Memories without fear

C&I Issue 2, 2012

Imagine being able to tinker with a traumatic memory so that you can still remember what happened but no longer feel anxious when doing so. Researchers are using drugs – some commonly prescribed for other disorders – to do just that. But although they’ve shown that memory and its associated emotion can be modulated, it is not yet clear exactly how it works or which drugs are most suitable for the job.

Merel Kindt and Marieke Soeter at the University of Amsterdam, the Netherlands, for example, have found that propranolol, a commonly prescribed beta-blocker to treat high blood pressure, erases the fear response associated with a memory without affecting recall of the memory itself.

In their experiments, participants were given an electrical shock when shown an image of spiders. Their ‘startle’ response – how much their eyes blinked – was measured. The next day, they were given either propronalol or placebo and were shown the pictures again. Both groups had the same startle response.

But on the third day, those who had been given propranolol on the second day – which was now out of their system – had a reduced startle response when shown the pictures again, compared with those who had received the placebo. Another group, which was given propranolol but did not see the pictures again on the second day, had the same response as those given the placebo – suggesting that recalling a memory while under the influence of propranolol is what alters the associated emotion (Nature Neuroscience, doi:10.1038/nn.2271).

Further work showed this effect was persistent even a month later (Neurobiology of Learning and Memory, doi:10.1016/j.nlm.2010.03.004), indicating the approach could be used to treat anxiety disorders (doi/10.1101/lm.2148511).

So what is happening at the cellular level? Basically, a sensory experience activates protein receptors at nerve junctions or synapses in the brain, triggering a biochemical cycle resulting in memory formation. The initial memory is plastic and will fade away unless protein synthesis takes place to make it more stable, storing it in the long-term memory for the first time (consolidation), at which point the associated emotion is locked in. One specific memory activates a specific subset of synapses whereas another memory activates a different subset.

‘For a very long time, we thought that memories were unstable following their initial encoding but that after their consolidation completed, it was impossible to modify them,’ explains Marie-France Marin at the University of Montreal, Canada. ‘However, it has been shown that by recalling (reactivating) an already consolidated memory, it becomes unstable again and it is thus possible to act on this memory trace before it stabilises again in the brain (reconsolidation).’

The molecular mechanism of recall is not fully known. It is thought that strong emotions activate the beta-adrenergic receptors, which in turn enhance protein synthesis and therefore consolidation of memory. If a specific memory is revisited, a process of reconsolidating occurs, during which the specific synapses that encoded that memory are more likely to change, explains Harel Shouval, associate professor of neurobiology and anatomy at the University of Texas, US.

Propranolol blocks the noradrenergic receptors required for protein synthesis. ‘If propranolol is used during reconsolidation, these specific synapses might be weakened due to less protein synthesis,’ says Shouval. ‘It is not the whole memory that is erased, but rather its emotional content.’

However, it is not yet understood why treatment with propranolol has a more significant, longer lasting effect once the drug is out of the system.

Alain Brunet, associate psychiatry professor at McGill University in Canada, and Roger Pitman, professor of psychiatry at Harvard Medical School, are currently testing a propranolol-based treatment for post-traumatic stress disorder (PTSD).

The idea is to treat PTSD by blocking consolidation of the memory – as opposed to reconsolidation,which is based on the recall of a bad memory. ‘To prevent the PTSD memory from consolidating, ideally you’d need to take the drug immediately after the event because the window of opportunity is very small: consolidation starts within minutes and lasts a few hours, while propranolol takes up to 90 minutes to reach its peak bioavailability,’ says Brunet.

Others are studying the use of beta-blockers in treating drug addiction. Many addicts find it hard to stay off drugs because they are surrounded by drug-associated cues that remind them of how good drugs are. Preventing them from remembering the drug-associated memories these cues provoke could help prevent them relapsing.

Scientists at the University of Wisconsin-Milwaukee, US, conditioned cocaine-addicted rats to associate one chamber with cocaine but not another. Rats subsequently given propranolol were not able to remember which chamber contained cocaine, even two weeks later or following an injection of cocaine (Neuropsychopharmacology, doi:10.1038/npp.2011.77).

Yet other researchers, meanwhile, have found that the strength of an emotional memory can be reduced long-term by treating patients with metyrapone, an endocrine drug normally used to treat the hormone disorder Cushing’s syndrome by lowering cortisol levels.

Previous research has shown that healthy patients with normal cortisol levels consolidate memory if they are given metyrapone when they first learn something, which is the time of encoding.

In a later study, conducted by Marin and colleagues in Canada, participants were shown a slide show containing neutral and emotional information. After the initial memory was formed and stabilised, the participants were given one or two doses of metyrapone or placebo. The researchers found that the subsequent retrieval of emotional information was acutely impaired in the double-dose metyrapone group and that this effect was still present four days later, when glucocorticoids levels were not different between groups (The Journal of Clinical Endocrinology & Metabolism, doi: 10.1210/jc.2011-0226).

‘Metyrapone prevents the synthesis of cortisol, and we know that there is a close relationship between the levels of cortisol and memory retrieval performance,’ explains Marin. ‘This relationship seems to follow an inverted U-shape function, where very low and very high levels of cortisol are detrimental to memory performance.’

However, metyrapone is unlikely to be used for treating PTSD. ‘What is not clear is how lowering levels of glucocorticoids [hormones such as cortisol]in people with PTSD will help decrease emotional memory, because those with PTSD already have decreased levels of glucocorticoids,’ says Natalie Tronson, instructor in psychiatry & behavioral science at Northwestern University, US. ‘There is better evidence for increasing glucocorticoids to allow people to extinguish memory – to learn not to associate it with traumatic emotion, possibly by replacing the old memory with a new one.’

So how likely is it that propranolol or metyrapone will be developed into treatments for anxiety or addiction disorders?

Although the current findings are only a ‘proof of principle’, Kindt says that disrupting reconsolidation has the potential of becoming a new treatment for psychiatric disorders such as anxiety discorders.

The use of either drug would be relatively safe from a pharmacological point of view as they would be given only when memories were being recalled (activated), not on a daily basis. Some caution would be required as propranolol can interact with a few other drugs, for example, while metyrapone can cause nausea if not taken with dairy products. But there are really no major downsides, says Brunet.

However, tampering with memory is an emotive issue for some, who have questioned the ethics of such drugs. ‘There are consequences if memory is less emotional – there needs to be a balance,’ acknowledges Kindt, who points out that, although some details may be lost through this kind of treatment, the core of the event is still there.

‘The idea of decreasing the emotional component is good one, while leaving the original memory intact – that’s an important goal,’ adds Tronson.

Nevertheless, treating PTSD with either drug seems unlikely because of the timing issue. ‘To block consolidation you have to act very fast with individuals whose PTSD status is unknown to the treatment provider,’ points out Brunet.

And it is hard to say whether metyrapone will ever be commercialised for anxiety disorders as current results will need to be replicated in clinical populations with larger groups, says Marin, who adds that metyrapone is not currently available in Canada for clinical use. ‘Metyrapone might be useful in a clinical setting but in terms of people taking it in practice, I’m not sure,’ says Tronson.

The jury is also out on propranolol. For example, ‘it is a concern that the blood brain barrier blocks some forms of propranolol,’ says Richard Jennings, professor of psychiatry at the University of Pittsburgh, US.
‘I’m not sure about propranolol,’ agrees Brunet. ‘But I am sure reconsolidation blockade will [be developed into treatments for anxiety conditions] some day. Several drugs can potentially do this. Have we found the best drug yet to do this? Not sure.’

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