Increased Impulsivity following progressive nigral degenereation and chronic pramipexole treatment in an animal model of Parkinson's disease

Dopamine agonists (DA) that are widely used to treat motor deficits in patients with Parkinson’s disease (PD) are frequently associated with the development of abnormal-impulsive behaviors (AIB). The pathophysiology of AIB is poorly understood and there is a need for reliable animal models. We have analyzed the behavior of parkinsonian (injection of adeno-associated viral vectors (AAV) encoding for A53T mutated hα-syn in the substantia nigra compacta) and control (AAV- GFP expression) rats under chronic treatment with the D2/D3 receptor DA pramipexole (PPX) during 4 weeks, in OFF and ON medication states, using the 5-Choice Serial Reaction Time-Task (5-CSRTT). Before PPX treatment, the dopaminergic lesion increased the premature responses rate (waiting impulsivity) that was further increased with PPX during the 4 weeks of treatment in ON medication state and that was significantly higher than in control rats. A similar pattern of changes was observed in the variables related to attention (reduced accuracy in the responses and increased omissions). Premature response rate before and after treatment (both in ON and OFF medication) were correlated. In turn, premature responses before treatment and in OFF correlated with the striatal dopaminergic depletion (Dopamine transporter (DAT) immunochemistry). No significant changes were observed in OFF medication state in premature responses rate respect to the pretreatment state. The striatal expression of FosB/ΔFosB inversely correlated with the DAT expression and was higher in the lateral region of both striata and in the shell and core of the nucleus accumbens in parkinsonian than in control rats. In conclusion, these results indicate that the dopaminergic lesion is a risk factor to develop abnormal impulsive behaviors in PD under DA treatment and that this model could be a valid tool to investigate the pathophysiology of AIB in PD (DFG11/019, PI11/02109).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

A model of increased impulsivity in rats with bilateral parkinsonism treated with Pramipexole

Impulse control disorders (ICD) is a common side effect of the dopaminergic treatment in patients with Parkinson's disease, which is more associated with dopamine agonists than with levodopa. To understand its pathophysiology, reliable animal models are essential. Using the variable delay-to-signal (VDS) paradigm, impulsivity was evaluated in bilateral parkinsonian rats treated with pramipexole (PPX). In this test, rats have to introduce the snout into a nose poke that is signaled by a light (presented at variable delays) triggering the delivery of a food reward after a correct response. Reaching a stable baseline performance, a partial bilateral dopaminergic lesion with 6-OHDA was induced in the dorsolateral striatum (AP: +1mm, L: ±3.4mm, V:-4.7 mm, Bregma). Rats undertook the VDS test under 5 conditions: basal state, 6-OHDA-induced lesion, the effect of two doses of PPX (0,25mg/kg and 3mg/kg; Latin-square design), and the day after the last dose of PPX. Only the acute administration of 3 mg/kg of PPX significantly rised the number of premature responses, indicating an increase of impulsive behavior, in parkinsonian but not in sham rats. Both doses of PPX significantly decreased the accuracy of responding (correct/total number of responses) and increased the incorrect and perseverative (compulsive behavior) responses in both parkinsonian and sham treated groups when compared with saline-treated groups. In conclusion, PPX induced attention deficit (lack of accuracy) as well as compulsive behavior in control and parkinsonian rats, but increased impulsivity only in the parkinsonian animals. This model could constitute a valid tool to investigate the pathophysiology of ICD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Different susceptibility to pramipexole-induced impulsivity in a rat model of parkinson’s disease

