Role of Dopamine D2 Receptors in Human Reinforcement Learning

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, while loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically-determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.Neuropsychopharmacology accepted article peview online, 09 April 2014; doi:10.1038/npp.2014.84

Verbal memory impairment in polydrug ecstasy users:A clinical perspective

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group. Conclusion: The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments

The median (red line), 25th and 75th percentiles (box edges), range excluding outliers (whiskers), and outliers (red +) of the Total Immediate Recall (IR) Score (upper graph) and Delayed Recall (DR) Score (lower graph) of Controls, and Ecstasy users (E-Users) in the placebo condition and MDMA condition.

<p>The median (red line), 25th and 75th percentiles (box edges), range excluding outliers (whiskers), and outliers (red +) of the Total Immediate Recall (IR) Score (upper graph) and Delayed Recall (DR) Score (lower graph) of Controls, and Ecstasy users (E-Users) in the placebo condition and MDMA condition.</p

Mean and standard deviation of immediate recall (IR) and delayed recall (DR) in the word learning task for each study.

<p>Mean and standard deviation of immediate recall (IR) and delayed recall (DR) in the word learning task for each study.</p

Frequency distribution of the raw IR (left panel) and DR (right panel) scores in the Ecstasy users during MDMA intoxication and placebo, and healthy controls.

<p>The straight line represents the mean IR (left) or DR (right) score in the healthy control group, the dotted lines represent the memory criterion, that is, 1.5 SDs of the healthy control group. Participants that fall on the left side of the left dotted line have impaired memory relative to the criterion; participants that fall on the right side of the right dotted line have superior memory performance relative to the criterion.</p