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1.
Sci Rep ; 8(1): 10068, 2018 07 03.
Article in English | MEDLINE | ID: mdl-29968767

ABSTRACT

Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark of Parkinson's disease (PD). Here we investigate how chronic dopamine denervation and dopamine replacement with L-DOPA affect the morphology and physiology of direct pathway SPNs (dSPNS) in the rat striatum. We used a lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs in rats with 6-hydroxydopamine (6-OHDA) lesions. Changes in morphology and physiology of dSPNs were assessed through a combination of patch-clamp recordings and two photon microscopy. The 6-OHDA lesion caused a significant reduction in dSPN dendritic complexity. Following chronic L-DOPA treatment, dSPNs segregated into two equal-sized clusters. One group (here called "cluster-1"), showed sustained dendritic atrophy and a partially normalized electrophysiological phenotype. The other one ("cluster-2") exhibited dendritic regrowth and a strong reduction of intrinsic excitability. Interestingly, FosB/∆FosB induction by L-DOPA treatment occurred preferentially in cluster-2 dSPNs. Our study demonstrates the feasibility of retrograde FuG-B-GFP labeling to study dSPNs in the rat and reveals, for the first time, that a subgroup of dSPNs shows dendritic sprouting in response to chronic L-DOPA treatment. Investigating the mechanisms and significance of this response will greatly improve our understanding of the adaptations induced by dopamine replacement therapy in PD.


Subject(s)
Neurons/pathology , Parkinson Disease/physiopathology , Striatonigral Degeneration/physiopathology , Animals , Corpus Striatum/metabolism , Disease Models, Animal , Dopamine/metabolism , Dyskinesia, Drug-Induced/metabolism , Female , Levodopa/pharmacology , Mice , Mice, Transgenic , Neostriatum/metabolism , Phenotype , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/metabolism
2.
Exp Neurol ; 271: 335-50, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26037043

ABSTRACT

L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L-DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms.


Subject(s)
Antiparkinson Agents/toxicity , Brain/drug effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/toxicity , Piperidines/therapeutic use , Pyridines/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Adrenergic Agents/toxicity , Animals , Brain/metabolism , Catalepsy/chemically induced , Catalepsy/drug therapy , Disease Models, Animal , Drug Interactions , Dyskinesia, Drug-Induced/etiology , Female , Haloperidol/toxicity , Movement/drug effects , Neurotransmitter Agents/metabolism , Oxidopamine/toxicity , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Serotonin Syndrome/drug therapy , Serotonin Syndrome/etiology , Swimming/psychology , Vocalization, Animal/drug effects
3.
Neuropharmacology ; 93: 52-67, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25645393

ABSTRACT

Serotonin 5-HT1A receptor agonists reduce L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished L-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of L-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the L-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of L-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and L-DOPA dose-sparing effects in PD patients.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced/etiology , Levodopa/adverse effects , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Adrenergic Agents/toxicity , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Disease Models, Animal , Female , Male , Motor Activity/drug effects , Neurotransmitter Agents/metabolism , Oxidopamine/toxicity , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Piperidines/therapeutic use , Psychomotor Performance/drug effects , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Tyrosine 3-Monooxygenase/metabolism
4.
Mol Neurobiol ; 52(3): 1152-1164, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25307288

ABSTRACT

Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements in a genetic mouse model of synucleinopathy. This mouse model will be useful to identify novel therapeutic targets that can counteract abnormal dopamine-dependent striatal plasticity during both prodromal and manifest stages of PD.


Subject(s)
Apomorphine/toxicity , Dyskinesias/etiology , Locomotion/drug effects , MAP Kinase Signaling System/physiology , Parkinsonian Disorders/physiopathology , Stereotyped Behavior/drug effects , alpha-Synuclein/genetics , Animals , Corpus Striatum/metabolism , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Disease Models, Animal , Dopaminergic Neurons/pathology , Dopaminergic Neurons/physiology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , Mutation, Missense , Nerve Tissue Proteins/metabolism , Parkinsonian Disorders/genetics , Phosphorylation/drug effects , Point Mutation , Post-Synaptic Density/drug effects , Prions/genetics , Promoter Regions, Genetic , Protein Processing, Post-Translational/drug effects , Substantia Nigra/metabolism , Substantia Nigra/physiopathology , Transgenes
5.
CNS Neurol Disord Drug Targets ; 10(6): 670-84, 2011 Sep 01.
Article in English | MEDLINE | ID: mdl-21838677

