Abolishing addiction Brainwashing Sep 15th 2005 From The Economist print edition A new way to treat drug

abuse (in rats, at least) A DRUG addict's brain alters in response to the drugs he takes. There is the instant change that provides the chemical high, of course, but there are also more subtle, longterm modifications. It is these that turn a user into an addict. Some of them are responses to the drug itself. But some are responses to the circumstances in which the drug is taken. Such things as viewing the paraphernalia of drug taking, for example, serve to remind abstinent addicts of forbidden pleasures and tempt them to relapse. Two pieces of research just published in Neuron, a specialist journal, suggest that it is possible to impair the brain's memory of such associationsat least, if the brain concerned is a rat's. Courtney Miller and John Marshall, of the University of California, Irvine, have worked out how to disrupt the memories that cocaine-taking rats develop for the place where they get their fix. And a team led by Jonathan Lee, of the University of Cambridge, has prevented rats from using environmental cues to seek cocaine. Three regions of the brain are thought to be linked to addiction: the prefrontal cortex, the nucleus accumbens and the amygdala. All three have a multitude of receptors for a chemical called dopamine, which is part of the nervous circuitry involved in the perception of desire, and all are involved in the laying down of long-term memories. That process, surprisingly, is not a one-off event for each memory. Every time a memory is recalled, it seems to be actively refiled afterwardsa process known as reconsolidation. This is why people are vulnerable to suggestion when recalling memories of, for example, childhood abuse. Observing this, Dr Miller and Dr Marshall wondered if they could manipulate the refiling process to abolish a memory altogether. To do so, they first had to establish the memory they wanted to abolish. They did this by putting their rats into an apparatus containing two chambers and teaching them to associate one of those chambers with cocaine use. (Rats are at least as keen on Bolivian marching powder as humans are.) The two rooms had different colours, textures and smells, so the rats could easily tell them apart. In normal circumstances, when trained rats were allowed to chose which room to enter, they preferred to spend most of their time hanging out in the cocaine chamber even when no cocaine was available. Having established this preference, Dr Miller and Dr Marshall then sought to abolish it using a drug that inhibits the production of a protein called Extracellular Signal-related

Kinase. This protein, which is generated in the core of the nucleus accumbens, causes long-term changes in gene expression that are thought to be involved in the storage and retrieval of memories, including those of drug use. Two days after being trained to associate one of the chambers with cocaine, the rats were divided into three groups. Some were given the inhibitor drug and then returned to their cages. Some were given it and then returned to the two chambers. And some were first returned to the two rooms, giving them the opportunity to remember the cocaine chamber, and were then given the inhibitor drug. In these tests, rats in the first group who had not been given the opportunity to retrieve their memories of cocaine when they received the treatment drugpreferred to spend time in the cocaine chamber. But rats in the other two groups showed no particular preference for either room. Their previously strong memories had become disrupted. Dr Lee and his colleagues, meanwhile, were studying the amygdala. This part of the brain serves as a Pavlovian learning machine that associates a pleasurable event, such as being fed, with a neutral event, such as the sound of a bell ringing. Dr Lee's rats learned that they received cocaine when they poked their noses into a particular hole. At the same time, a light went on. The rats were then put into a similar set-up, but this time they received no cocaine when they poked their noses into the hole, and there was no light. Dr Lee and his team then treated their rats to shut down the gene that produces a protein called Zif268, which seems to have a similar role in the amygdala to that of Extracellular Signal-related Kinase in the nucleus accumbens. (They did this using pieces of antisense DNA that attach themselves to the gene in question and stop it being read by the cellular machinery that transcribes genes.) Several days later, the rats were returned to the test site, but this time two levers had been installed in it. One of these levers did nothing. The other lit the light associated with cocaine use. The rats who had not received the treatment pressed the lever that lit the light many more times than did the rats who had received the injection, suggesting that only they remembered the light's association with cocaine. Both teams of researchers believe that the amnesia they have induced relates only to memories of drug use, because those were the memories that were being recalled at the time the inhibitor drugs were given. That will bear further investigation. But if it is true, and drug-related memories can be abolished without affecting other memories, then this work might be a first step on the road to a therapy that would eliminate the powerful urges addicts experience when in the social situations in which drugs are taken.

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