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Brain Mechanism Turns Off Cocaine-Related Memory in Rats

An exploration of memory's molecular basis suggests potential novel therapeutic approaches to cue-induced craving.
October 01, 2006
Patrick Zickler, NIDA Notes Contributing Writer

Scientists at the University of California, Irvine, have added to evidence that a brain enzyme controls key memory processes that link drug experiences, the surroundings in which they take place, and the urge to repeat them. In a series of experiments, inhibiting the enzyme attenuated a rat behavior that is a laboratory stand-in for human cue-induced drug-seeking. The findings suggest that in the future, therapeutically manipulating levels of the enzyme might cut addicted individuals' vulnerability to environmental triggers for drug craving and abuse.

The NIDA-funded scientists, Drs. Courtney Miller and John Marshall, focused on the enzyme in an attempt to elucidate the ways cellular activities promote cue-induced drug-seeking.

rat
Enzyme Blockage Disrupts Drug-Seeking: In experiments with rats, researchers used a compound called U0126 to block ERK, an enzyme that facilitates memory formation and consolidation.
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Group 1

Researchers trained rats to associate cocaine with a specific setting. The animals signaled their successful conditioning by exhibiting conditioned place preference—spending more time in a chamber where they had received cocaine injections over 9 days.

Rats received infusions of U0126 or a control vehicle. After 30 minutes, they were tested for CPP.

Rats given U0126 showed no preference for a cocaine- associated chamber. Control rats did show preference for the cocaine- associated chamber.
Rats given U0126 still exhibited no CPP.

Control rats retained CPP.
  Inhibiting ERK activity can block retrieval of cocaine- associated memories for 24 hours.
Group 2

Researchers trained rats to associate cocaine with a specific setting. The animals signaled their successful conditioning by exhibiting conditioned place preference—spending more time in a chamber where they had received cocaine injections over 9 days.

Rats were tested for CPP and immediately infused with either U0126 or the control vehicle. Rats given U0126 showed no CPP.

Control rats showed CPP.
  Inhibiting ERK activity immediately after cocaine- associated memories are retrieved can make the memories unavailable for subsequent retrieval at 24 hours and for at least 2 weeks.
Group 3

Researchers trained rats to associate cocaine with a specific setting. The animals signaled their successful conditioning by exhibiting conditioned place preference—spending more time in a chamber where they had received cocaine injections over 9 days.

Rats were tested for CPP and immediately infused with either U0126 or the control vehicle.   Rats given U0126 showed no CPP.

Control rats showed CPP.
same as above
Group 4

Researchers trained rats to associate cocaine with a specific setting. The animals signaled their successful conditioning by exhibiting conditioned place preference—spending more time in a chamber where they had received cocaine injections over 9 days.

Rats received an infusion of U0126 and remained in their home cage with no testing and therefore no opportunity for memory retrieval. Rats showed a strong CPP for the cocaine- associated environment.   ERK inhibition is effective only when induced at the time of memory formation or memory retrieval.

"Although studies have established that nerve cells in the core of the nucleus accumbens are critically involved," Dr. Miller says, "we haven't had much information about the molecular mechanisms that transform environmental cues into an urge to repeat drug-associated behavior." One likely candidate for a role in the process, however, was extracellular signal-regulated kinase (ERK). This enzyme is known both to foster the new cellular connections that register emotional and object recognition memories in the brain and to be affected by cocaine.

The researchers explored ERK's role in a behavior called conditioned place preference (CPP). By exhibiting CPP—lingering in a part of a cage where it has had a drug experience—an animal indicates that it remembers the experience, associates it with the preferred cage area, and is seeking to have it again (for more on CPP, see "Animal Experiments in Addiction Science (Archives)"). In previous research, blocking ERK activity in the nucleus accumbens (NAc) prior to exposing rats to drugs prevented them from developing CPP. Drs. Miller and Marshall reasoned that if blocking ERK forestalls initial formation of the memory links underlying CPP, it might also weaken links that had already been formed. The potential therapeutic implications would be significant if this were so; they would suggest that manipulating ERK might be a means to disrupt drug-environment associations that are already established by the time patients begin therapy.

New Findings on Memory Have Implications For Treatment

Groundbreaking research on the molecular basis of long-term memory could open a new path to the treatment of drug addiction, post-traumatic stress disorder (PTSD), and other conditions in which memories exert a powerful influence on behavior, according to neuroscientists who presented research at a NIDA conference, "Frontiers in Addiction Research." Their findings suggest that when long-term memories are recalled, they return to a state in which they can be altered or erased before undergoing "reconsolidation" for future potential use. This discovery could lead to the development of medications that disrupt the reconsolidation process and thereby prevent memories associated with drug abuse or trauma from being reestablished.

Dr. Karim Nader of McGill University in Montreal, Canada, explained the process of reconsolidation and how interventions based on that process might work. The goal, he said, is not to simply erase memory, but rather to modulate the memory so that its effects are more manageable in conditions such as PTSD or addiction. "Our research shows that when a consolidated long-term memory is reactivated, it returns to a labile state similar to short-term memory. Neurons must synthesize new proteins in order for the memory to persist. If protein synthesis is inhibited after reactivation, reconsolidation can't occur," he said.

