Single dose of a dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness

Abstract

Rationale: The dopaminergic system, particularly D2-like dopamine receptors, has been strongly implicated in reward processing. Animal studies have emphasized the role of phasic dopamine (DA) signaling in reward-related learning, but these processes remain largely unexplored in humans.

Objectives: To evaluate the effect of a single, low dose of a D2/D3 agonist--pramipexole--on reinforcement learning in healthy adults. Based on prior evidence indicating that low doses of DA agonists decrease phasic DA release through autoreceptor stimulation, we hypothesized that 0.5 mg of pramipexole would impair reward learning due to presynaptic mechanisms.

Materials and methods: Using a double-blind design, a single 0.5-mg dose of pramipexole or placebo was administered to 32 healthy volunteers, who performed a probabilistic reward task involving a differential reinforcement schedule as well as various control tasks.

Results: As hypothesized, response bias toward the more frequently rewarded stimulus was impaired in the pramipexole group, even after adjusting for transient adverse effects. In addition, the pramipexole group showed reaction time and motor speed slowing and increased negative affect; however, when adverse physical side effects were considered, group differences in motor speed and negative affect disappeared.

Conclusions: These findings show that a single low dose of pramipexole impaired the acquisition of reward-related behavior in healthy participants, and they are consistent with prior evidence suggesting that phasic DA signaling is required to reinforce actions leading to reward. The potential implications of the present findings to psychiatric conditions, including depression and impulse control disorders related to addiction, are discussed.

Conflict of interest statement

Disclosure/Conflict of Interest Dr. Pizzagalli has received research support from GlaxoSmithKline and Merck & Co., Inc., manufactures of antidepressants. Dr. Evins has received research grant support from Janssen Pharmaceutica, Sanofi-Aventis, Astra Zeneca; research materials from GSK and Pfizer, and honoraria from Primedia, Inc. Moreover, Dr. Evins is an investigator in a NIDA-funded collaborative study with GSK. Dr. Frank, Ms. Schetter, Ms. Culhane, and Ms. Pajtas report no competing interests.

Figures

Figure 1. Schematic summary of the experimental session timeline

VAMS: Visual Analog Mood Scale (Bond and Lader, 1974). EEG: electroencephalogram.

Figure 2. Probabilistic reward task

(a) Response bias, (b) Accuracy for the more frequently rewarded stimulus (“rich stimulus”), and (c) Accuracy for the less frequently rewarded stimulus (“lean stimulus”) as a function of Blocks for the pramipexole (n = 11) and placebo group (n = 13). Error bars correspond to S.E. Solid arrows and dashes arrows denote significant between-group and within-group differences, respectively.

Figure 3. Probabilistic reward task

Probability of choosing the more frequently rewarded stimulus (“rich stimulus”) as a function of whether the immediately preceding rich stimulus had been rewarded (left side) or not (right side) for the pramipexole (n = 11) and placebo group (n = 13). See Figure 2 for more detail.

Figure 4. Simple RT task

Reaction time before and after administration of study medication for the pramipexole (n = 11) and placebo group (n = 15). See Figure 2 for more detail.

Figure 5. BRAIN task

Square-root transformed kinesia score before and after administration of study medication for the pramipexole (n = 12) and placebo group (n = 15). See Figure 2 for more detail.

Figure 6. VAMS

Baseline-corrected VAMS scores at several time points during the experimental session for the pramipexole (n = 16) and placebo group (n = 14). See Figure 2 for more detail.