Impulse Control Disorders (ICD) in patients with Parkinson’s disease are abnormal behaviors caused by long-term use of dopamine agonists, which pathophysiology is poorly understood. Using parkinsonian rats (adeno-associated viral vectors-mediated overexpression of A53T human α-synuclein in the substantia nigra compacta), we evaluated the impulsive behaviour under acute (0.25 and 3 mg/kg) and chronic (0.25 mg/kg for 4 weeks) administration of pramipexole (PPX) with the Variable Delay-to-Signal (VDS) task (motor and choice impulsivities). Changes in striatal D1 and D2 receptors expression were also analysed. Before treatment, the striatal dopaminergic depletion caused a significant increase of both impulsivity domains with respect to basal condition. In lesioned rats, acutely given PPX 0.25 mg/kg dose increased choice impulsivity only with regard to basal values. Meanwhile, 3 mg/kg PPX increased choice impulsivity compared to their own values at different conditions: basal, before treatment and after acute 0.25 mg/kg PPX administration. After chronic administration, two populations of lesioned animals were distinguished, one showing the same behaviour as control animals and other displaying an increased motor/response (first week of treatment) and cognitive/choice impulsivities (third week of treatment) compared to control animals. This impulsive behaviour disappeared when animals were tested in OFF state. Lower D2 expression in both Caudate-Putamen and Nucleus Accubens and lower D1 levels in Nucleus Accumbens in lesioned rats than in control animals were observed. Therefore, our results indicate that the pro-impulsive effect of PPX in this animal model of PD depends on the dose and administration paradigm employed and the individual predisposition, and it is associated to striatal dopamine receptors expression changes, especially in Nucleus Accumbens. Thus, this model could constitute a valid tool to investigate the pathophysiology of ICD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. DFG11/019, PI11/0210

Disrupted salience network dynamics in Parkinson's disease patients with impulse control disorders

Available online 16 December2019Background: Dynamic functional network analysis may add relevant information about the temporal nature of the neurocognitive alterations in PD patients with impulse control disorders (PD-ICD). Our aim was to investigate changes in dynamic functional network connectivity (dFNC) in PD-ICD patients, and topological properties of such networks. Methods: Resting state fMRI was performed on 16 PD PD-ICD patients, 20 PD patients without ICD and 17 healthy controls, whose demographic, clinical and behavioral scores were assessed. We conducted a group spatial independent component analysis, sliding window and graph-theory analyses. Results: PD-ICD patients, in contrast to PD-noICD and HC subjects, were engaged across time in a brain configuration pattern characterized by a lack of between-network connections at the expense of strong withinnetwork connections (State III) in temporal, frontoinsular and cingulate cortices, all key nodes of the salience network. Moreover, this increased maintenance of State III in PD-ICD patients was positively correlated with the severity of impulsivity and novelty seeking as measured by specific scales. While in State III, these patients also exhibited increased local efficiency in all the aforementioned areas. Conclusions: Our findings show for the first time that PD-ICD patients have a dynamic functional engagement of local connectivity involving the limbic circuit, leading to the inefficient modulation in emotional processing and reward-related decision-making. These results provide new insights into the pathophysiology of ICD in PD patients and indicate that the dFC study of fMRI could be a useful biomarker to identify patients at risk to develop ICD.This work was supported by the Carlos III Institute of Health [PI11/ 02109] and by the ERA-NET Neuron program [PIM2010ERN-00733]. I.N-G. held a Mobility of Research Staff 2017 grant [MV17/00015] from the Carlos III Institute of Health under the framework of a Rio Hortega 2016 grant [CM16/00033]. J.K. has no disclosures to declare. P.M.P-A was supported by grants from the Spanish Ministry of Economy and Competitiveness [MINECO, RYC-2014-15440 and PGC2018- 093408-B-I00], and Neuroscience Research Projects programme from the Fundación Tatiana Pérez de Guzmán el Bueno. BCBL acknowledges funding from the Basque Government through the BERC 2018–2021 program and by the Spanish State Research Agency through BCBL Severo Ochoa excellence accreditation [SEV-2015-0490]. A.P.S. is supported by the Canadian Institute of Health Research and Canada Research Chair program. M.C.R–O. received financial support for her research from national and local government institutions in Spain (Carlos III Institute of Health, Basque Country Government, Diputacion Foral Guipuzcoa and the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED))