Using [11C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism

Anne Lingford-Hughes,James Myers,Ben Watson,Alastair G Reid,Nicola Kalk,Adrian Feeney,Alexander Hammers,Daniela A Riaño-Barros,Colm J Mcginnity,Lindsay G Taylor,Lula Rosso,David J Brooks,Federico Turkheimer,David J Nutt

doi:10.1016/j.neuroimage.2016.02.005

Anne Lingford-Hughes, James Myers + Show 12 more

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https://doi.org/10.1016/j.neuroimage.2016.02.005

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Abstract

The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [11C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n=12) underwent an [11C]Ro15 4513 PET scan and compared with matched healthy controls (n=13). We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [11C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.

Highlights

Opiate addiction and its treatment is a global health issue
No significant correlations with memory performance were found. In this first [11C]Ro15 4513 PET study of opiate dependence, we have shown significantly reduced levels of [11C]Ro15 4513 volume of distribution (VT) in individuals on opiate substitute medication compared with controls
This complements our study in abstinent alcohol dependence where we reported reduced [11C]Ro15 4513 VT in the nucleus accumbens

Summary

Introduction

Opiate addiction and its treatment is a global health issue. In the US, 1.8% of individuals over the age of 12 have tried heroin in their lifetime, with 0.1% in the past month (National Survey of Drug Use and Health, 2012). In England, there are an estimated ~ 300,000 opiate and/or crack users (8.67 per 1000 of 15 to 64 year olds; Statistics on Drug Misuse: England, 2013). Many addicts relapse or find it hard to achieve abstinence, with only about 50% leaving treatment drug-free (Statistics on Drug Misuse: England, 2013). Treatment of opiate addiction, characterising its underlying neurobiology is critical. Heroin and other opioid agonists act on opioid receptors, preclinical evidence supports involvement of the GABA system in their effects (Zetterström and Fillenz, 1990; Finlay et al, 1992 and Creed et al, 2014). Endorphins or mu opiate agonists inhibit GABAergic tonic inhibition of dopamine neuronal activity in the ventral tegmental area (VTA) resulting in increased dopamine neuronal firing and may contribute to the desire or compulsion to use opiates (Johnson and North, 1992 and Ting-A-Kee and van der Kooy, 2012)

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