ABSTRACT

Dyskinesia and motor fluctuations affect up to 90% of patients with Parkinson's disease (PD) within ten years of L-DOPA pharmacotherapy, and represent a major challenge to a successful clinical management of this disorder. There are currently two main treatment options for these complications, namely, deep brain electrical stimulation or continuous infusion of dopaminergic agents. The latter is achieved using either subcutaneous apomorphine infusion or enteric L-DOPA delivery. Some patients also benefit from the antidyskinetic effect of amantadine as an adjunct to L-DOPA treatment. Ongoing research in animal models of PD aims at discovering additional, novel treatment options that can either prevent or reverse dyskinesia and motor fluctuations. Alternative methods of continuous L-DOPA delivery (including gene therapy), and pharmacological agents that target nondopaminergic receptor systems are currently under intense experimental scrutiny. Because clinical response profiles show large individual variation in PD, an increased number of treatment options for dyskinesia and motor fluctuations will eventually allow for antiparkinsonian and antidyskinetic therapies to be tailor-made to the needs of different patients and/or PD subtypes.


Subject(s)
Antiparkinson Agents/adverse effects , Deep Brain Stimulation/trends , Dopamine Agents/administration & dosage , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/surgery , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Animals , Deep Brain Stimulation/methods , Dyskinesia, Drug-Induced/physiopathology , Humans , Movement/drug effects , Movement/physiology
6.
J Parkinsons Dis ; 1(4): 347-57, 2011.
Article in English | MEDLINE | ID: mdl-23933656

ABSTRACT

The transcription factor ΔFosB is a mediator of maladaptive neuroplasticity in animal models of Parkinson's disease (PD) and L-DOPA-induced dyskinesia. Using an antibody that recognizes all known isoforms of FosB and ΔFosB, we have examined the expression of these proteins in post-mortem basal ganglia sections from PD patients. The patient cases were classified as being dyskinetic or non-dyskinetic based on their clinical records. Sections from neurologically healthy controls were also included in the study. Compared to both controls and non-dyskinetic cases, the dyskinetic group showed a higher density of FosB/ΔFosB-immunopositive cells in the posterior putamen, which represents the motor region of the striatum in primates. In contrast, the number of FosB/ΔFosB-positive cells did not differ significantly among the groups in the caudate, a region primarily involved with the processing of cognitive and limbic-related information. Only sparse FosB/ΔFosB immunoreactivity was found in the in the pallidum externum and internum, and no significant group differences were detected in these nuclei. The putaminal elevation of FosB/ΔFosB-like immunoreactivity in patients who had been affected by L-DOPA-induced dyskinesia is consistent with results from both rat and non-human primate models of this movement disorder. The present findings support the hypothesis of an involvement of ΔFosB-related transcription factors in the molecular mechanisms of L-DOPA-induced dyskinesia.


Subject(s)
Basal Ganglia/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Putamen/metabolism , Up-Regulation/physiology , Aged , Aged, 80 and over , Analysis of Variance , Antiparkinson Agents/adverse effects , Autoradiography , Dopamine Plasma Membrane Transport Proteins/metabolism , Dyskinesia, Drug-Induced/pathology , Female , Humans , Levodopa/adverse effects , Male , Neurons/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Postmortem Changes , Putamen/pathology , Up-Regulation/drug effects
7.
Braz J Biol ; 70(4): 1109-13, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21180922

ABSTRACT

The aim of this study was to determine the potency (ITU) and efficacy of a liquid formulation of Bacillus thuringiensis israelensis developed by the State University of Londrina named BioUel, against early fourth instar larvae of Aedes aegypti and Culex quinquefasciatus. The ITU/mg of BioUel was 960, the LC50 was of 0.271 (± 0.39) ppm, and the LC95 was 0.634 (± 0.099) ppm, in larvae of C. quinquefasciatus. In A. aegypti larvae, LC50 was 0.332 (± 0.042) ppm and LC95 was 0.694 (± 0.073) ppm. The ITU level of BioUel and its control results were similar to most commercial products tested. Stability was of approximately 90 days, which allows for local production.


