Disrupting Cocaine-memories To Battle Addiction

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

In one paper, Jonathan Lee and his colleagues at the Universityof Cambridge create an animal model of such cocaine memory formation byfirst teaching rats to associate the poking of their noses into a foodbin with an infusion of cocaine into the brain and with the activationof a signal light. They infused cocaine into the amygdala, a brainregion involved in forming and processing emotional memories.

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

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

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

To discover whether they could disrupt reconsolidation of thedrug-related memory, before the animals were exposed to the newlever-pressing task, the researchers injected into the amygdalas of thetrained animals a molecule that would effectively shut down the genethat produces a protein called Zif268. This protein is known to beactive when cocaine-conditioned memories are created. The injectedmolecule was "anti-sense" DNA that would attach to the gene, blockingits activation.

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

The researcher wrote that "Drug-associated stimuli arecritically important in the acquisition of prolonged periods ofdrug-seeking behavior, maintenance of this behavior in the absence ofreward, and precipitation of relapse to drug seeking in the absence ofreward. Therefore, the ability to disrupt retroactively the conditionedreinforcing properties of a drug cue provides a potentially powerfuland novel approach to the treatment of drug addiction by diminishingthe behavioral impact of drug cues and thereby relapse."

Lee and his colleagues point out that the basic processes ofsuch drug-associated memory reconsolidation are distinct enough fromnormal memory that "it is possible to manipulate preexistingmaladaptive memories in a highly specific manner, without affectingeither the reconsolidation of other established memories or theconsolidation of new memories."

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

In their experiments, the researchers taught rats to associateone of two connected chambers with receiving cocaine and measured howwell the rats remembered that association and chose to move to thatchamber.

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

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

And to their surprise the researchers found that the drugs alsoblocked 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 amolecular mechanism that blocks both retrieval and reconsolidation ofany type of memory," wrote Miller and Marshall.

"While much remains to be understood concerning the cellularprocesses underlying the effects of ERK in drug-stimulus associationsand other types of learning and memory, the present findings offer hopefor treating cue-elicited relapse in addicts," concluded Miller andMarshall.

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

The researchers include Jonathan L.C. Lee, Patricia Di Ciano, KerrieL. Thomas, and Barry J. Everitt of the University of Cambridge inCambridge, United Kingdom. This work was supported by a grant from theUK Medical Research Council.

Lee et al.: "Disrupting reconsolidation of drug memoriesreduces cocaine seeking behavior" Published in Neuron, Vol. 47,795-801, September 15, 2005, DOI 10.1016/j.neuron.2005.08.007 http://www.neuron.org.

The researchers include Courtney A. Miller and John F. Marshallof the University of California, Irvine in Irvine, California. Thiswork was supported by DA 12204 to J.F.M.

Miller et al.: "Molecular Substrates for Retrieval andReconsolidation of Cocaine-Associated Contextual Memory" Published inNeuron, Vol. 47, 873-884, September 15, 2005, DOI10.1016/j.neuron.2005.08.006 http://www.neuron.org.