Objective: The objective was to investigate the effect of dopaminergic therapy on healthy young adults to test the dopamine overdose hypothesis.

Background: Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson’s disease. These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on cognitive functions is determined by the baseline dopamine levels in brain regions mediating these functions. We directly tested this hypothesis, evaluating the effects of levodopa on stimulus-reward and stimulus-response learning in healthy young adults, who have optimal baseline dopamine levels and dopamine regulation.

Methods: In each experiment, half of the participants were tested on 100/25 mg of levocarb whereas the other half were tested on placebo in a randomized, double-blind design. In Experiment 1, healthy participants (n = 26) completed a probabilistic reversal learning task in which they acquired stimulus-reward relations and re-learned new associations via unexpected punishment until a total of nine reversals were achieved. Error rates provided a measure of learning efficiency. Greater errors suggested poorer learning. In Experiment 2, healthy adults (n = 40) performed a stimulus-response learning task. Participants learned to associate different abstract stimuli to specific key-press responses through trial-and-error via feedback. Blocks of stimulus-response trials were performed until participants reached at 75% criterion to ensure sufficient learning. Mean improvement scores describing the rate at which stimulus-response associations were acquired as a function of blocks were computed. Higher improvement scores indicated superior learning efficiency.

Results: Participants treated with levodopa demonstrated significantly poorer learning performance than those treated with placebo.

Conclusions: We demonstrated that levodopa impairs learning of stimulus-reward and stimulus-response associations in healthy young adults who have optimal endogenous dopamine levels and regulation. Our findings support the notion that brain regions replete of dopamine are sensitive to overdose by dopaminergic therapy. Critically, these effects are independent of Parkinson’s disease pathology, severity, and receptor sensitization from chronic exposure to medication.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/levodopa-impairs-learning-in-healthy-young-adults-implications-for-parkinsons-disease/