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Stress-induced changes in brain circuitry linked to cocaine relapse
Date:10/30/2009

ring a troubling experience. Research suggests that this response is mediated by the stress-evoked release of dynorphins, the "feel bad" brain signals.

For mice, meeting a dominant male mouse is disheartening. Dr. Land likened the stressfulness of this situation to sitting in a classroom with the schoolyard bully. Facing an aggressor, mice will admit social defeat by raising their paws in an "I give up" pose. If the lab mice have received cocaine before and are abstaining now, they will want the drug again.

"Stress appears to be a motivator for the relapse in drug seeking," Land said, "They feel crummy so they go where there might be something that will make them feel okay again." They head to a spot that had the drug available in the past, an action researchers call cocaine place preference.

Scientists had previously proposed that an activated dynorphin/kappa opioid receptor system stopped the release of dopamine and thereby made the mice feel miserable enough to cause aversions. However, even mice bred to be dopamine-deficient still responded with aversions. When scientists inactivated the kappa opioid receptors involved in the serotonin system in the dorsal raphe nucleus -- the serotonin-abundant region of the brain -- they were able to block both the aversive responses and the stress-induced reinstatement of cocaine-place preference.

Mice that had their kappa opioid receptors genetically "knocked out" did not develop aversive responses to chemical triggers. After the scientists genetically restored these missing receptors in the dorsal raphe nucleus of the brain, the mice responded to the trigger with place aversion. However, the researchers found that genetically installed, mutated receptors that can't activate a brain protein called p38 MAPK couldn't provoke aversive responses.

The researchers concluded that activation of the kappa opioid receptor, either pharmacologically or by stress-evoked release of dynorph
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Contact: Leila Gray
leilag@u.washington.edu
206-685-0381
University of Washington
Source:Eurekalert

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