Addiction

Lead Research Organisation: MRC London Institute of Medical Sciences

Abstract

Addiction to opiates and to alcohol is a major cost to the public both in terms of ill-health and in crime and policing. Intoxication with these drugs has huge costs to society in terms of accidents and violence. Together these costs have been estimated as equivalent to those of all other psychiatric disorders combined (ca. #4billion p.a. in the UK). Understanding the actions of these drugs in the brain is a necessary component in combating these problems. We are trying to identify the brain mechanisms of addiction to, and pleasure from, these drugs. We know that drugs including alcohol act by changing chemical messengers in the brain called neurotransmitters. Our study tries to show how these are altered in people addicted to heroin or alcohol. We also want to understand how treatments work, so we also study the effects that current treatments have in the brain to help design new and better ones. This could have big implications for health and reduce the costs of the damage that these drugs do to society. It may also lead to new investment from pharmaceutical companies which are one of the UKs leading wealth-creating industries. This work continues our successful previous research which uses the newest scanning technique, positron emission tomography (PET). This allows us to directly measure levels of neurotransmitters and their receptors in the human brain. We also perform studies using drugs to alter these neurotransmitter systems to investigate how they are functioning in healthy individuals and those that are addicted. We focus on three key neurotransmitters in addiction- the dopamine system involved in mediating pleasure, the GABA system, the brains natural calming system that mediates many effects of alcohol, and lastly the opiate system which mediates many effects of opiate drugs such as heroin and also the pleasurable effects of alcohol.

Technical Summary

Neurotransmitters in opiate and alcohol addiction. We are building on our successful collaboration that combines imaging, pharmacodynamic measures to further characterise the role of dopamine and GABA systems in alcohol and opiate addiction. Our programme is one of few in the world that is studying and comparing such addictions and performing the vital testing in humans of key theories of addiction that are emerging from animal addiction research to test their clinical relevance and application. GABA system. We are completing the pharmacological characterization of 11C-Ro15 4513 to determine its utility in testing theories relating to GABA function and the alpha5 receptor subtype. [A].We have shown by using using competition experiments with the alpha1 selective agonist, zolpidem and 11C-Ro15 4513 and 11C-flumazenil PET, that 11C-Ro15 4513 predominantly meaures the alpha5 subunit in the limbic system. We are using spectral analysis to characterize alpha1 vs alpha5 binding components to more accurately estimate occupancy of zolpidem at alpha1 subtype. [B] We are currently investigating if 11C-Ro15 4513 is sensitive to endogenous GABA levels by using complementary rat and human PET and post-mortem studies where synaptic GABA concentrations are altered and Ro15 4513 binding measured. In rat ex vivo studies we showed that 3H-Ro15 4513 binding is sensitive to GABA. In man, we are using tiagabine to increase GABA. These studies are complemented by measuring changes in GABA with MRS and MEG. [C] The role of the alpha5 in alcohol reward has been explored using an inverse agonist at this subtype and we have found that in heavy drinkers this did not alter the rewarding actions of alcohol but did reverse the memory impairing effects. [D] Many opiate addicts misuse benzodiazepines and this increases the treatment challenge. We are performing 11C-Ro15 4513 scans in opiate addicts (~10) for comparison with controls and with alcohol dependent individuals. In addition the sensitivity of the benzodiazepine system will be tested using a pharmacological (midazolam) challenge whilst measuring effects on eye movements, memory and subjective experiences. Dopamine We tested the theory from animal work and later confirmed in humans for stimulants that dopamine release in the ventral striatum relates to the euphoric (high) action of drugs of abuse. We have shown that in opiate addicts, a dose of heroin sufficient to cause a high and impair eye movements is not associated with dopamine release using the standard 2-scan 11C-raclopride protocol. Therefore we have separated high from dopamine release. More recently however the role of dopamine has been broadened to involve drug expectation, motivation and learning. Before concluding that dopamine release has no observable role in mediating the effects of opiates in opiate addicts, we are testing that expectation of reward, rather than reward per-se is the main determinant of dopamine release. We have completed a 3 11C-raclopride scan protocol, the first 2 of which will have equivalent expectation in the presence of differing amounts of diamorphine and the last one is to measure baseline dopamine D2 receptor levels. As before, subjective and objective measures have been obtained. We are currently analysing the data. If expectation is associated with increased dopamine release, we shall consider extending these investigations to the expectations and actions of alcohol.

Publications

10 25 50
 
Description mrc
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact showed applicaitons and opportunities for translational research
 
Title pet tracer 
Description vlaidation of 11C-ro154513 as an alpha-5 selctive GABA-A receptor tracer in humans 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact lower binding in the brainms of alcoholics especially in brain regions relating to addiction and memory 
 
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
 
Description presentation at CFS meeting in 2016\ 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact british sleep society meeting

more interviews - and public lectures eg cafe scientifiques
Year(s) Of Engagement Activity 2016