Abstract
Treatment with dopamine agonists in Parkinson’s disease (PD) is associated with debilitating neuropsychiatric side-effects characterized by impulsive and compulsive behaviors. The vulnerability to develop such impairments is thought to involve interactions between individual vulnerability traits, types of antiparkinsonian medications, and the neurodegenerative process. We investigated the effect of the dopamine D3/D2 agonist pramipexole (PPX) and selective nigrostriatal degeneration achieved by viral-mediated expression of alpha-synuclein on the expression of repetitive and compulsive-like behaviors in rats. In a task assessing spontaneous food hoarding behavior, PPX increased the time spent interacting with food pellets at the expense of hoarding. This disruption of hoarding behavior was identical in sham and lesioned rats. In an operant post-training signal attenuation task, the combination of nigrostriatal lesion and PPX decreased the number of completed trials and increased the number of uncompleted trials. The lesion led to an increased compulsive behavior after signal attenuation, and PPX shifted the overall behavioral output towards an increased proportion of compulsive lever-presses. Given the magnitude of the behavioral effects and the lack of strong interaction between PPX and nigral degeneration, these results suggest that extra-nigral pathology may be critical to increase the vulnerability to develop compulsive behaviors following treatment with D3/D2 agonists.
Highlights
Publisher’s Note: MDPI stays neutralChronic treatment with dopamine agonists can lead to a number of cognitive and neuropsychiatric side-effects in a significant proportion of patients with Parkinson’s disease (PD)
(repetitive, stereotyped, and purposeless behavior), hobbyism [3], as well as hoarding behavior [4]. Since these behaviors are reported in patients treated with D3/D2 agonists for other non-neurodegenerative conditions such as restless legs syndrome [5] or prolactinoma [6], the respective contributions of the drug and of dopaminergic neurodegeneration remain poorly understood
Impulsive-compulsive behaviors are increasingly recognized as a major issue related to the chronic treatment with dopamine agonists in PD and other conditions such as restless leg syndrome or prolactinoma [2,5,6]
Summary
Chronic treatment with dopamine agonists can lead to a number of cognitive and neuropsychiatric side-effects in a significant proportion of patients with Parkinson’s disease (PD). Perseverance of the behavior in spite of lack of reward is a common process in all impulsive-compulsive behaviors experienced by the patients In rodents, both spontaneous behaviors and operant conditioning procedures can be used to investigate how nigrostriatal degeneration and treatment with D3/D2 agonists may affect behaviors that are relevant to those occurring in PD patients. We tested the hypothesis that the respective contributions of nigrostriatal degeneration, treatment with dopamine agonists, as well as lesion and drug interactions in the emergence of impulsive-compulsive behaviors could be identified using behavioral procedures that can lead to perseverative and compulsive behaviors To this end, we investigated the effect of the D3/D2 agonist pramipexole (PPX) on repetitive and perseverative behaviors using either spontaneous behavior in a food hoarding task, or operant responding in the PTSA task in normal rats and in animals with alpha-synucleininduced degeneration of nigrostriatal dopaminergic neurons
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