Feature: The neuroscience of addiction: Uncovering cues

Read part I of the neuroscience of addiction.

Professor Andrew Lawrence and his team at the Florey Neuroscience Institute sought an animal model of drug-seeking behaviour and relapse to help investigate the phenomena. “If you think about human addicts simplistically, they fall into two categories: those who seek assistance, and undertake rehabilitation, and those who try to withdraw alone, cold turkey. Irrespective of which category they fall into, most addicts still relapse.”

Lawrence’s group has developed animal models of drug-seeking behaviour after passive withdrawal and reinstatement of drug-seeking behaviour after extinction training. “We send our rats off to rehab to allow them to withdraw, then precipitate drug-seeking behaviour after withdrawal or a period of extinction training, by placing them back in an environment where they are exposed to cues that we previously coupled with drug availability.”

Extinction training in animals can be thought of as equivalent to cue-exposure therapy in humans in a rehabilitation setting. “Cue-induced reinstatement of drug-seeking is a known mechanism in human behaviour; it’s equivalent to an alcoholic who has been to rehabilitation to dry out, and then walks out of the house and sees billboards featuring an alcoholic product like a glass of scotch, which is often sufficient to reinstate their craving for alcohol.

“Our animal model replicates the alcoholic who stops drinking, and is walking past Young and Jackson’s hotel on the way to Flinders Street Station in Melbourne, and smells beer and is exposed to the sights and sounds of people drinking. All those cues have very high salience to the alcoholic person, which is sufficient to induce craving and precipitate alcohol-seeking behaviour.”

Lawrence’s group’s experiments, mainly carried out by postgraduate student Cameron Adams, implicate the mGlu5 receptor in relapse behaviour, whether the rats that have undergone passive withdrawal or extinction training. “What is exciting is that our work implicates mGlu5 in other forms of drug-seeking. Specifically, we have been able to show at the mGlu5 receptor interacts with receptors for other substances. That was not known previously.”

However, they’re still to resolve details of the mechanism involved. “It could be that other receptors link up with mGlu5 in the nerve cell membrane, or the interaction may be via a shared signalling mechanism, or it could be both. The beauty of this discovery is that we can experiment with different combinations of antagonists for mGlu5 and various other receptors, at very low doses, that have no effect when used individually, but show powerful effects when paired.

“That confirms the receptors are interacting. When we combine two drugs that show sub-threshold activity alone, we can reduce self-administration of alcohol in rats by 50 per cent. But what is really exciting is that the combination of antagonists completely prevents relapse to alcohol seeking behaviour.”

Lawrence suggests this finding is significant because a large number of individual drugs used to treat brain disorders have unpleasant off-target effects that can reduce patient compliance. “mGlu5 is implicated in fundamental processes of addiction. Blocking mGlu5 directly may not be clinically useful by itself, but it can help us identify more subtle ways of modulating the receptor’s activity with combination low-dose therapies, which should improve our chances of minimising any off-target side effects.”

Some of those off-target effects involve reactions with the same receptor in other regions of the brain. At sub-threshold doses, the non-target receptors should not be activated; the therapeutic action is more likely to be restricted to those areas of the brain where the receptors are co-located with mGlu5 receptors.

“Take a hypothetical situation where the two receptors are linked in a large complex of neurons. If we can identify compounds that interact preferentially with that complex, the drug combinations effectively specify an ‘address’ for their localised activity. Whether we can achieve this remains to be seen, but the approach is showing promise in our early experiments.”

A potential problem for human therapies is that human addicts tend to be polyabusers – for example, many individuals become addicted both to alcohol and nicotine, and may also be addicted to gambling – effectively, an addiction to the brain’s internal chemical reward system.

Many human addicts may use more than one drug, and in more than one class – for example, heroin and methamphetamine – which can complicate treatment efforts. “But in a cued exposure setting, related to where they have used each drug, their craving will likely be specific to a particular drug.”

A related issue is cross-sensitisation to drugs of abuse. “If people have used one drug, they are more likely to be hyper- responsive to other drugs, which may be part of the reason why people switch from one drug to another when their preferred drug is unavailable, then switch back when it’s available again.”

Lawrence describes an “elegant” experiment in which Canadian researchers trained rats to self-administer alcohol, and then subjected them to alcohol extinction training, equivalent to human rehabilitation. After the rats’ alcohol- seeking behaviour was extinguished, the researchers injected the rats with nicotine and returned them to the familiar chamber where they had previously self- administered alcohol. “The rats had never seen nicotine before, yet injecting them with nicotine was sufficient to reinstate their alcohol-seeking behaviour.”

Read part III of the neuroscience of addiction.