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

Anna Murphy, Liam J Nestor, John McGonigle, Louise Paterson, Venkataramana Boyapati, Karen D Ersche, Remy Flechais, Shankar Kuchibatla, Antonio Metastasio, Csaba Orban, Filippo Passetti, Laurence Reed, Dana Smith, John Suckling, Eleanor Taylor, Trevor W Robbins, Anne Lingford-Hughes, David J Nutt, John Fw Deakin, Rebecca Elliott

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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 normalised 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 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 behavioural drug effects on response inhibition.

CONCLUSION: GSK598809 modulated the neural network underlying reward anticipation but not response inhibition suggesting DRD3 antagonists may restore reward deficits in addiction.Neuropsychopharmacology accepted article preview online, 02 January 2017. doi:10.1038/npp.2016.289.

Original languageEnglish
Early online date2 Jan 2017
Publication statusPublished - 2017


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