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How stress triggers drug relapse

BROWN / U. PENNSYLVANIA (US) — By identifying an exact region in the brains of rats, scientists were able to block a key step in the chain of events that causes stress-related drug relapse.

The new findings could accelerate progress toward a medicine that prevents stress from undermining addiction recovery.

In the paper published in Neuron, researchers demonstrated specific steps in the sequence of neural events underlying stress-related drug relapse and showed that they take place within a brain region called the ventral tegmental area (VTA), which helps reinforce behaviors related to fulfilling basic needs.

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They also showed that a closely related neural process believed to be crucial to this type of relapse may not be involved after all.

When researchers treated rats that had recovered from cocaine addiction with a chemical that blocks the “kappa opioid receptors” that stress activates in the VTA, the rats didn’t relapse to cocaine use under stress. Untreated rats who had also recovered from addiction did relapse after the same stress.

The chemical that helped the rats, “nor-BNI,” may be one that would someday be tried in humans, says study senior author Julie Kauer, professor of biology in the department of molecular pharmacology, physiology, and biotechnology at Brown University.

“We’re at the point of coming to understand the processes and possible therapeutic targets. Remarkably, this has worked,” Kauer says.

Exactly how stress acts in the brain to trigger relapse is a complicated sequence that is still not fully understood, but the new study focuses on three key players: GABA-releasing neurons, dopamine-releasing neurons, and the kappa opioid receptors that affect their connections.

Apply the brakes

Fulfilling natural needs such as hunger or thirst results in a rewarding release of dopamine from the VTA’s dopamine neurons, Kauer says. Using drugs can elicit the same response.

In normal brain function, GABA applies the brakes on the rewarding dopamine release, slowing it back to a normal level. It achieves this by forging and then strengthening the connections, called synapses, with the dopamine neuron. The strengthening process is called long-term potentiation (LTP).

In the first of their experiments, Kauer and colleagues, including lead author Nicholas Graziane, showed that stress interrupts the LTP process, hindering GABA’s ability to slam the brakes on dopamine release.

Previous research implicated kappa opioid receptors as one of many neural entities that could have a role in stress-related relapse. Kauer, Graziane, and co-author Abigail Polter investigated that directly by blocking the receptors in some rats with a treatment of nor-BNI in the VTA and leaving others untreated.

Then they subjected the rats to a standardized five-minute stress exercise. After 24 hours they looked at the cells in the VTA and found that LTP was hindered in the untreated rats but still present and underway in the rats whose receptors had been blocked with nor-BNI.

With the role of stress and the receptors in the GABA-dopamine dynamic both confirmed and then mitigated, the question remained: Could this knowledge be used to prevent relapse?

To answer that, University of Pennsylvania co-authors Lisa Briand and Christopher Pierce performed the experiment demonstrating that nor-BNI delivered directly to the VTA prevented stressed rats from relapsing to cocaine seeking, while untreated rats subjected to the same stress did relapse.

“Our results indicate that the kappa receptors within the VTA critically control stress-induced drug seeking in animals,” the authors write.

Along the way, the team also discovered evidence that another stress-affected synapse in the VTA—one that excites dopamine release rather than inhibits it—does not play a role in the stress-related relapse as many researchers have thought. The nor-BNI treatment that prevented stress-related relapse, for example, did not affect those synapses.

“If we can figure out how not only stress, but the whole system works, then we’ll potentially have a way to tune it down in a person who needs that,” says Kauer.

The National Institutes of Health supported the research.

Source: Brown University

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