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 F. W. Deakin, Rebecca Elliott

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1049-1057
Number of pages9
JournalNeuropsychopharmacology
Volume42
Early online date2 Jan 2017
DOIs
Publication statusPublished - 2017
Externally publishedYes

Fingerprint

Reward
Alcoholism
Substance-Related Disorders
Corpus Striatum
Pharmaceutical Preparations
Motivation
Opiate Alkaloids
Placebos
Dopamine D3 Receptors
Frontal Lobe
Substantia Nigra
GSK598809
Cross-Over Studies
Dopamine
Healthy Volunteers
Alcohols
Magnetic Resonance Imaging
Recurrence
Inhibition (Psychology)

Cite this

Murphy, Anna ; Nestor, Liam J. ; McGonigle, John ; Paterson, Louise ; Boyapati, Venkataramana ; Ersche, Karen D. ; Flechais, Remy ; Kuchibatla, Shankar ; Metastasio, Antonio ; Orban, Csaba ; Passetti, Filippo ; Reed, Laurence ; Smith, Dana ; Suckling, John ; Taylor, Eleanor ; Robbins, Trevor W. ; Lingford-Hughes, Anne ; Nutt, David J. ; Deakin, John F. W. ; Elliott, Rebecca. / Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response during Monetary Reward Anticipation in Drug and Alcohol Dependence. In: Neuropsychopharmacology. 2017 ; Vol. 42. pp. 1049-1057.
@article{8dc00029e55f4b66a7e7c89ee7c7053e,
title = "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.",
author = "Anna Murphy and Nestor, {Liam J.} and John McGonigle and Louise Paterson and Venkataramana Boyapati and Ersche, {Karen D.} and Remy Flechais and Shankar Kuchibatla and Antonio Metastasio and Csaba Orban and Filippo Passetti and Laurence Reed and Dana Smith and John Suckling and Eleanor Taylor and Robbins, {Trevor W.} and Anne Lingford-Hughes and Nutt, {David J.} and Deakin, {John F. W.} and Rebecca Elliott",
year = "2017",
doi = "10.1038/npp.2016.289",
language = "English",
volume = "42",
pages = "1049--1057",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",

}

Murphy, A, Nestor, LJ, McGonigle, J, Paterson, L, Boyapati, V, Ersche, KD, Flechais, R, Kuchibatla, S, Metastasio, A, Orban, C, Passetti, F, Reed, L, Smith, D, Suckling, J, Taylor, E, Robbins, TW, Lingford-Hughes, A, Nutt, DJ, Deakin, JFW & Elliott, R 2017, 'Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response during Monetary Reward Anticipation in Drug and Alcohol Dependence', Neuropsychopharmacology, vol. 42, pp. 1049-1057. https://doi.org/10.1038/npp.2016.289

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response during Monetary Reward Anticipation in Drug and Alcohol Dependence. / Murphy, Anna; Nestor, Liam J.; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D.; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W.; Lingford-Hughes, Anne; Nutt, David J.; Deakin, John F. W.; Elliott, Rebecca.

In: Neuropsychopharmacology, Vol. 42, 2017, p. 1049-1057.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response during Monetary Reward Anticipation in Drug and Alcohol Dependence

AU - Murphy, Anna

AU - Nestor, Liam J.

AU - McGonigle, John

AU - Paterson, Louise

AU - Boyapati, Venkataramana

AU - Ersche, Karen D.

AU - Flechais, Remy

AU - Kuchibatla, Shankar

AU - Metastasio, Antonio

AU - Orban, Csaba

AU - Passetti, Filippo

AU - Reed, Laurence

AU - Smith, Dana

AU - Suckling, John

AU - Taylor, Eleanor

AU - Robbins, Trevor W.

AU - Lingford-Hughes, Anne

AU - Nutt, David J.

AU - Deakin, John F. W.

AU - Elliott, Rebecca

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?eid=2-s2.0-85010867756&doi=10.1038%2fnpp.2016.289&partnerID=40&md5=7568dc8a5552cabd123508f97086e779

U2 - 10.1038/npp.2016.289

DO - 10.1038/npp.2016.289

M3 - Article

VL - 42

SP - 1049

EP - 1057

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

ER -