Subject(s)
Aedes , Bacillus thuringiensis , Culex , Pest Control, Biological/methods , Animals , Larva , Lethal Dose 50
8.
Exp Neurol ; 219(1): 355-8, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19393238

ABSTRACT

In some patients, graft-induced dyskinesia develops following intrastriatal transplantation of embryonic neural tissue for the treatment of Parkinson's disease. The mechanisms underlying these involuntary movements need to be clarified before this approach to clinical cell therapy can be developed further. We previously found that rats with 6-OHDA lesions, primed with L-DOPA treatment and that have subsequently undergone intrastriatal graft surgery exhibit involuntary movements when subjected to amphetamine. This model of amphetamine-induced AIMs reflects a pattern of post-graft behaviours that in the absence of robust spontaneous GID in the rat is the closest approximation that we currently have available. We now show that they are associated with the chronic administration of L-DOPA prior to the transplantation surgery. We also demonstrate that neither changes in c-fos nor FosB/DeltaFosB expression in the lateral striatum are associated with the expression of these behaviours. Taken together, these data reveal that the severity of abnormal movements elicited by amphetamine in grafted animals may relate to previous L-DOPA exposure and dyskinesia development, but they develop through mechanisms that are independent of FosB/DeltaFosB upregulation.


Subject(s)
Amphetamine/toxicity , Brain Tissue Transplantation/adverse effects , Dyskinesia, Drug-Induced/physiopathology , Levodopa/toxicity , Animals , Antiparkinson Agents/toxicity , Brain Tissue Transplantation/methods , Central Nervous System Stimulants/toxicity , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Disease Models, Animal , Drug Synergism , Dyskinesia, Drug-Induced/metabolism , Female , Oxidopamine/toxicity , Parkinson Disease/drug therapy , Parkinson Disease/surgery , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/surgery , Proto-Oncogene Proteins c-fos/drug effects , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/methods , Sympatholytics/toxicity
9.
Neurobiol Dis ; 32(2): 220-8, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18675359

ABSTRACT

The observation that neural grafts can induce dyskinesias has severely hindered the development of a transplantation therapy for Parkinson's disease (PD). We addressed the hypothesis that inflammatory responses within and around an intrastriatal graft containing dopamine neurons can trigger dyskinetic behaviors. We subjected rats to unilateral nigrostriatal lesions with 6-hydroxydopamine (6-OHDA) and treated them with L-DOPA for 21 days in order to induce abnormal involuntary movements (AIMs). Subsequently, we grafted the rats with allogeneic embryonic ventral mesencephalic tissue in the dopamine-denervated striatum. In agreement with earlier studies, the grafted rats developed dyskinesia-like AIMs in response to amphetamine. We then used two experimental approaches to induce an inflammatory response and examined if the amphetamine-induced AIMs worsened or if spontaneous AIMs developed. In one experiment, we challenged the neural graft hosts immunologically with an orthotopic skin allograft of the same genetic origin as the intracerebral neural allograft. In another experiment, we infused the pro-inflammatory cytokine interleukin 2 (IL-2) adjacent to the intrastriatal grafts using osmotic minipumps. The skin allograft induced rapid rejection of the mesencephalic allografts, leading to disappearance of the amphetamine-induced AIMs. Contrary to our hypothesis, the rejection process itself did not elicit AIMs. Likewise, the IL-2 infusion did not induce spontaneous AIMs, nor did it alter L-DOPA-induced AIMs. The IL-2 infusions did, however, elicit the predicted marked striatal inflammation, as evidenced by the presence of activated microglia and IL2Ralpha-positive cells. These results indicate that an inflammatory response in and around grafted dopaminergic neurons is not sufficient to evoke dyskinetic behaviors in experimental models of PD.


Subject(s)
Brain Tissue Transplantation/adverse effects , Dyskinesias/etiology , Dyskinesias/metabolism , Encephalitis/etiology , Adrenergic Agents/toxicity , Amphetamine/pharmacology , Analgesics, Non-Narcotic/administration & dosage , Analysis of Variance , Animals , Antiparkinson Agents , Brain Tissue Transplantation/immunology , Central Nervous System Stimulants/pharmacology , Corpus Striatum/transplantation , Disease Models, Animal , Embryo, Mammalian , Female , Interleukin-2/adverse effects , Interleukin-2 Receptor alpha Subunit/metabolism , Levodopa/adverse effects , Mesencephalon/surgery , Motor Activity/drug effects , Motor Activity/physiology , Oxidopamine/toxicity , Parkinson Disease/drug therapy , Parkinson Disease/etiology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Skin Transplantation
10.
Neuroscience ; 144(1): 198-207, 2007 Jan 05.
Article in English | MEDLINE | ID: mdl-17055656

