RESUMO
L-DOPA-induced dyskinesia (LID) is a significant complication of dopamine replacement therapy in Parkinson's disease (PD), and the specific role of different dopamine receptors in this disorder is poorly understood. We set out to compare patterns of dyskinetic behaviours induced by the systemic administration of L-DOPA and D1 or D2 receptor (D1R, D2R) agonists in mice with unilateral 6-hydroxydopamine lesions. Mice were divided in four groups to receive increasing doses of L-DOPA, a D1R agonist (SKF38393), a D2/3 agonist (quinpirole), or a selective D2R agonist (sumanirole). Axial, limb and orofacial abnormal involuntary movements (AIMs) were rated using a well-established method, while dystonic features were quantified in different body segments using a new rating scale. Measures of abnormal limb and trunk posturing were extracted from high-speed videos using a software for markerless pose estimation (DeepLabCut). While L-DOPA induced the full spectrum of dyskinesias already described in this mouse model, SKF38393 induced mostly orofacial and limb AIMs. By contrast, both of the D2-class agonists (quinpirole, sumanirole) induced predominantly axial AIMs. Dystonia ratings revealed that these agonists elicited marked dystonic features in trunk/neck, forelimbs, and hindlimbs, which were overall more severe in sumanirole-treated mice. Accordingly, sumanirole induced pronounced axial bending and hindlimb divergence in the automated video analysis. In animals treated with SKF38393, the only appreciable dystonic-like reaction consisted in sustained tail dorsiflexion and stiffness. We next compared the effects of D1R or D2R selective antagonists in L-DOPA-treated mice, where only the D2R antagonist had a significant effect on dystonic features. Taken together these results indicate that the dystonic components of LID are predominantly mediated by the D2R.
Assuntos
Discinesia Induzida por Medicamentos/fisiopatologia , Distonia/fisiopatologia , Movimento/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Antiparkinsonianos/efeitos adversos , Benzimidazóis/farmacologia , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Distonia/induzido quimicamente , Distonia/metabolismo , Camundongos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistasRESUMO
Striatal neurons forming the indirect pathway (iSPNs) are particularly vulnerable in Huntington's disease (HD). In this study we set out to investigate morphological and physiological alterations of iSPNs in two mouse models of HD with relatively slow disease progression (long CAG repeat R6/2 and zQ175-KI). Both were crossed with a transgenic mouse line expressing eGFP in iSPNs. Using the open-field and rotarod tests, we first defined two time points in relation to the occurrence of motor deficits in each model. Then, we investigated electrophysiological and morphological properties of iSPNs at both ages. Both HD models exhibited increased iSPN excitability already before the onset of motor deficits, associated with a reduced number of primary dendrites and decreased function of Kir- and voltage-gated potassium channels. Alterations that specifically occurred at symptomatic ages included increased calcium release by back-propagating action potentials in proximal dendrites, due to enhanced engagement of intracellular calcium stores. Moreover, motorically impaired mice of both HD models showed a reduction in iSPN spine density and progressive formation of huntingtin (Htt) aggregates in the striatum. Our study therefore reports iSPN-specific alterations relative to the development of a motor phenotype in two different mouse models of HD. While some alterations occur early and are partly non-progressive, others potentially provide a pathophysiological marker of an overt disease state.
Assuntos
Modelos Animais de Doenças , Doença de Huntington/complicações , Doença de Huntington/fisiopatologia , Transtornos dos Movimentos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Animais , Cloreto de Cádmio/farmacologia , Césio/farmacologia , Cloretos/farmacologia , Corpo Estriado/patologia , Dendritos/metabolismo , Dendritos/patologia , Comportamento Exploratório/fisiologia , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Neurônios/ultraestrutura , Potássio/farmacologia , Desempenho Psicomotor/fisiologia , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Dopamine replacement therapy for Parkinson's disease is achieved using L-DOPA or dopamine D2/3 agonists, such as ropinirole. Here, we compare the effects of L-DOPA and ropinirole, alone or in combination, on patterns of glial and microvascular reactivity in the striatum. Rats with unilateral 6-hydroxydopamine lesions were treated with therapeutic-like doses of L-DOPA (6 mg/kg), an equipotent L-DOPA-ropinirole combination (L-DOPA 3 mg/kg plus ropinirole 0.5 mg/kg), or ropinirole alone. Immunohistochemistry was used to examine the reactivity of microglia (ionized calcium-binding adapter molecule 1, IBA-1) and astroglia (glial fibrillary acidic protein, GFAP), as well as blood vessel density (rat endothelial cell antigen 1, RECA-1) and albumin extravasation. L-DOPA monotreatment and L-DOPA-ropinirole cotreatment induced moderate-severe dyskinesia, whereas ropinirole alone had negligible dyskinetic effects. Despite similar dyskinesia severity, striking differences in perivascular microglia and astroglial reactivity were found between animals treated with L-DOPA vs. L-DOPA-ropinirole. The former exhibited a marked upregulation of perivascular IBA-1 cells (in part CD68-positive) and IBA-1-RECA-1 contact points, along with an increased microvessel density and strong perivascular GFAP expression. None of these markers were significantly upregulated in animals treated with L-DOPA-ropinirole or ropinirole alone. In summary, although ropinirole cotreatment does not prevent L-DOPA-induced dyskinesia, it protects from maladaptive gliovascular changes otherwise associated with this disorder, with potential long-term benefits to striatal tissue homeostasis.
