Single dose of a dopamine agonist impairs reinforcement learning in humans: Behavioral evidence from a laboratory-based measure of reward responsiveness
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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.
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.
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.
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.
KeywordsDopamine D2 agonists Reward processing Depression Mesolimbic system Addiction
This work was supported by grants from NIMH (R01 MH68376; DAP) and Harvard College Research Program (ECS). Dr. Evins and Ms. Culhane were supported by a grant from the National Institute on Drug Abuse (K23 DA00510-01; AEE). Dr. Frank was supported by a grant from the National Institute on Drug Abuse (DA022630). The authors would like to thank Dr. Catherine Fullerton, Kyle Ratner, Elena Goetz, and Jeffrey Birk for their assistance with the project, Dr. David Standaert for his helpful review of the results, and three anonymous reviewers for their constructive criticisms.
Disclosure/Conflict of interest statement
Dr. Pizzagalli has received research support from GlaxoSmithKline and Merck & Co., manufacturers 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. 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.
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