Abstract
Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson’s disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder hitherto considered to stem from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and mainly characterized by cardinal motor symptoms (Samii et al, 2004)
Rats were first trained in a Delay Discounting Task (DDT) under which the delay increased progressively within each test session, in order to measure individuals’ basal level of impulsive choice and distribute them in the various experimental groups
At resumption of within-DDT training, all rats maintained a preference for the large reinforcer over the smaller one in absence of delay, and irrespective of the lesion (Figure 3A; delay 0 s), indicating that, in agreement with previous results (Drui et al, 2014), the relative reinforcing value of natural rewards was not influenced by the nigrostriatal DA denervation
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder hitherto considered to stem from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and mainly characterized by cardinal motor symptoms (Samii et al, 2004). Since only a subset of PD patients is affected by ICDs, the degeneration of the nigrostriatal DA system does not appear to be sufficient to promote ICDs, indicating a potential interaction with an endophenotype of vulnerability, as suggested in a previous study (Engeln et al, 2016). Based on 6-OHDA-induced bilateral but partial lesions of the nigrostriatal DA system, this model has been demonstrated to reveal denervation-induced behavioral impairments, such as motivational- and affective-related deficits, without displaying significant impairments of motor functions (Carnicella et al, 2014; Drui et al, 2014; Favier et al, 2014)
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