title: Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy.
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.
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Engeln
authors.affiliation: Service de neurologie de l'hôpital de Poitiers, F-86021, Poitiers, France; Université de Poitiers, F-86000, Poitiers, France; CIC INSERM 1402, CHU de Poitiers, Poitiers, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Ansquer
authors.affiliation: Université de Poitiers, F-86000, Poitiers, France; CIC INSERM 1402, CHU de Poitiers, Poitiers, France; INSERM U1084 Laboratoire de Neurosciences Experimentales et Cliniques, F-86000, Poitiers, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dugast
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: INSERM U1084 Laboratoire de Neurosciences Experimentales et Cliniques, F-86000, Poitiers, France; Department of Pharmacology, University of Cambridge, CB2 1PD, Cambridge, UK; Behavioural and Clinical Neuroscience Institute of the University of Cambridge, CB2 3ED, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Belin
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000, Bordeaux, France. Electronic address: pierre-olivier.fernagut@u-bordeaux.fr.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D018491:Dopamine Agonists; D004298:Dopamine
keywords: Alpha-synuclein; Impulsivity; Parkinson; Pramipexole; Substantia nigra