Neurotransmitters in Opiate and Alcohol Addiction

Addiction is a widespread problem in our society and globally. This series of investigations continues our work in the study of 2 of the commonest and most harmful addictions, opiates (heroin) and alcohol. Many factors influence the entrance to addiction, its maintenance and the relapse to drugs in people who have abstained. We are studying in detail one of these factors, the brain mechanisms behind addiction, and in particular what brain chemicals (neurotransmitters) are involved. We have found that people with different addictions may have a shared deficit in the key neurotransmitter that calms the brain (GABA) which may explain why they have trouble controlling their desire to take drugs. Also we have evidence that the brain?s own pleasure system, the endorphins, may play a role in addiction. The current research program follows up these leads to see if they may also be important in an addiction that does not involve drugs ? gambling ? to see if they have a more general role in addiction. From these findings we have already identified potential avenues for development of new treatments and we hope that further discoveries we make will encourage companies to develop new research into treatments.
We are a unique group in the UK because we have been using brain scanning (PET neuroimaging) techniques in addicts and in healthy volunteers to look at brain mechanisms for some years. Our group is comprised of doctors who treat addicts, specialists in PET and MRI imaging, and psychopharmacologists with expertise in drugs of addiction and brain receptors. We have been fortunate to interest many of the clients we meet in our day-to-day practice, who have volunteered in our studies and allowed us to scan their brains, and this interest continues.
We are experienced in and committed to publishing our results to the scientific community by presenting at conferences and writing in journals. We hold regular meetings with organisations helping addicts in their recovery. We communicate a lot with to the public through events such as science festivals and public science events, and through the media by taking part in radio and TV programmes about addiction.

This program of research tackles the brain mechanisms underpinning two of the most prevalent and costly addictions in the UK, those to opioids (heroin) and to alcohol. Using complementary techniques of brain imaging with PET tracers and challenge tests with neurotransmitter-targeted drugs we will build on the findings of our previous work to explore further the role of the dopaminergic system with two of its key modulators, GABA and opioid. PET studies of the dopaminergic system in addiction have had an immense influence on our understanding and we now have the tools to similarly comprehensively investigate GABA and opioid systems. To explore if significant findings are of general relevance to addiction rather than being a consequence of prior drug/alcohol use, key experiments will be made in the behavioural addiction of gambling.

Specifically we shall explore the following theories:

1. using the first alpha5 subtype-selective GABA-A tracer 11C-Ro154513 (we developed, validated and demonstrated lower levels in alcohol and heroin addicts in key areas involved in addiction eg nucleus accumbens), we shall explore if similar reductions are found in pathological gambling addiction. We shall test the hypothesis that GABA-ergic function is dysregulated in heroin and alcohol addiction by exploiting the fact that 11C-Ro15 4513 is sensitive to changing endogenous GABA levels and by using challenge tests and monitor subjective and objective (EEG, saccadic eye movements) outcomes with the GABA reuptake blocker, tiagabine and GABA-B agonist, baclofen.

2. using the mu selective agonist PET tracer 11C-carfentanil to test the theory that increased endogenous opioids are involved in mediating pleasurable effects of alcohol and are evident in response to salient cues in alcohol, heroin addiction and pathological gambling. We shall test the hypothesis that there is reduced endogenous opioid reserve in alcoholism. We will test the theory that mu opiate receptors are implicated in impulsivity in these addicts.

3. using the DRD2/3 selective dopamine PET tracer 11C-PHNO, with a selective DRD3 antagonist, we will determine whether the dopamine DRD3 receptor levels are increased in heroin addiction as well as in alcohol addiction.

Our results will help characterize the brain mechanisms of addiction and so further underpin the evidence base for its being, at least in part, a brain disorder. Our programme will lead to a better understanding of how current treatments work and will assist in the development of new ones.