Abstract
The use of dopamine replacement therapies (DRT) in the treatment of Parkinson’s disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.
Highlights
In accordance with a theory of dopamine (DA) ‘‘overdose’’, dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD) in Parkinson’s disease (PD) have been linked to an excessive dopaminergic stimulation of the relatively spared mesocorticolimbic pathway caused by Dopamine replacement therapies (DRT) (Dagher and Robbins, 2009; O’Sullivan et al, 2009; Voon et al, 2017)
We aimed at assessing the behavioral consequences of LD administration in an animal model of PD, with a focus on reward and impulsivity
In addition to the dopaminergic degeneration in A9 and A10 regions, we observed a significant reduction in DA content in their major projection targets, dorsal striatum (dSTR) and nucleus accumbens (NAcc), respectively
Summary
Parkinson’s disease (PD) is a chronic neurodegenerative disorder affecting the dopaminergic system, causing significant neuronal loss in the substantia nigra pars compacta (SNc, or A9), and in the ventral tegmental area (VTA, or A10; Hirsch et al, 1988; German et al, 1989; Parkinson, 2002), and characterized by a number of different motor and non-motorLevodopa Affects Reward and Impulsivity symptoms (Jankovic, 2008; Obeso et al, 2008; Chaudhuri and Schapira, 2009; Dirnberger and Jahanshahi, 2013). Regardless of the fact that the causal mechanisms for DDS and ICD are unknown, it is interesting to observe that they share many behavioral features, including a compulsive pattern of DRT abuse (for DDS) and engagement in ‘‘behavioral addictions’’ (for ICD; Giovannoni et al, 2000; Voon et al, 2017), the hedonic value that DRT abuse and ‘‘behavioral addictions’’ can hold (Giovannoni et al, 2000; Evans et al, 2009); and the development of withdrawal symptoms if LD or DAg dosages are reduced, or if engagement in ‘‘behavioral addiction’’ is restricted (Giovannoni et al, 2000; Evans et al, 2009; Pondal et al, 2013) Both of these syndromes share behavioral and functional similarities with substance addictions or impulsive behaviors in healthy individuals (Voon and Fox, 2007; Dagher and Robbins, 2009). Support for this hypothesis is found in human studies showing that in PD patients, DRT can significantly impair reward-based learning, making patients overvalue positive rewards while desensitizing them to risk or negative outcomes (Bódi et al, 2009; Housden et al, 2010; Voon et al, 2010a, 2011), and foster impulsive responding (Housden et al, 2010; Voon et al, 2010b)
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