Impact of DRD3 antagonism on brain mechanisms in addiction

Sandra Helinski

Rebecca Elliott


Much evidence suggests that disturbances in neurobiological mechanisms of reward maintain addiction and provoke relapse during abstinence. Impaired responsiveness to non-drug rewards may drive the desire for drugs of abuse, manifested as craving and increased drug use and brain response to drug-related stimuli. Dopamine plays a pivotal role in reward mechanisms and in addiction and there has been much interest in developing therapies to prevent relapse through targeting dopamine mechanisms, notably via the D3 dopamine receptor (DRD3). The exact role of the DRD3 is currently unknown, although there is evidence to suggest the DRD3 acts as an autoreceptor to control the synthesis and release of dopamine.  The ICCAM Platform study is a multicentre research study that aimed to 1) identify brain networks underlying addiction to alcohol, cocaine and opiates and relapse vulnerability and 2) identify potential new treatments for addiction based upon their ability to modulate these networks. Here, we present an fMRI study examining the effects of the novel DRD3 antagonist GSK598809 on networks underlying the anticipation of reward, using the monetary incentive delay task (Knutson et al. 2000).  A double blind, placebo controlled, crossover design approach was used in abstinent alcohol dependent (n=18), abstinent poly-drug dependent (n=32) and healthy control volunteers (n=33). There was evidence of blunted ventral striatal activation to reward anticipation in the abstinent poly-drug dependent group and a trend for a blunted response in the abstinent alcohol dependent group under placebo.  In all participants, ventral striatal activation was negatively correlated with impulsivity as measured by the Barratt Impulsiveness Scale. GSK598809 appeared to partially normalise ventral striatal activation although this was not statistically significant.  GSK598809 significantly increased reward anticipatory response within the ventral pallidum, which is the major output node of the reward system and a region of high DRD3 density, in both dependence groups but not healthy controls Conclusion: GSK598809 may remediate reward deficits in addiction by enhancing ventral pallidum signalling during reward anticipation. GSK598809 may achieve this effect by disinhibiting brain dopamine systems.