Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

Abstract

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction.

Figure 1

Regions of interest: (a) ROIs for the MID task, left/blue (when in color) shows the ventral striatum, middle/red shows the ventral pallidum (both defined according to the guidelines of Tziortzi et al, 2011), and right/yellow shows the substantia nigra. (b) ROIs for the GNG task, left/cyan shows the right inferior frontal gyrus, middle/green shows the left inferior frontal gyrus, and right/purple shows the anterior cingulate.

Figure 2

ROI response during the MID task: mean reward-neutral anticipation BOLD contrast estimate for both the placebo and the GSK598809 sessions. White bars represent the placebo session, whereas light gray/blue (when in color) represent the GSK598809 session. Histograms on the top show the main effect of drug within each ROI (*p<0.01, **p<0.001), whereas histograms below show the BOLD contrast estimates for the placebo and GSK598809 sessions for each group separately (†significant effect of group at p<0.01 in the placebo condition only). Error bars indicate within-subject SEM (Cousineau and O’Brien, 2014) suitable for assessing drug rather than group effects. A full color version of this figure is available at the Neuropsychopharmacology journal online.

Figure 3

ROI response during the GNG task: mean ‘stops-go’ BOLD contrast estimate within each ROI for the placebo (white bars) and the GSK598809 (gray or blue when in color) sessions. Error bars indicate within-subject SEM (Cousineau and O’Brien, 2014). *Main effect of group, significant at a Bonferroni corrected value of p<0.017. A full color version of this figure is available at the Neuropsychopharmacology journal online.