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

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

doi:10.1038/npp.2016.289

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.

Highlights

Evidence suggests dysregulation of neurobiological networks involved in reward processing and inhibitory control contributes to the risk and maintenance of addiction and relapse during abstinence
Deficits in dopamine neurotransmission may impair impulse control, as low striatal D2/D3 binding is associated with increased impulsivity in rodents and humans (Clark et al, 2012; Ghahremani et al, 2012)
Mixed ANOVAs demonstrated a significant main effect of drug within the left ventral pallidum (VP), caudate, and cerebellum (Table 1 and Supplementary Figure S5). These effects appear to be driven by increased reward-neutral anticipation response in the GSK598809 session compared with the placebo session, in particular for the AD group and to a lesser extent the PD group

Summary

Introduction

Evidence suggests dysregulation of neurobiological networks involved in reward processing and inhibitory control contributes to the risk and maintenance of addiction and relapse during abstinence. Disturbances in reward functioning involve hyporesponsivity to non-drug reward, which is associated with increased craving, drug use, and brain response to drug-related stimuli (Blum et al, 2000; Lubman et al, 2009; Wrase et al, 2007). Reductions in dopamine release and receptor density are associated with increased drug use and craving and may precede the development of addiction (Casey et al, 2014; Heinz et al, 2004). Deficits in dopamine neurotransmission may impair impulse control, as low striatal D2/D3 binding is associated with increased impulsivity in rodents and humans (Clark et al, 2012; Ghahremani et al, 2012).

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