Assessment of Repetitive and Compulsive Behaviors Induced by Pramipexole in Rats: Effect of Alpha-Synuclein-Induced Nigrostriatal Degeneration

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.