ABSTRACT

In this study, we have used 6-hydroxydopamine-lesioned rats to examine changes in striatal junD and fosB/deltafosB expression induced by acute and chronic treatment with L-DOPA (5 and 15 days). Changes at the protein levels were studied using Western immunoblotting while mRNA changes were compared using in situ hybridization histochemistry. We observed a significant increase in the level of deltaFosB proteins after chronic treatment with L-DOPA, an effect that was not observed for JunD proteins. In addition, the upregulation of deltaFosB was already present after an acute treatment but increased upon chronic treatment. By contrast, junD and deltafosB mRNA were both upregulated significantly above control levels after an acute injection of L-DOPA. In conclusion, this study suggests a differential expression pattern of junD and deltafosB in a rat model of L-DOPA-induced dyskinesia. The upregulation of deltaFosB protein, but not JunD, is likely to reflect an increased stability of the deltaFosB proteins without ongoing enhanced transcription of the encoding genes.


Subject(s)
Antiparkinson Agents/pharmacology , Levodopa/pharmacology , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-jun/biosynthesis , Animals , Blotting, Western , Denervation , Female , Gene Expression Regulation/drug effects , Immunohistochemistry , In Situ Hybridization , Neostriatum/drug effects , Neostriatum/metabolism , Oxidopamine/toxicity , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley
11.
Curr Opin Neurobiol ; 17(6): 665-71, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18308560

ABSTRACT

The crucial role of dopamine (DA) in movement control is illustrated by the spectrum of motor disorders caused by either a deficiency or a hyperactivity of dopaminergic transmission in the basal ganglia. The degeneration of nigrostriatal DA neurons in Parkinson's disease causes poverty and slowness of movement. These symptoms are greatly improved by pharmacological DA replacement with L-3,4-dihydroxy-phenylalanine (L-DOPA), which however causes excessive involuntary movements in a majority of patients. L-DOPA-induced dyskinesia (abnormal involuntary movements) provides a topic of investigation at the interface between clinical and basic neuroscience. In this article, we review recent studies in rodent models, which have uncovered two principal alterations at the basis of the movement disorder, namely, an abnormal pre-synaptic handling of exogenous L-DOPA, and a hyper-reactive post-synaptic response to DA. Dysregulated nigrostriatal DA transmission causes secondary alterations in a variety of non-dopaminergic transmitter systems, the manipulation of which modulates dyskinesia through mechanisms that are presently unclear. Further research on L-DOPA-induced dyskinesia will contribute to a deeper understanding of the functional interplay between neurotransmitters and neuromodulators in the motor circuits of the basal ganglia.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced , Levodopa/adverse effects , Animals , Disease Models, Animal , Dopamine/metabolism , Dyskinesia, Drug-Induced/metabolism , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/physiopathology , Humans , Models, Neurological , Neural Pathways/pathology , Synaptic Transmission
12.
J Neurochem ; 96(6): 1718-27, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16539687

ABSTRACT

We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.


Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dyskinesia, Drug-Induced/metabolism , Levodopa/blood , Levodopa/pharmacokinetics , Parkinsonian Disorders/drug therapy , Animals , Corpus Striatum/physiopathology , Disease Models, Animal , Dopamine/metabolism , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/physiopathology , Extracellular Fluid/chemistry , Extracellular Fluid/drug effects , Extracellular Fluid/metabolism , Female , Levodopa/adverse effects , Microdialysis , Microinjections , Neural Pathways/drug effects , Neural Pathways/metabolism , Neural Pathways/physiopathology , Oxidopamine , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/physiopathology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiopathology , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Up-Regulation/drug effects , Up-Regulation/physiology
13.
Neurobiol Dis ; 22(2): 334-45, 2006 May.
Article in English | MEDLINE | ID: mdl-16406222

