Impulse-control disorders in Parkinson's Disease: development of an animal model

206 p.El objetivo de la presente tesis es el desarrollo de un modelo animal de parkinsonismo e impulsividad inducido por la administración del agonista dopaminérgico pramipexol (PPX).La enfermedad de Párkinson (EP) es una enfermedad neurodegenerativa caracterizada por el desarrollo de alteraciones motoras (temblor, rigidez y bradicinesia) que están asociadas a una progresiva muerte de neuronas dopaminérgicas de la sustancia negra compacta pars compacta (SNc), la consecuente depleción dopaminérgica en el estriado y la aparición de agregados proteicos intracelulares (principalmente de ¿-sinucleína, (¿-syn)). La fisiopatología de la muerte neuronal es aún desconocida en gran medida, y los tratamientos disponibles actualmente están enfocados a mitigar los signos motores de la enfermedad mediante la reposición exógena del déficit dopaminérgico, principalmente mediante la administración de levodopa (precursor de la dopamina) y/o agonistas dopaminérgicos como el PPX. Sin embargo, estos tratamientos promueven un progresivo desarrollo de efectos secundarios motores y no motores a medio-largo plazo, de los que las disquinesias (movimientos involuntarios de tipo coréico) y las complicaciones psiquiátricas como el trastorno de control de impulsos (TCI) (que incluye el juego patológico, las compras compulsivas, la hipersexualidad y la ingesta compulsiva de comida) y otros trastornos impulsivos-compulsivos (síndrome de disregulación dopaminérgica (SDD)), son los más frecuentes e incapacitantes. A pesar de su negativa influencia sobre la vida diaria de los pacientes, la fisiopatología subyacente al TCI en la EP no está bien definida, a lo que contribuye la falta de modelos animales que reflejen lo más fielmente posible las características de este trastorno y se pueden llevar a cabo estudios en ellos.En este sentido, se han realizado diferentes aproximaciones en la literatura, pero se hacen imprescindibles nuevos estudios por diferentes motivos: el análisis de un único rasgo de la impulsividad en los tests conductuales usados o el uso de refuerzos artificiales (como la estimulación eléctrica de la amígdala) en vez de refuerzos naturales como la comida o el sexo, alejándose así del contexto clínico. Por ello, el uso de tests que puedan medir simultáneamente diferentes aspectos de los comportamientos impulsivos-compulsivos y que empleen refuerzos naturales se hace particularmente necesario

Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism

Synaptic impairment might precede neuronal degeneration in Parkinson’s disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. Sequential window acquisition of all theoretical mass spectra proteomics identified deregulated proteins involved first in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics was followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres was evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolved. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated postsynaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells to delay or prevent the development of Parkinson’s disease.This study was funded by the Instituto de Salud Carlos III through the projects PI14/00763 and PI19/01915 (co-funded by ERDF/ESF, ‘Investing in your future’). L.M.-G. held a Predoctoral Research Fellowship from the University of the Basque Country (UPV/EHU). T.R.-C. and A.Q.-V. were funded by CIBERNED. T.R.-C. held a Fundación Jesús de Gangoiti Barrera Foundation grant (Bilbao, Spain). H.J.-U. and A.B.-I. held a Predoctoral Research Fellowship from the Government of the Basque Country. Israel Science Foundation (536/19) and the Spanish Ministry of Science (SAF2016-78071-R) funded the contribution of S.K. and A.O

Impulse-control disorders in Parkinson's Disease: development of an animal model

206 p.El objetivo de la presente tesis es el desarrollo de un modelo animal de parkinsonismo e impulsividad inducido por la administración del agonista dopaminérgico pramipexol (PPX).La enfermedad de Párkinson (EP) es una enfermedad neurodegenerativa caracterizada por el desarrollo de alteraciones motoras (temblor, rigidez y bradicinesia) que están asociadas a una progresiva muerte de neuronas dopaminérgicas de la sustancia negra compacta pars compacta (SNc), la consecuente depleción dopaminérgica en el estriado y la aparición de agregados proteicos intracelulares (principalmente de ¿-sinucleína, (¿-syn)). La fisiopatología de la muerte neuronal es aún desconocida en gran medida, y los tratamientos disponibles actualmente están enfocados a mitigar los signos motores de la enfermedad mediante la reposición exógena del déficit dopaminérgico, principalmente mediante la administración de levodopa (precursor de la dopamina) y/o agonistas dopaminérgicos como el PPX. Sin embargo, estos tratamientos promueven un progresivo desarrollo de efectos secundarios motores y no motores a medio-largo plazo, de los que las disquinesias (movimientos involuntarios de tipo coréico) y las complicaciones psiquiátricas como el trastorno de control de impulsos (TCI) (que incluye el juego patológico, las compras compulsivas, la hipersexualidad y la ingesta compulsiva de comida) y otros trastornos impulsivos-compulsivos (síndrome de disregulación dopaminérgica (SDD)), son los más frecuentes e incapacitantes. A pesar de su negativa influencia sobre la vida diaria de los pacientes, la fisiopatología subyacente al TCI en la EP no está bien definida, a lo que contribuye la falta de modelos animales que reflejen lo más fielmente posible las características de este trastorno y se pueden llevar a cabo estudios en ellos.En este sentido, se han realizado diferentes aproximaciones en la literatura, pero se hacen imprescindibles nuevos estudios por diferentes motivos: el análisis de un único rasgo de la impulsividad en los tests conductuales usados o el uso de refuerzos artificiales (como la estimulación eléctrica de la amígdala) en vez de refuerzos naturales como la comida o el sexo, alejándose así del contexto clínico. Por ello, el uso de tests que puedan medir simultáneamente diferentes aspectos de los comportamientos impulsivos-compulsivos y que empleen refuerzos naturales se hace particularmente necesario

