Remembering to forget
We’re publishing the shortlisted entries to the 2012 Wellcome Trust Science Writing Prize. Today, Ravi Das on how new understanding of memory may help us treat drug addiction.
Welcome to the game. The rules of this game are simple: Forget about the game. Forget I ever mentioned it. If ever you remember the game, you lose. If you lose, you must say aloud that you have done so. If this causes others to remember the game, they also lose.
Now that you are playing the game, you probably realise that there is no real way to win, nor will your participation ever end (sorry). You may ‘forget’ about playing for weeks, even years, but at some point, there will be a trigger that will cause you to remember, and to lose. The memory of the game will not disappear, but will lay dormant, etched into your neurons, waiting to emerge from the recesses of your mind.
The game highlights something that has been historically definitive in the neuroscience of memory: once something is learned, it is hard, if not impossible, to unlearn. However, emerging research suggests that there might be a way to win the game after all and that this same technique might hold the key to ‘curing’ drug addiction.
Our memories form a highly adaptive system that is involved in virtually every aspect of our behaviour, constantly working to steer us towards rewards and allowing us to make predictions in an uncertain world. We are seamlessly guided around our environment, told what to pay attention to and what actions are appropriate in a given situation by our memories. We would hope, then, that they are serving our best interests. This is true most of the time. However, in addiction these very processes are hijacked by drugs, causing a vicious cycle of compulsive drug use at the expense of quality of life.
Physical withdrawal symptoms from drugs last a relatively short time, a few days at most, yet addicts often relapse after months, sometimes years, of abstinence. Addictive drugs, much like food or sex, are highly rewarding, causing releases of dopamine in the brain’s motivational pathways. The brain is fine-tuned to learn about stimuli that predict such rewards. When taking drugs, associative memories are formed between drug-related stimuli and drugs themselves. Over time, these stimuli come to trigger cravings, drug seeking and relapse when they are encountered. This is the same mechanism that makes us salivate at the smell of food and will almost certainly make you lose the game in the future. An ability to change or erase memories could potentially solve the problem of relapse in addicts, although historically this possibility has existed only in the realms of science fiction, as it has long been known that, once well learned, memories are virtually impossible to destroy.
The key to forgetting, however, might be as simple as remembering. In 2000, Karim Nader and colleagues found that if rats were reminded of a well-learned memory and injected with a chemical that prevents the brain from making new proteins, the memory seemed to disappear. This startling finding suggested that, like a house of cards, memories are constantly rebuilt when recalled.
This window of memory fragility, a process dubbed ‘reconsolidation’, offers a ray of hope for treating addiction. By interfering with reconsolidation, we may be able to make the house collapse, erasing memories altogether. Subsequent studies have shown that various neurotransmitters, genes, proteins and an enzyme called PKM-zeta are vital for memory reconsolidation. If we can block these processes, we might be able to destroy the maladaptive memories responsible for drug addiction.
While the drugs used by Nader et al, are not safe for use in humans, it may be possible to block reconsolidation with a common beta-blocker called propranolol or an Alzheimer’s drug called memantine. This is a crude approach to memory interference, but still opens the dizzying possibility of erasing memories with nothing more than a pill.
Promisingly, drugs might not even be needed at all. Earlier this year, Lin Lu and colleagues reported that showing heroin addicts a short video of heroin use to cause drug memory reconsolidation meant that subsequent training to reduce craving ‘updated’ the memory trace. When tested later, the addicts experienced markedly decreased drug cravings when shown heroin-related stimuli, with the effect appearing robust and long lasting.
Research is ongoing and it remains to be seen whether blocking reconsolidation can actually ‘cure’ addiction in humans – there are of course a multitude of social and economic factors involved. However, we will no doubt be hearing a lot more about the ethics of erasing memories and new techniques for doing so in the near future. This means the first truly effective treatments for addiction may be on the horizon. It also means to ever truly win the game, you will have to lose it first.
- Nader, K., Schafe, G.E. & LeDoux, J.E. (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature, 406, 722-726
- Xue, Y.X. et al (2012) A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse. Science, 336: 241:245.
This is an edited version of Ravi’s original essay. Views expressed are the author’s own.
Over the next couple of months, we’re publishing the shortlisted essays from the 2012 competition. Read all, and the 2011 essays, in our archive.
Image credits: Neil Webb / Wellcome Images (top); Wellcome Images (Ravi)