By Kristina Fiore, Staff Writer, MedPage Today
Published: April 13, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Using a type of exposure therapy to wipe out the emotional triggers that drive drug addiction may be most effective when the brain is in the process of recalling and re-storing memories, Chinese researchers found.
Calling up a drug-related memory just before having "extinction" therapy -- seeing drug-related cues without being able to use -- was associated with diminished cravings in rat and human models, Lin Lu, PhD, of Peking University in Beijing, and colleagues reported in Science.
Performing this type of emotional-memory-scrambling as a memory is "reconsolidating" may eventually provide a means of treating addiction, according to David Epstein, PhD, of the National Institute on Drug Abuse (NIDA), a co-author on the paper.
The idea behind memory reconsolidation is that once a patient consciously recalls a memory, it has to be stored in the brain as a new memory all over again. It can be altered, however, during that process.
Epstein explained that by itself, extinction therapy -- similar to exposure therapy, which tempers PTSD symptoms in veterans by having them relive the traumatic moment -- doesn't work all that well in drug addiction because it doesn't weaken the initial memory that drives the user to seek out more drugs.
"It's only new learning that's superimposed on top of an old memory that stubbornly sticks around," he said.
But if you perform extinction during memory reconsolidation and that memory is vulnerable to interference, Epstein said, it can be weakened.
"So when you do the extinction [during reconsolidation], you're doing more than just creating the usual new learning," he said. "You're overwriting the old memory."
Researchers have already tinkered with emotional-memory reconsolidation in addicts by using pharmacologics, mainly propranolol (Inderal), but also in animal models with other agents not approved for use in humans. So Lu and colleagues' aim was to be able to interfere with the process without using any drugs.
In a series of experiments in rats, they found that those addicted to cocaine or heroin had no interest in the drugs after having reconsolidation and extinction -- but only if the reminder occurred 10 minutes or an hour before extinction therapy.
Drug-seeking behaviors returned if 6 hours had elapsed between the memory trigger and the exposure therapy, the researchers reported.
"The timing is really crucial," Epstein said. "It reflects the limited time window during which memories are vulnerable to disruption."
In another model in which the rats were able to self-administer drugs, only those that had reconsolidation and extinction -- not extinction alone -- were less likely to resume drug-seeking behaviors a month later, they found.
Lu and colleagues then tested the treatment in Chinese heroin addicts who'd had medically supervised detoxification and were inpatients at a treatment facility.
Patients had either extinction therapy alone, or memory retrieval -- a 5-minute video of heroin use -- either 10 minutes or 6 hours before extinction therapy in which they were exposed to drug images and paraphernalia but not given any drugs.
Only those who had the 10-minute interval between the memory trigger and extinction therapy had significantly reduced cravings (P<0.01) and a trend toward decreases in blood pressure (P=0.09) that were sustained for about 6 months, the researchers reported, noting, however, that there were no changes in heart rate.
"That's kind of astonishing considering how nonintrusive and how seemingly inconsequential this procedure is," Epstein said.
But he noted that the trial reveals nothing about what would happen to the heroin addicts if they were exposed to the real-world environmental cues that got them hooked in the first place.
One of the next steps, he said, would be to conduct similar trials in an outpatient setting. No such U.S.-based trial is planned, but Epstein said NIDA is currently conducting an outpatient trial that uses propranolol to interfere with memory reconsolidation in addicts -- although it "would be nice to be able to do it completely behaviorally," he said.
In terms of potential neural mechanisms, reconsolidation and extinction have been shown to depend on activation of N-methyl-D-aspartate (NMDA) receptors, the researchers said. In their study, they also saw increased expression of protein kinase C in the infralimbic cortex and diminished expression in the basolateral amygdala.
This may lead to structural changes in neurons that stabilize memory, they wrote.
In an accompanying editorial, Amy Milton, PhD, and Barry Everitt, PhD, of the University of Cambridge in England, agreed that "targeting maladaptive memories that play an important role in the persistence of addictive behavior may provide a new avenue for treatment interventions."
The study was supported by the National Basic Research Program of China, the Natural Science Foundation of China, and the National Institute on Drug Abuse.
Neither the researchers nor the editorialists reported any conflicts of interest.
Primary source: Science
Source reference:
Xue YX, et al "A memory retrieval-extinction procedure to prevent drug craving and relapse" Science 2012; 366: 241-245.
Additional source: Science
Source reference:
Milton AL, Everitt BJ "Wiping drug memories" Science 2012; 336: 167-168.
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