ABSTRACT

Intrastriatal transplants of embryonic ventral mesencephalon can cause dyskinesia in patients with Parkinson's disease (PD). We assessed the impact of transplant size on the development of graft-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions were primed to exhibit L-DOPA-induced dyskinesia. They were then intrastriatally grafted with different quantities of embryonic ventral mesencephalic tissue to give small and large grafts. Without drug treatment, discrete dyskinetic-like movements were observed in most rats with large grafts 2-6 weeks after transplantation, but disappeared later. Amphetamine evoked severe abnormal involuntary movements (AIMs) in grafted animals, which were more striking with large grafts. The AIMs coincided with contralateral rotation, but displayed a different temporal profile and pharmacological properties. Thus, selective dopamine uptake blockade elicited rotational behavior, whereas coadministration of both dopamine and serotonin uptake blockers was required to evoke significant orolingual and limb AIMs. In conclusion, robust and reproducible AIMs were evoked in rats with large grafts by blockade of monoamine reuptake. These AIMs may provide a new tool for assessing dyskinetic effects of neural grafting.


Subject(s)
Brain Tissue Transplantation/adverse effects , Corpus Striatum/physiopathology , Dopamine/metabolism , Dyskinesia, Drug-Induced/prevention & control , Dyskinesia, Drug-Induced/physiopathology , Neurons/transplantation , Amphetamine/adverse effects , Animals , Corpus Striatum/cytology , Corpus Striatum/surgery , Disease Models, Animal , Dopamine Agents/adverse effects , Dopamine Uptake Inhibitors/pharmacology , Dyskinesia, Drug-Induced/etiology , Female , Levodopa/adverse effects , Movement/drug effects , Movement/physiology , Neurons/drug effects , Neurons/metabolism , Oxidopamine , Parkinsonian Disorders/surgery , Rats , Rats, Sprague-Dawley , Rotation , Selective Serotonin Reuptake Inhibitors/pharmacology , Substantia Nigra/cytology , Substantia Nigra/embryology , Substantia Nigra/transplantation , Transplantation Tolerance/drug effects , Transplantation Tolerance/physiology
14.
Exp Neurol ; 194(1): 66-75, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15899244

ABSTRACT

Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.


Subject(s)
Basal Ganglia/drug effects , Basal Ganglia/physiopathology , Disease Models, Animal , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Adenosine A2 Receptor Agonists , Adrenergic Agents/adverse effects , Amantadine/pharmacology , Animals , Antiparkinson Agents/pharmacology , Basal Ganglia/metabolism , Buspirone/pharmacology , Disease Progression , Dopamine Agonists/pharmacology , Drug Administration Schedule , Dyskinesia, Drug-Induced/drug therapy , Dyskinesia, Drug-Induced/metabolism , Indoles/pharmacology , Levodopa/administration & dosage , Male , Mice , Mice, Inbred C57BL , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/physiopathology , Purines/pharmacology , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Reproducibility of Results , Riluzole/pharmacology , Treatment Outcome
15.
Neurobiol Dis ; 16(1): 110-23, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15207268

ABSTRACT

L-DOPA-induced dyskinesia is a major complication of L-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. In this study, we have addressed the possibility to model L-DOPA-induced dyskinesia in the mouse at both the behavioral and the molecular level. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) either in the medial forebrain bundle (MFB) or in the sensorimotor part of the striatum. Both types of lesion produced a similar degree of forelimb akinesia on the contralateral side of the body. The lowest dose of L-DOPA that could significantly relieve this akinetic deficit (i.e., 6 mg/kg) did not differ between MFB and intrastriatal lesions. The L-DOPA threshold dose for the induction of dyskinesia did however differ between the two lesion types. A daily dose of 6 mg/kg L-DOPA caused MFB lesioned mice to develop abnormal movements affecting orofacial, trunk, and forelimb muscles on the side contralateral to the lesion, whereas a daily dose of 18 mg/kg was required to produce comparable dyskinetic effects in the intrastriatally lesioned animals. The development of abnormal movements was accompanied by a striatal induction of DeltaFosB-like proteins and prodynorphin mRNA, that is, molecular markers that are associated with L-DOPA-induced dyskinesia in both rats and nonhuman primates. We conclude that 6-OHDA lesioned mice exhibit behavioral and cellular features of akinesia and L-DOPA-induced dyskinesia that are similar to those previously characterized in rats. The mouse model of L-DOPA-induced dyskinesia will provide a useful tool to study the molecular determinants of this movement disorder in transgenic mice strains.