Although he cautioned that there is an enormous amount of work to be done before testing the effect in human patients, Dr. Nader said his animal studies have significant clinical implications. "In the case of drug addiction, if drug-related memories could be reactivated and prevented from being restored, drug-seeking behavior could in principle be greatly reduced in one session," he said. "It sounds like science fiction, but it is not."

Dr. Susan Volman of NIDA's Division of Basic Neuroscience and Behavioral Research and Dr. Barbara Sorg from Washington State University cochaired the session on "Reconsolidation of Memory: A New Approach to Treat Drug Addiction?" at the conference,which was held in Washington, D.C., November 11, 2005, in conjunction with the annual meeting of the Society for Neuroscience.

To test their hypothesis, the researchers administered cocaine to rats daily for 9 days, after which the rats exhibited CPP whenever they were placed back in their test cage. The researchers then conducted a series of trials and assays that showed:

  • CPP involves activation of ERK: Rats that lingered in the cocaine-associated area of the test cage had higher ERK levels in the core area of the NAc than a group of rats that had not been exposed to cocaine or a third group exposed to cocaine but not trained to exhibit CPP.
  • Inhibiting ERK activity can block retrieval of cocaine-associated memories for 24 hours: The investigators infused a compound called U0126, which reduces ERK activity, directly into the NAc cores of some of the CPP-trained rats. When placed in the test cage 30 minutes later, these rats gravitated to the cocaine-associated area much less consistently than did a group of CPP-trained rats that were injected with saline rather than U0126. Tested again 24 hours later, they still exhibited little or no preference for the area.
  • Inhibiting ERK activity at the time cocaine-associated memories are retrieved can make them unavailable for subsequent retrieval for at least 2 weeks: Rats were placed in the test cage and given U0126 immediately after exhibiting CPP. When retested the following day, they showed no partiality to the drug-associated cage area, nor did a similarly treated group of animals tested 2 weeks later. "These animals had effectively recollected their cocaine experience on day 1, but on day 2 and even 14 days later, there was no evidence that the memory was active," Dr. Miller notes.

"This last observation provides powerful evidence that disruption of ERK activity blocks memory reconsolidation," Dr. Miller says. "Memories are unstable during the interval between being recalled and being refiled, and, if the reconsolidation process is disrupted, the memory can be lost. The animals behave as though it had never been formed to begin with. The fact that powerful memories associated with drugs may become pliant and susceptible to disruption by ERK inhibition during reconsolidation suggests opportunities for new therapies." For example, pending much further research, it is conceivable that an approach combining exposure to a cue with administration of an ERK inhibitor might prevent a patient from reconsolidating—and thus erase—the memory chain linking the cue to craving.

"This research provides important new understanding of the processes that take place when the brain is manipulating memories, and it identifies specific molecules that help shape those processes," comments Dr. Jerry Frankenheim of NIDA's Division of Basic Neuroscience and Behavioral Research. "The fact that the intervention with U0126 came after the animals had already learned the cocaine-place association may be important for translating this research to possible clinical application. There are many ways to block the initial consolidation of memory, but the approach used in this research—interrupting reconsolidation—is much more relevant to intervening in cocaine abuse," he adds.

Source

Miller, C.A., and Marshall, J.F. Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47(6):873-884, 2005. [Abstract]

Blocking Protein Also Stops Drug-Linked Memory

NIDA-sponsored researchers at Mount Sinai School of Medicine, New York, have found another way to break the chain of molecular events that binds drug-taking to a familiar environment: inhibiting protein synthesis. Earlier research established that gene-directed protein manufacture is necessary to stabilize a new memory and that blocking this molecular process can keep lasting memories from being formed and even disrupt an established memory.

The Mount Sinai researchers, led by Dr. Cristina Alberini, performed experiments similar to those done by Drs. Miller and Marshall, but exposed the rats to morphine rather than cocaine and used chemicals that blocked protein synthesis rather than ERK. Like ERK inhibition, the protein blocker weakened conditioned place preference, but it did so only when given in close conjunction with an actual morphine administration.

Unlike the ERK inhibition technique used by the UC researchers, "blocking protein synthesis only worked after a repeat of the full experience," says Dr. Susan Volman of NIDA's Division of Basic Neuroscience and Behavioral Research. But the take-home message is the same: "It is possible to disrupt the strong association between a drug and place cues."

The chemicals used in this experiment inhibit protein synthesis in general, and it will take a lot more research to develop pharmacotherapy that goes after specific proteins and molecular pathways involved in CPP, Dr. Volman says. But potential applications, she suggests, might go beyond the addiction-environment link: "If we can use protein synthesis inhibition to uncouple place from relapse, perhaps we'll ultimately be able to uncouple cues like paraphernalia, or even the memory of the drug experience."

Source

Milekic, M.H., et al. Persistent disruption of an established morphine conditioned place preference. Journal of Neuroscience 26(11):3010-3020, 2006. [Full Text]

This page was last updated October 2006

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