Brain Mechanism Turns Off Cocaine-Related Memory in Rats

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.

"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"). 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.

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]