Subject(s)
Corpus Striatum/metabolism , Disease Models, Animal , Dyskinesia, Drug-Induced/metabolism , Motor Skills/physiology , Substantia Nigra/metabolism , Animals , Corpus Striatum/drug effects , Dyskinesia, Drug-Induced/genetics , Dyskinesia, Drug-Induced/physiopathology , Levodopa/adverse effects , Male , Mazindol/metabolism , Mice , Mice, Inbred C57BL , Motor Skills/drug effects , Oxidopamine/toxicity , Protein Binding/drug effects , Protein Binding/physiology , Substantia Nigra/drug effects , Substantia Nigra/physiopathology
16.
Neurobiol Dis ; 15(3): 630-9, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15056471

ABSTRACT

We examined the role of a striatal lesion in the development of L-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of striatonigral degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. L-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose L-DOPA treatment in SND. Whereas L-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/Delta FosB up-regulation in SND and PD rats correlated with the severity of L-DOPA-induced dyskinesias. Pulsatile L-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic L-DOPA response and induction of dyskinesias with transient orolingual predominance.


Subject(s)
Antiparkinson Agents/pharmacology , Dyskinesias/drug therapy , Levodopa/pharmacology , Striatonigral Degeneration/drug therapy , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Forelimb/drug effects , Forelimb/physiology , Image Processing, Computer-Assisted , Male , Movement Disorders/drug therapy , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Rats , Striatonigral Degeneration/pathology , Striatonigral Degeneration/physiopathology
17.
Neuroscience ; 118(4): 1063-77, 2003.
Article in English | MEDLINE | ID: mdl-12732251

ABSTRACT

Previous studies have shown that intrastriatal transplants of dopamine (DA)-rich fetal ventral mesencephalic (VM) tissue can correct denervation-induced changes in the cellular expression of neuropeptide and receptor mRNAs in the rat Parkinson model. However, with the standard transplantation approach normalization of all cellular parameters has not been obtained. This may be due either to the incomplete striatal reinnervation achieved by these transplants, or to the ectopic placement of the grafts. In the present study we have used a microtransplantation approach to obtain a more complete reinnervation of the denervated striatum (20 micrograft deposits spread over the entire structure). Neurons were also implanted directly into the substantia nigra. In rats with multiple intrastriatal VM transplants the lesion-induced upregulation of mRNAs encoding for preproenkephalin (PPE), the D(2)-type DA-receptor, and the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD(67)) was normalized throughout the striatum, whereas the lesion-induced downregulation of preprotachykinin mRNA was unaffected. Intranigral grafts of either fetal DA-rich VM tissue or GABA-rich striatal tissue did not induce any changes in striatal neuropeptide and D(2)-receptor mRNA expression despite significant behavioral improvement. Comparison of the behavioral data with levels of neuropeptide expression showed that in rats with intrastriatal VM transplants a complete normalization of striatal PPE and GAD(67) mRNA expression did not translate into a complete recovery of spontaneous motor behaviors. The results show that extensive DA reinnervation of the host striatum by multiple VM microtransplants is insufficient to obtain full recovery of all lesion-induced changes at both the cellular and the behavioral level. A full reconstruction of the nigrostriatal pathway or, alternatively, modulation of basal ganglia function by grafting in non-striatal regions may be required to further improve the functional outcome in the DA-denervated brain.


Subject(s)
Basal Ganglia/metabolism , Gene Expression Regulation , Neuropeptides/genetics , Septal Nuclei/transplantation , Substantia Nigra/transplantation , Adrenergic Agents/toxicity , Animals , Autoradiography/methods , Brain Mapping , Disease Models, Animal , Embryo, Mammalian , Enkephalins/genetics , Enkephalins/metabolism , Entopeduncular Nucleus/metabolism , Female , Fetal Tissue Transplantation , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/metabolism , Immunohistochemistry/methods , In Situ Hybridization/methods , Neuropeptides/metabolism , Oxidopamine/toxicity , Parkinsonian Disorders/metabolism , Protein Precursors/genetics , Protein Precursors/metabolism , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Regression Analysis , Septal Nuclei/embryology , Substantia Nigra/embryology , Tachykinins/genetics , Tachykinins/metabolism
18.
J Neurochem ; 84(6): 1398-410, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12614340

ABSTRACT

We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.


