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

Lead Research Organisation: University of Sussex
Department Name: Research and Enterprise Services

Abstract

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.

Technical Summary

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.

Publications

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Baldwin DS (2013) Benzodiazepines: risks and benefits. A reconsideration. in Journal of psychopharmacology (Oxford, England)

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Caldarone BJ (2015) Rodent models of treatment-resistant depression. in European journal of pharmacology

 
Description Royal College of Psychiatry
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description NIH INIA Stress Consortium
Amount $80,000 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2012 
End 09/2013
 
Description provision of genetically manipulated mice 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Behavioural and neurobiological characterisation of genetically manipulated mice
Collaborator Contribution Partner provided 2 strains of genetically manipulated mice
Impact PMD 19501766 PMD 18313124 PMD 18358520 PMD 16706856