Imaging D3 receptors in alcoholism.

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.

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.