Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson’s Disease

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.

Effects of Parkinson's disease on molar bite force, electromyographic activity and muscle thickness of the masseter, temporal and sternocleidomastoid muscles: A case‐control study

“…Medication administered to patients with chronic degenerative diseases may be associated with the functional state of muscle deterioration by promoting a reduction in muscle mass . Levodopa is the drug most commonly used to control Parkinson's disease and improve muscle control and cognitive response of patients; however, it may have adverse side effects . Levodopa is transformed into dopamine by enzymes present in various organs of the body .…”

“…Levodopa is the drug most commonly used to control Parkinson's disease and improve muscle control and cognitive response of patients; however, it may have adverse side effects 40. Levodopa is transformed into dopamine by enzymes present in various organs of the body 41.…”

Neuropsychiatric Disorders in Parkinson’s Disease: What Do We Know About the Role of Dopaminergic and Non-dopaminergic Systems?

“…Similarly, α-synuclein-induced nigrostriatal neurodegeneration increases impulsivity by itself, subsequent chronic pramipexole administration exacerbating it (Engeln et al, 2016). Impulsive behavior does not develop in 6-OHDA-lesioned rodents (Baunez and Robbins, 1999;Carvalho et al, 2017). Differences may rely on the severity and topography of the dopaminergic lesions and on the tests used.…”

Neuropsychiatric Traits Associated with Refractory Impulse Control Disorder in Parkinson’s Disease

“…Our data suggests that punding-like behaviors need to be monitored when implementing a dopamine-agonist switch-off therapy in PD patients. Together with these observations, PD patients with chronic levodopa treatment tend to have high impulsivity and risk-taking behaviors as with those taking dopamine agonists, especially when they are taking high doses [21][22][23]. The poor-outcome group had a high levodopa dose relative to the good-outcome group at baseline in this trial (daily levodopa dose = 0.831.7 ± 637.2 vs. 550.3 ± 508.3 mg/day, respectively, p = 0.240, and total levodopa daily equivalent dose = 1,436.9 ± 858.0 vs. 978.7 ± 696.1 mg/day, respectively, p = 0.064).…”