Researchers selectively knock out memory associations connected with receiving cocaine

Sep 19 2005

Addicts crave drugs and suffer relapse not just because of the alluring high of drugs, but also because they are compelled by the powerful, haunting memory associations with the environment surrounding their drug taking. Thus, treatments that could eliminate those memory associations could prove effective in treating addiction, researchers believe.

In two papers in the September 15, 2005, issue of Neuron, two groups of researchers report important progress toward such treatments, showing that they can selectively knock out memory associations connected with receiving cocaine.

In one paper, Jonathan Lee and his colleagues at the University of Cambridge create an animal model of such cocaine memory formation by first teaching rats to associate the poking of their noses into a food bin with an infusion of cocaine into the brain and with the activation of a signal light. They infused cocaine into the amygdala, a brain region involved in forming and processing emotional memories.

The researchers then extinguished the drug-related memory by giving the animals only saline solution when they poked their nose into the bin, activating the light.

In their procedure, the researchers then added a new drug-associated response by requiring the animals to press a lever to obtain cocaine, with the lever also activating the same signal light.

Their purpose was to test the effects of treatment on a memory process called "reconsolidation." The theory underlying reconsolidation is that when memories are recalled they become malleable, subject to disruption.

To discover whether they could disrupt reconsolidation of the drug-related memory, before the animals were exposed to the new lever-pressing task, the researchers injected into the amygdalas of the trained animals a molecule that would effectively shut down the gene that produces a protein called Zif268. This protein is known to be active when cocaine-conditioned memories are created. The injected molecule was "anti-sense" DNA that would attach to the gene, blocking its activation.

The researchers found that such anti-sense DNA treatment disrupted the rats' ability to learn to associate the new lever-pressing behavior with the signal light to obtain cocaine, despite the fact that the animals showed no other differences from a control group in lever-pressing activity or nosepoke response and thus no difference in general motivation or activity.

The researcher wrote that "Drug-associated stimuli are critically important in the acquisition of prolonged periods of drug-seeking behavior, maintenance of this behavior in the absence of reward, and precipitation of relapse to drug seeking in the absence of reward. Therefore, the ability to disrupt retroactively the conditioned reinforcing properties of a drug cue provides a potentially powerful and novel approach to the treatment of drug addiction by diminishing the behavioral impact of drug cues and thereby relapse."

Lee and his colleagues point out that the basic processes of such drug-associated memory reconsolidation are distinct enough from normal memory that "it is possible to manipulate preexisting maladaptive memories in a highly specific manner, without affecting either the reconsolidation of other established memories or the consolidation of new memories."

In a second Neuron paper, Courtney Miller and John Marshall of the University of California, Irvine, explored how another brain region, the nucleus accumbens, operated in cocaine-associated memories. The nucleus accumbens receives neural input from the amygdala and is involved in motivating such reward-related behavior as drug seeking.

In their experiments, the researchers taught rats to associate one of two connected chambers with receiving cocaine and measured how well the rats remembered that association and chose to move to that chamber.

The researchers' analysis of molecular regulatory pathways in the animals' nucleus accumbens revealed that a master neural regulatory pathway, triggered by a molecular switch called ERK, was activated when the trained animals showed a preference for the "cocaine chamber."

What's more, the researchers discovered that drugs that blocked the ERK pathway prevented the trained animals' memory retrieval of their preference for that chamber.

And to their surprise the researchers found that the drugs also blocked memory reconsolidation--significantly reducing the rats' preference for the cocaine chamber even two weeks after being given.

"To our knowledge, the current study is the first to identify a molecular mechanism that blocks both retrieval and reconsolidation of any type of memory," wrote Miller and Marshall.

"While much remains to be understood concerning the cellular processes underlying the effects of ERK in drug-stimulus associations and other types of learning and memory, the present findings offer hope for treating cue-elicited relapse in addicts," concluded Miller and Marshall.

"It is widely accepted that memories for drug-associates stimuli, which are strong and resistant to extinction, are responsible for much of the relapse seen in addicts. The present findings suggest that these highly resistant memories may again be made labile and thus susceptible to disruption by pharmacological or other neurobiological interventions, providing opportunities for new therapies," they concluded.