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Nestor LJ1,2, Murphy A3, McGonigle J1, Orban C1, Reed L1, Taylor E3, Flechais R1, Paterson L1, Smith D2,4, Bullmore ET2, Ersche KD2,4, Suckling J2, Tait R2, Elliott R3, Deakin B3, Rabiner I5, Lingford-Hughes A1, Nutt DJ1, Sahakian B2,4 and Robbins TW2,4 ICCAM Consortium

1Centre for Neuropsychopharmacology, Imperial College London, United Kingdom
2Department of Psychiatry, University of Cambridge, United Kingdom 3Neuroscience and Psychiatry Unit, University of Manchester, United Kingdom
4Department of Psychology, University of Cambridge, United Kingdom 5Imanova, Centre for Imaging Sciences, London, United Kingdom

Background: Identifying the neural substrates of addiction in an attempt to elucidate potential neural targets for future treatment development remains a major challenge in neuroscience. One such neural target that has emerged is the brain’s opioid system due to its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of fronto-striatal mu opioid receptors that predict impulsivity and substance relapse, and demonstrate disturbances in these regions during the pursuit of non-drug rewards. Therefore, disturbances to the opioid system may confer a risk for relapse to substance rewards if there is a diminished incentive value of non-drug rewards in the presence of weakened impulse control.

Objective: To examine the acute remediating effects of naltrexone (50mg) in abstinent substance-dependent individuals. We aimed to show that (i) substance-dependent groups exhibit disturbances within brain regions that govern impulse control and respond to the pursuit of non-drug rewards and 2) that acute naltrexone ameliorates these disturbances, thus elucidating a potential therapeutic target for treating neural substrates that potentially trigger relapse to addictive behaviour.

Methods: A randomized double blind placebo controlled pharmaco-MRI study using a monetary incentive delay (MID) task and a go/no-go (GNG) task in (i) pure abstinent alcoholics (ALCminus n=21); (ii) abstinent alcoholic poly substance-dependent individuals (ALCplus n=25) and (iii) healthy controls (HC n=35).

Results: Acute naltrexone treatment did not remediate disturbances within fronto-striatal regions (ventral striatum, anterior cingulate, insular and orbitofrontal cortices) in either the ALCminus or ALCplus groups during the pursuit of non-drug rewards. Naltrexone, however, did ameliorate disturbances in the bilateral anterior insula of the ALCplus group during motor response inhibition, with both substance-dependent groups demonstrating increased activation in lateral (inferior frontal gyrus) and medial (anterior cingulate) prefrontal regions during motor response inhibition and error monitoring across drug treatments.

Conclusion: Abstinent substance-dependent groups exhibit fronto-striatal disturbances during the pursuit of non-drug rewards that are not remediated by acute naltrexone. Abstinent alcoholic poly substance-dependent individuals exhibit disturbances in insular inhibitory functioning that are remediated by acute naltrexone. Abstinent substance-dependent groups demonstrate increased “top-down” control in prefrontal regions that might characterise successful abstinence.