Imaging D3 receptors in alcoholism.

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer

Abstract

Alcohol misuse, especially dependent alcohol use, costs UK society around #20bn/yr and the NHS #1.7bn/yr. In the UK it is estimated that there are 1.1 million people dependent on alcohol. Typically treatment consists of psychosocial approaches however medication is increasingly recognised to play an important role to support any changes or progress made. Increasing knowledge about how alcohol or addiction can affect the brain?s chemistry has led to new medications becoming available. One particular chemical system in the brain, dopamine has been known for a long time to be involved in mediating ?alcohol-liking? but is also involved in ?alcohol-seeking? in those that have become dependent on alcohol (i.e. alcoholic). Within the dopaminergic system, the dopamine D3 receptor (DRD3), has been recently shown in animal models to play a role in cue or stress induced relapse and in addition chronic alcohol exposure can increase DRD3 levels. Therefore blocking the DRD3 is likely to be of clinical benefit in reducing the commonly cited reasons for relapsing ? seeing a cue or reminder of their drinking or stress. The aim of this proposal is to measure for the first time DRD3 levels in the living human brain. We are using a specialised brain imaging technique called positron emission tomography (PET) which involves using a tracer (called 11C-PHNO) which labels the DRD3 receptor throughout the brain including in key areas involved in addiction. Since this tracer also labels another type of dopamine receptor (DRD2) a second scan will take place after blocking all DRD3 with a drug, called a DRD3 antagonist. The difference between the two scans will represent DRD3 levels in the brain. Since the DRD3 appears important in mediating cue-induced relapse we will also measure activity in the brain using another brain imaging technique, functional magnetic resonance imaging (fMRI), as the person is looking at alcohol-related cues as well as when they are anticipating a different type of ?reward?, money. We will then be able to investigate the relationship between DRD3 levels and brain activity during these experiences. We are only able to conduct this study now due to the availability of the PET tracer and DRD3 antagonist. This study will give us important information about DRD3 to help understand its role in human alcoholism. Building on this, further studies will investigate the DRD3 system in other addictions eg opiate, gambling to inform future therapeutic approaches.

Technical Summary

The mesolimbic dopaminergic system has long been known to play a critical role in substance misuse ? from drug-liking to drug-seeking, from impulsive to compulsive behaviour. The role of the D2 family of dopamine receptors has received particular attention and there is evidence to support a role for dopamine D3 receptors (DRD3) in cue-induced alcohol-seeking and that chronic exposure to alcohol increases DRD3 levels. Clinically therefore, a DRD3 antagonist is likely to be of therapeutic benefit in reducing cue or stress induced relapse. Investigating the DRD3 throughout the brain in humans with in vivo imaging has not been possible until now. None of the DRD2/3 available PET tracers including 11C-raclopride which labels striatal DRD2/3 or 18F-fallypride which labels extra-striatal DRD2/3 have sufficient selectivity for D3 over D2 receptors. The newly available 11C-PHNO PET tracer is a DRD3 preferring tracer and importantly also labels extra-striatal regions including a key area in addiction, the ventral tegmental area. Therefore 11C-PHNO in combination with a DRD3 antagonist can measure the level of DRD3 throughout the brain in alcohol dependent individuals by characterizing the regional DRD2 and DRD3 contributions of 11C-PHNO signal. A selective DRD3 antagonist has been made available by GSK. Each abstinent alcohol dependent participant will undergo 2 11C-PHNO PET scans, one at baseline and one after the DRD3 antagonist when it has reached maximal DRD3 receptor occupancy. A two-tissue compartmental model with metabolite corrected arterial input function will be used to fully quantify 11C-PHNO binding. The generated binding potential (BP; a quantification parameter proportional to receptor availability) of the baseline scan and that of the post-D3 blocker scan will be used to derive the BP for DRD3. The abstinent alcohol dependent individuals will also undergo fMRI to probe neural activity during exposure to alcohol-associated cues and during anticipation of a monetary reward. This will enable us to understand the relationship between this neural activity and DRD3 levels as measured by 11C-PHNO. We will also explore whether there are any associations with clinical variables and outcome. Given the potential of DRD3 antagonists in treating alcoholism by reducing cue or stress-induced relapse it is important therefore to characterize the DRD3 in alcoholism in man. Future studies will then investigate the DRD3 system further in other addictions eg opiate, gambling, as well as assessing the amount of amphetamine induced dopamine release and impact of DRD3 antagonism on dopaminergic sensitivity.

Publications

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Erritzoe D (2014) In vivo imaging of cerebral dopamine D3 receptors in alcoholism. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Erritzoe, David (2012) In Vivo Imaging of Cerebral Dopamine D3 receptors in Alcoholism. in Journal of Psychopharmacology

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Orban C (2013) Resting state synchrony in anxiety-related circuits of abstinent alcohol-dependent patients. in The American journal of drug and alcohol abuse

 
Description MRC Neuroscience & Mental Health Board
Amount £1,733,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2011 
End 03/2016
 
Description Imperial Open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Poster and information about our imaging research programme including this study.

Increased public awareness of addiction research
Year(s) Of Engagement Activity 2012
 
Description Met with Clinical services 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Met Head of Clinical Services in City & Hackney Alcohol Service, London to discuss with her how to inform participants about the study in the best way.

Aided recruitment
Year(s) Of Engagement Activity 2010
 
Description Presentation at ISAM conference (International Society of Addiction Medicine). 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact I presented the data from this grant at an International conference to disseminate knowledge about the latest theories of the role of dopamine in addiction. This resulted in a debate about how the role and function of dopamine and in particular the DRD3 in alcoholism.
Year(s) Of Engagement Activity 2015
 
Description Visit to Foundation66 to meet Users 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact ABout 15 Users attended to hear about our research programmes to understand more about the neurobiology of alcoholism. We gave 3 brief presentations and had Q&A session.

The event was well received by the host organisation and attendees.
Year(s) Of Engagement Activity 2010