Assuntos
Discinesia Induzida por Medicamentos , Levodopa , Ratos , Animais , Antiparkinsonianos/efeitos adversos , Microglia/metabolismo , Dopamina , Discinesia Induzida por Medicamentos/tratamento farmacológico , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêuticoRESUMO
Parkinson's disease (PD) is a neurodegenerative disorder characterized by typical motor features that result from dopamine (DA) depletion in the striatum. DA replacement therapy with L-DOPA is the most efficacious symptomatic treatment, but causes complications that limit its utility, in particular, L-DOPA-induced dyskinesia (LID). LID is primarily caused by pre-synaptic and post-synaptic changes in DA neurotransmission, although it also depends on altered glutamatergic transmission at several nodes of the cortico-basal ganglia-thalamocortical network. The important functional interplay between dopaminergic and glutamatergic systems has stimulated an interest in metabotropic glutamate receptors (mGluRs) as potential therapeutic targets in PD and LID. We here review the antiparkinsonian and antidyskinetic potential of modulating group I, II, and III mGluRs in several preclinical models of PD. We also provide an update on clinical trials evaluating mGluR5 or mGluR4 ligands in PD.
Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Doença de Parkinson/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidoresRESUMO
Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
Assuntos
Levodopa/efeitos adversos , Vias Neurais/metabolismo , Doença de Parkinson Secundária/tratamento farmacológico , Receptor Muscarínico M3/agonistas , Receptores de Dopamina D2/agonistas , Córtex Visual/metabolismo , Animais , Humanos , Levodopa/farmacologia , Camundongos , Camundongos Transgênicos , Vias Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Ratos , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Córtex Visual/patologiaRESUMO
Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia.
Assuntos
Estimulação Encefálica Profunda/efeitos adversos , Dopamina/efeitos adversos , Dopamina/uso terapêutico , Discinesia Induzida por Medicamentos/fisiopatologia , Ácido Glutâmico/metabolismo , Doença de Parkinson/terapia , Animais , Gânglios da Base/metabolismo , Gânglios da Base/fisiopatologia , Humanos , Doença de Parkinson/fisiopatologia , Receptores de AMPA/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Discinesias/metabolismo , Eletrofisiologia , Levodopa/farmacologia , Locus Cerúleo/fisiopatologia , Transtornos Parkinsonianos/patologia , Anfetamina/farmacologia , Animais , Discinesias/etiologia , Discinesias/fisiopatologia , Feminino , Ácido Ibotênico/farmacologia , Locus Cerúleo/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lacking. In the present study, we investigated the changes occurring at the protein level in striatal samples obtained from the unilaterally 6-hydroxydopamine-lesion rat model of PD treated with saline, L-DOPA or bromocriptine using two-dimensional difference gel electrophoresis and mass spectrometry (MS). Rats treated with L-DOPA were allocated to two groups based on the presence or absence of LID. Among the 2000 spots compared for statistical difference, 67 spots were significantly changed in abundance and identified using matrix-assisted laser desorption/ionization time-of-flight MS, atmospheric pressure matrix-assisted laser desorption/ionization and HPLC coupled tandem MS (LC/MS/MS). Out of these 67 proteins, LID significantly changed the expression level of five proteins: alphabeta-crystalin, gamma-enolase, guanidoacetate methyltransferase, vinculin, and proteasome alpha-2 subunit. Complementary techniques such as western immunoblotting and immunohistochemistry were performed to investigate the validity of the data obtained using the proteomic approach. In conclusion, this study provides new insights into the protein changes occurring in LID.