Neuropsychiatric and Cognitive Deficits in Parkinson’s Disease and Their Modeling in Rodents

International audienceParkinson’s disease (PD) is associated with a large burden of non-motor symptoms including olfactory and autonomic dysfunction, as well as neuropsychiatric (depression, anxiety, apathy) and cognitive disorders (executive dysfunctions, memory and learning impairments). Some of these non-motor symptoms may precede the onset of motor symptoms by several years, and they significantly worsen during the course of the disease. The lack of systematic improvement of these non-motor features by dopamine replacement therapy underlines their multifactorial origin, with an involvement of monoaminergic and cholinergic systems, as well as alpha-synuclein pathology in frontal and limbic cortical circuits. Here we describe mood and neuropsychiatric disorders in PD and review their occurrence in rodent models of PD. Altogether, toxin-based rodent models of PD indicate a significant but non-exclusive contribution of mesencephalic dopaminergic loss in anxiety, apathy, and depressive-like behaviors, as well as in learning and memory deficits. Gene-based models display significant deficits in learning and memory, as well as executive functions, highlighting the contribution of alpha-synuclein pathology to these non-motor deficits. Collectively, neuropsychiatric and cognitive deficits are recapitulated to some extent in rodent models, providing partial but nevertheless useful options to understand the pathophysiology of non-motor symptoms and develop therapeutic options for these debilitating symptoms of PD

Transcriptomic integration of D4R and MOR signaling in the rat caudate putamen.

Morphine binding to opioid receptors, mainly to μ opioid receptor (MOR), induces alterations in intracellular pathways essential to the initial development of addiction. The activation of the dopamine D4 receptor (D4R), which is expressed in the caudate putamen (CPu), mainly counteracts morphine-induced alterations in several molecular networks. These involve transcription factors, adaptive changes of MOR signaling, activation of the nigrostriatal dopamine pathway and behavioural effects, underlining functional D4R/MOR interactions. To shed light on the molecular mechanisms implicated, we evaluated the transcriptome alterations following acute administration of morphine and/or PD168,077 (D4R agonist) using whole-genome microarrays and a linear regression-based differential expression analysis. The results highlight the development of a unique transcriptional signature following the co-administration of both drugs that reflects a countereffect of PD168,077 on morphine effects. A KEGG pathway enrichment analysis using GSEA identified 3 pathways enriched positively in morphine vs control and negatively in morphine + PD168,077 vs morphine (Ribosome, Complement and Coagulation Cascades, Systemic Lupus Erythematosus) and 3 pathways with the opposite enrichment pattern (Alzheimer's Disease, Neuroactive Ligand Receptor Interaction, Oxidative Phosphorilation). This work supports the massive D4R/MOR functional integration at the CPu and provides a gateway to further studies on the use of D4R drugs to modulate morphine-induced effects

Assessment of Repetitive and Compulsive Behaviors Induced by Pramipexole in Rats: Effect of Alpha-Synuclein-Induced Nigrostriatal Degeneration

International audienceTreatment with dopamine agonists in Parkinson’s disease (PD) is associated with debilitating neuropsychiatric side-effects characterized by impulsive and compulsive behaviors. The vulnerability to develop such impairments is thought to involve interactions between individual vulnerability traits, types of antiparkinsonian medications, and the neurodegenerative process. We investigated the effect of the dopamine D3/D2 agonist pramipexole (PPX) and selective nigrostriatal degeneration achieved by viral-mediated expression of alpha-synuclein on the expression of repetitive and compulsive-like behaviors in rats. In a task assessing spontaneous food hoarding behavior, PPX increased the time spent interacting with food pellets at the expense of hoarding. This disruption of hoarding behavior was identical in sham and lesioned rats. In an operant post-training signal attenuation task, the combination of nigrostriatal lesion and PPX decreased the number of completed trials and increased the number of uncompleted trials. The lesion led to an increased compulsive behavior after signal attenuation, and PPX shifted the overall behavioral output towards an increased proportion of compulsive lever-presses. Given the magnitude of the behavioral effects and the lack of strong interaction between PPX and nigral degeneration, these results suggest that extra-nigral pathology may be critical to increase the vulnerability to develop compulsive behaviors following treatment with D3/D2 agonists

Biomarkers for Dementia and Mild Cognitive Impairment in Parkinson’s Disease

Version of record online: 19 May 2016Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinson's disease. Around 30% of patients with Parkinson's disease experience mild cognitive impairment, a well-established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinson's disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinson's disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinson's disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin-like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia.Institute of Health Carlos III (ISCIII), grants PI08/1539 and PI14/00763; Government of the Basque Country, grants 2011111074 and SAIO12-PE12BN012; and CIBERNED. M.D.-A. is funded by a Basque Country Ph.D. studentship and a Jes us de Gangoiti Barrera Foundation grant

Correction to: Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.

In the original version of this article, the Figure 3 was published in an incorrect format, even though the data and the related information in the text are correct

Pramipexole-induced impulsivity in mildparkinsonian rats: a model of impulse control disorders in Parkinson's disease

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