Amphetamine-induced dopamine release and impulsivity in Parkinson disease

Abstract

Abstract Impulsive-compulsive behaviors manifest in a substantial proportion of persons with Parkinson disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson disease. Here, we applied [18F]fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson disease patients with impulsive-compulsive behaviors would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty persons with Parkinson disease (mean age = 64.1 ± 5.8) both with (N = 10) and without (N = 10) impulsive-compulsive behaviors, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an off-dopamine state. All completed PET imaging with [18F]fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise, and region-of-interest analyses, revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum positively correlated with patient-reported participation in reward-based behaviors, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson’s disease Rating Scale. In participants without impulsive-compulsive behaviors, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviors. These findings emphasize that reward-based behaviors in PD are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviors.