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.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.

Serotonin and Dopamine Play Complementary Roles in Gambling to Recover Losses

“…There are good reasons to suppose that the subjective (Hamidovic et al, 2008) and behavioral (Pizzagalli et al, 2008;Riba et al, 2008;Santesso et al, 2009) effects of low doses of dopaminergic agents reflect pre-synaptic actions at the auto-receptors that regulate the activity of mid-brain dopaminergic neurons (Frank and O'Reilly, 2006;Grace, 1995). As described below, we replicate findings that single (1 mg) low doses of PPX reduce psychometric measurements of state-positive affect in healthy adults and that have been taken to suggest a presynaptic mode of action (Hamidovic et al, 2008).…”

“…Changes in reinforcement learning following treatment with PPX (Pizzagalli et al, 2008) are associated with altered signalling within the anterior cingulate region following bad outcomes (Santesso et al, 2009) and blunted signalling within the striatum following good outcomes (Riba et al, 2008). Previously, we have observed that attenuated neural responses to bad gambling outcomes within the anterior cingulate sulcus is also associated with continued chasing behavior during performance of our loss-chasing game (Campbell-Meiklejohn et al, 2008).…”

“…Single low doses of PPX (eg, 0.5 mg) can impair reinforcement learning in healthy adults (Pizzagalli et al, 2008), and increase risky choices in lottery-type games (Riba et al, 2008), possibly through blunted reward signalling of mesolimbic pathways (Riba et al, 2008;Santesso et al, 2009). In the light of this, and evidence that low doses of PPX, and other agents acting upon D 2 receptors, impair the signalling of bad outcomes ('negative prediction errors') (Frank and O'Reilly, 2006;Santesso et al, 2009;van Eimeren et al, 2009), we tested the hypothesis that single doses of PPX increase loss-chasing behavior and, perhaps, influence the value of losses that healthy individuals are prepared to chase.…”

The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

“…Nonetheless, some evidence that the D 2 family of receptors might play a role in learning from bad outcomes is provided by the demonstration that small single doses (0.5 mg) of the D 2 /D 3 receptor agonist, pramipexole, impair the acquisition of a response bias toward the most frequently rewarded choice in a probabilistic reward learning task, consistent with a hypothesized pre-synaptic diminution of the phasic signalling of positive prediction errors (Pizzagalli et al, 2008). This behavioral effect of low doses of pramipexole may also involve increased feedback-related neuronal responses to unexpected rewards, probably originating within the ACC region, and possibly reflecting the altered integration of decision outcomes over an extended reinforcement history (Santesso et al, 2009).…”

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

“…The task, which has been previously validated in three independent samples (Bogdan and Pizzagalli, 2006;Pizzagalli et al, , 2008, is rooted within signal-detection theory and allows for the objective assessment of the subject's propensity to modulate behavior as a function of prior reinforcements. Briefly, in signaldetection paradigms, subjects are asked to select whether stimulus A or stimulus B was presented by making an appropriate response A or response B (McCarthy, 1991).…”