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:
- 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 e.g. 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 the GABA-B agonist, baclofen.
- 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, 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.
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.
PI: Professor David Nutt