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The science behind addiction

As part of the Addiction Research Strategy of the Medical Research Council (MRC), interdisciplinary and interinstitutional teams of researchers, including the GABA research cluster at Sussex, are working to understand the complex processes of addiction.

The GABA research cluster

Drug and alcohol abuse present a huge socioeconomic problem. In addition to the direct impact of addiction, there is an indirect healthcare burden in terms of associated mental health problems, depression and suicide.

By studying the mechanisms that underlie addictive behaviour, we may better understand the processes involved, discover why some individuals are more susceptible, and find new ways to help people manage their addiction.

To tackle this problem, and with the goal of making a significant impact in addiction research, the MRC's Addiction Research Strategy was set up to provide grant support to establish research projects countrywide.

Focusing on investigating the role of the brain chemical GABA (gamma-aminobutyric acid) in the process of addiction, the GABA research cluster at the ÄûÃÊÊÓƵ is one such project.

Led by Professor Dai Stephens, Research Professor in the School of Psychology, in collaboration with groups at the Universities of Dundee and Portsmouth, the cluster is conducting research into GABA_A receptors in the neurobiology of drug and alcohol addictions.

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Analysing GABA signals

GABA functions by signalling through protein receptors present on nerve cells of the central nervous system.

GABA_A receptors are present at high levels in areas of the brain such as the nucleus accumbens and the amygdala, regions involved in motivation and reward that are implicated in drug abuse.

They are particularly important in mediating the effects of environmental cues that condition us toward drug-seeking behaviour.

It is a feature of drug/alcohol abuse that objects or cues associated with the drug become attractive in their own right – eg specific labels on favourite brands of alcohol or cigarettes or, for a heroin addict, even the sight of a syringe.

In human and animal studies spanning psychology, genetics and neuroscience, the Sussex team are studying particular GABA receptors in the nucleus accumbens (those containing α2 and α4 subunits).

Through this research they hope better to understand how GABA functions in behaviour involving reward and motivation, potentially identifying new targets for treating addiction.

There are four main aspects to this research. In humans, there appear to be two genetic varieties of α2 receptors (haplotypes) – one that increases the risk of developing addictions, and one that protects against them.

The Sussex research cluster reported recently that people with the risk haplotype show an increased propensity toward cocaine abuse, which may be partly determined by dysfunction in anti-anxiety systems in the brain.

They are now carrying out research, supported by the MRC and the US National Institutes of Health, under the direction of Professor Theodora Duka, in non-addicted human volunteers, focusing on individuals carrying the risk versus protective haplotype.

As the cluster has already shown that mice with a mutated/deleted α2 subunit are impaired in learning about drug cues, the first question is whether people with risk or protective gene variants also differ in their response to cues predicting drug availability. Secondly, are they also particularly susceptible to stress effects on such responses?

If mice/rats/humans are given drugs (eg cocaine, amphetamines), the drugs become more effective with repeated doses, which may relate to an increased desire to take drugs.

Mouse studies have shown increased α2 subunit levels in response to such sensitisation, and in mice where the gene has been deleted (knock-outs) this escalation in drug response is not observed.

As a refinement to this experiment, Dr Sarah King is using a targeted virus to 'knock down' the gene in specific regions of the brain.

As 95 per cent of nerve cells in the nucleus accumbens use GABA as a neurotransmitter, it is predicted that knocking down the gene specifically in the nucleus accumbens, as opposed to other brain regions, might replicate the effects seen in the complete knock out.

The team is also interested in the pattern of expression of GABA_A receptors containing α2 or α4 subunits in the medium spiny neurons (of the nucleus accumbens), as such receptors are likely to play different roles depending on where they appear on the neuron's surface.

Specific imaging studies that demonstrate precisely where in the medium spiny neurons and nucleus accumbens the α2 and α4 subunits are located (in collaboration with Dr Jerome Swinny at Portsmouth) and what happens when these subunits are elevated or decreased, might inform us about the signals that regulate motivational behaviour.

The fourth aspect of the research is being carried out by an electrophysiology group, led by Professor Jeremy Lambert and Dr Delia Belelli at Dundee, evaluating the precise function of individual GABA_A receptors, using highly sensitive electrodes to record activity in single neurons in the nucleus accumbens.

In this way, the united project hopes to understand how subtle changes in signalling at the neuronal level translate into altered behaviour in mice and increased risk of developing addiction in people.