pre-synaptic host-derived receptors. By contrast, removal of the host 5-HT innervation or pre-treatment with a 5-HT_1A antagonist did not abolish the anti-GID effect of buspirone, showing that its effect is independent from activation of either pre- or post-synaptic 5-HT_1A receptors. Since buspirone is known to also act as a DA D₂ receptor antagonist, the selective D₂ receptor antagonist eticlopride was administered to test whether blockade of D₂ receptors could account for the anti-dyskinetic effect of buspirone. In fact, eticlopride produced complete suppression of GID in grafted animals already at very low dose. Together, these results point to a critical role of both 5-HT₁ and D₂ receptors in the modulation of GID, and suggest that 5-HT neurons exert a modulatory role in the development of this side effect of neuronal transplantation.

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¹: Current address: Toronto Western Research Institute, Division of Applied and Interventional Research, McLaughlin Wing, Room MC11-419, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8.

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Ropinirole versus l-DOPA effects on striatal opioid peptide precursors in a rodent model of Parkinson's disease: implications for dyskinesia

Abstract

Introduction

Section snippets

Unilateral lesion of the medial forebrain bundle

Assessment of lesion: [125I]-PE2I binding

Behavioural responses following drug treatment

Discussion

Conclusion

Acknowledgements

Neuron

Neuroscience

Neuroscience

Exp. Neurol

Exp. Neurol

Pharmacol. Biochem. Behav

Brain Res

Pharmacol. Biochem. Behav

Pharmacol. Biochem. Behav

Exp. Neurol

Exp. Neurol

Exp. Neurol

Neuroscience

Neuroscience

Cell

Brain Res. Mol. Brain Res

Brain Res. Mol. Brain Res

Brain Res. Mol. Brain Res

Neuropeptides

Neuroscience

Brain Res. Mol. Brain Res

Brain Res

Neuroscience

Brain Res

Neuroscience

Neuroscience

Assessment of lesion: [¹²⁵I]-PE2I binding