GABA-A receptors in accumbens neural circuits underlying drug abuse: novel targets for treatment?

Drug addiction is a major social and health problem with causes that are both social and biological. The project represents the first stage of a programme of work whose aim is i) to develop methods in non-addicted volunteers for studying forms of addiction and its treatment (experimental medicine), ii) to understand particular biological processes that underlie addictive behaviour, and iii) to identify potential targets for pharmacological or behavioural intervention to combat forms of addictive behaviour. Some of our aims will be delivered within the lifetime of this proposal, while others will be realised in extensions of the work outlined here, and in parallel proposals under the umbrella of the MRC Addiction Research Cluster ?GABA?. In the present proposal we will study people who carry one particular genetic risk for addiction to discover how their behaviour is altered in ways that might increase the likelihood of developing addictions. At the same time, we will study the brain mechanisms involved in the action of this, and related genes, with the hope of finding ways in which the genetic predisposition can be overcome, either with drug-treatment or by changing their risky behaviour.

GABAergic neurons are intimately involved in several brain systems that play decisive roles in development of addictions, but their particular importance has not hitherto been a focus of research. We have recently provided evidence of a role for the alpha2-subtype of GABA-A receptor in the function of accumbens motivational systems in mice, and demonstrated a genetic association between haplotypes of the gene encoding this subunit and human cocaine addiction (Dixon et al, PNAS, 2010). We will now study in non-addicted human volunteers whether such haplotypes give rise to biomarkers for addiction, and behavioural endophenotypes that may confer risk for development of addictive behaviours, particularly as a consequence of stressors. In parallel, we will use genetic manipulations of mouse genes encoding the alpha2, and other subtypes (alpha4,alpha5, and delta subtypes) of GABA-A receptor, and drugs specific to such subtypes, to study the consequences of such manipulation on the function of accumbal medium spiny neurons, and for behaviours known to model aspects of addiction-related behaviours in mice. We will thus develop methods for studying therapeutic effects in humans, as well as identify potential pharmacological and behavioural targets for future therapies.