Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy

Solène Ansquer,Erwan Bezard,Pierre-Olivier Fernagut,Michel Engeln,David Belin,Emilie Dugast

doi:10.1016/j.neuropharm.2016.05.013

Abstract

Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson’s disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral-mediated overexpression of α-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. α-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted α-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized both by degeneration of several neuronal populations, M
Our results provide the first evidence that impulsivity is associated with a differential vulnerability to a-synuclein-induced dopaminergic neurodegeneration, with high impulsive (HI) rats being less sensitive than Int and low impulsive (LI) rats
This study in a bilateral rat model of PD shows that nigrostriatal dopaminergic neurodegeneration, DRT and pre-morbid impulsivity interact, and differentially contribute to alter inhibitory control

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized both by degeneration of several neuronal populations, M. Motor and waiting impulsivity are related to a dysfunctional dopaminergic modulation of corticostriatal networks (Antonelli et al, 2013; Basar et al, 2010; D’AmourHorvat and Leyton, 2014; Jentsch et al, 2014): while drugs enhancing dopamine transmission increase, and dopamine antagonists decrease, motor impulsivity, the opposite modulation is found for waiting impulsivity (reviewed in (D’Amour-Horvat and Leyton, 2014; Dalley et al, 2008; Dalley and Roiser, 2012)). DRT increasing dopamine signaling may exacerbate motor impulsivity, while dopaminergic cell-loss would decrease dopamine levels and increase waiting impulsivity. Such influences of pharmacological manipulations of dopamine transmission may be biased in PD by the asymmetry in denervation between the relatively spared mesocorticolimbic network and the severely damaged nigrostriatal pathway. DRT may induce a dopaminergic overdose of the nucleus accumbens and frontal cortex that may increase impulsivity (Cools et al, 2003; Gotham et al, 1988) in a state-dependent manner (Caprioli et al, 2013)

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Discussion

Conclusion