Subject(s)
Behavior, Animal/drug effects , Dyskinesia, Drug-Induced/drug therapy , Levodopa/adverse effects , Purinergic P1 Receptor Antagonists , Purines/pharmacology , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Disease Models, Animal , Drug Therapy, Combination , Dyskinesia, Drug-Induced/complications , Enkephalins/genetics , Enkephalins/metabolism , Female , Motor Activity/drug effects , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/complications , Parkinsonian Disorders/drug therapy , Protein Precursors/genetics , Protein Precursors/metabolism , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Adenosine A2A , Treatment Outcome
19.
Eur J Neurosci ; 17(3): 661-6, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12581184

ABSTRACT

DeltaFosB-like proteins are particularly stable transcription factors that accumulate in the brain in response to chronic perturbations. In this study we have compared the time-course of striatal FosB/DeltaFosB-like immunoreactivity and prodynorphin mRNA expression after discontinuation of chronic cocaine treatment to intact rats and chronic L-DOPA treatment to unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats. The animals were killed between 3 h and 16 days after the last drug injection. In both treatment paradigms, the drug-induced FosB/DeltaFosB immunoreactivity remained significantly elevated in the caudate putamen even at the longest withdrawal period examined. The concomitant upregulation of prodynorphin mRNA, a target of DeltaFosB, paralleled the time-course of DeltaFosB-like immunoreactivity in the 6-OHDA-lesion/L-DOPA model, but was more transient in animals treated with cocaine. These results suggest that DeltaFosB-like proteins have exceptional in vivo stability. In the dopamine-denervated striatum, these proteins may exert sustained effects on the expression of their target genes long after discontinuation of L-DOPA pharmacotherapy.


Subject(s)
Dopamine/physiology , Enkephalins/biosynthesis , Neostriatum/metabolism , Protein Precursors/biosynthesis , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/biosynthesis , Animals , Aromatic Amino Acid Decarboxylase Inhibitors , Benserazide/pharmacology , Cocaine/pharmacology , Denervation , Dopamine Uptake Inhibitors/pharmacology , Enzyme Inhibitors/pharmacology , Female , Hydroxydopamines/toxicity , Immunohistochemistry , In Situ Hybridization , Levodopa/pharmacology , Neostriatum/cytology , Neural Pathways/metabolism , Neural Pathways/physiology , Rats , Rats, Sprague-Dawley , Sympathectomy, Chemical
20.
Amino Acids ; 23(1-3): 105-9, 2002.
Article in English | MEDLINE | ID: mdl-12373525

ABSTRACT

L-DOPA-induced dyskinesia (abnormal involuntary movements) is one of the most debilitating complications of chronic L-DOPA pharmacotherapy in Parkinson's disease. It is generally agreed that dyskinesia arises as a consequence of pulsatile dopamine-receptor stimulation in the brain, causing downstream changes in genes and proteins. Advance in our understanding of such changes is critically dependent on the availability of suitable animal models. We have introduced a new method to classify and rate L-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) lesioned rats. This method allows us to dissect the molecular correlates of a dyskinetic motor response to L-DOPA in this species. One of the most prominent molecular changes underlying the development of dyskinesia in the rat consists in the striatal induction of prodynorphin gene expression by L-DOPA. This effect is mediated by FosB-related transcription factors of 32-37 kDa, which are co-induced with prodynophin in striatal neurons of the "direct pathway". Both AIM development and the associated upregulation of prodynorphin mRNA by L-DOPA are significantly inhibited by the intrastriatal infusion of fosB antisense. Antisense-mediated knockdown of CREB (cyclic AMP response-element binding proteins) has however no effect. Our results identify fosB as a potential target for adjunctive antiparkinsonian therapies.


Subject(s)
Antiparkinson Agents/adverse effects , Dyskinesia, Drug-Induced , Levodopa/adverse effects , Parkinsonian Disorders/metabolism , Transcription Factors/metabolism , Animals , Antiparkinson Agents/therapeutic use , Corpus Striatum/pathology , Disease Models, Animal , Enkephalins/genetics , Enkephalins/metabolism , Gene Expression Regulation , Levodopa/therapeutic use , Oxidopamine/toxicity , Parkinsonian Disorders/drug therapy , Protein Precursors/genetics , Protein Precursors/metabolism , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Rats , Sympatholytics/toxicity
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