Journal
NEUROPSYCHOPHARMACOLOGY
Volume 34, Issue 13, Pages 2758-2766Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2009.124
Keywords
fMRI; impulse control disorder; dopamine agonist; reward; addiction; reinforcement
Categories
Funding
- Canadian Institutes of Health Research [MOP-64423]
- Safra Foundation
- Canadian Institutes of Health Research New Investigator Research Award
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The neurobehavioral underpinnings of pathological gambling are not well understood. Insight might be gained by understanding pharmacological effects on the reward system in patients with Parkinson's disease (PD). Treatment with dopamine agonists (DAs) has been associated with pathological gambling in PD patients. However, how DAs are involved in the development of this form of addiction is unknown. We tested the hypothesis that tonic stimulation of dopamine receptors specifically desensitizes the dopaminergic reward system by preventing decreases in dopaminergic transmission that occurs with negative feedback. Using functional magnetic resonance imaging, we studied PD patients during three sessions of a probabilistic reward task in random order: off medication, after levodopa (LD) treatment, and after an equivalent dose of DA (pramipexole). For each trial, a reward prediction error value was computed using outcome, stake, and probability. Pramipexole specifically changed activity of the orbitofrontal cortex (OFC) in two ways that were both associated with increased risk taking in an out-of-magnet task. Outcome-induced activations were generally higher with pramipexole compared with LD or off medication. In addition, only pramipexole greatly diminished trial-by-trial correlation with reward prediction error values. Further analysis yielded that this resulted mainly from impaired deactivation in trials with negative errors in reward prediction. We propose that DAs prevent pauses in dopamine transmission and thereby impair the negative reinforcing effect of losing. Our findings raise the question of whether pathological gambling may in part stem from an impaired capacity of the OFC to guide behavior when facing negative consequences. Neuropsychopharmacology (2009) 34, 2758-2766; doi:10.1038/npp2009124; published online 9 September 2009
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