Dopamine Agonists in Parkinson's Disease Decouple Risk-Taking from Reward-Paired Cues by Enhancing Risky Choice in Their Absence

Background: Common side effects of dopamine replacement therapy (DRT) for Parkinson's Disease (PD) are addiction-like impulse control disorders, including compulsive gambling. Gambling products such as slot machines prominently feature reward-paired audiovisual stimuli, which can promote riskier choices on laboratory gambling tasks in both humans and rodents. In rats, risky decision making in the presence of reward-paired cues is dependent on dopamine D3 receptor activity and is increased by ropinirole, a D2/3 receptor agonist with a higher affinity for D3 receptors. In humans, it remains uncertain whether cue-induced risky choice is amplified by dopamine agonism. Methods: We tested effects of DRT on cue-induced risky choice in 62 patients with PD (34 on levodopa monotherapy, 27 on levodopa and dopamine agonists). Patients performed two versions of a risky decision-making task: one with and one without reward-paired sensory cues, both ON and OFF DRT. A group of 36 age-matched controls completed the same task versions without DRT. Results: Across all groups, participants made riskier choices when the task included reward-paired sensory cues. Levodopa monotherapy did not affect risky decision-making. However, a combination of levodopa and dopamine agonists increased risky choices specifically in the uncued version of the task, making performance indistinguishable from that on the cued task. Conclusions: Dopamine agonists combined with levodopa promote risk-taking even in the absence of reward-paired cues. This could translate into risky reward-seeking behaviors that are decoupled from contextual factors.