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Researchers find relapse may be preventable

A study at Brown and Penn focused on the part of the brain reinforcing drug-craving behavior

Stress-induced addiction relapse may be preventable by blocking receptors in the part of the brain responsible for sex, pleasure and motivation, according to a study by researchers at Brown and Penn. Their research was published in the journal Neuron last week.

Stress and addiction affect similar pathways in the brain, said senior author Julie Kauer, professor of molecular pharmacology, physiology and biotechnology. “The part (of the brain) that responds to stress also responds to addiction and drugs,” Kauer said. Understanding the close relationship between stress and addiction could lead to new treatments and therapies for drug addiction, she added.

“The biggest clinical problem with addiction is relapse,” Kauer said, noting that stressful experiences heighten drug cravings.

The study focused on kappa opioid receptors in the ventral tegmentum area (VTA) — the part of the brain that reinforces drug-craving behavior. Chemicals, called neurotransmitters, are released from the VTA to send signals to many other parts of the brain. Kauer and her team thought the release of one specific neurotransmitter, dynorphin, might be triggered by stress.

Dynorphin may lead to addiction relapse by attaching to kappa opioid receptors in the VTA, Kauer said.

The most common way to study drug addiction is to allow rats to self-administer cocaine through a lever-pressing mechanism that administers cocaine intravenously, said lead author Nicholas Graziane, a former postdoctoral researcher at Brown who is now a postdoc at the University of Pittsburgh.

After the rats exhibit addictive behavior by pressing the lever at rapid rates, the cocaine is replaced with a saline solution to extinguish the addiction. Realizing that they are no longer receiving the drug, the rats stop pressing the lever. But exposing the rats to stress causes them to increase lever pressing and drug-seeking behavior, Graziane said.

The scientists improved upon this existing model by injecting the rats with a neurotransmitter called nor-BNI — which binds to the kappa opioid receptors — before subjecting them to a stress test, in which they were placed in cold water for five minutes. Then, when chemicals like dynorphin are released due to stress, they cannot attach to the opioid receptors.

The scientists were amazed at their results­­ ­— they found the rats much less likely to seek drugs if they had received nor-BNI before stress exposure, Kauer said.

“To almost completely block these animals from relapsing was a major breakthrough,” Graziane said.

“This is just another small piece of the puzzle,” said Abigail Polter, a postdoctoral researcher involved in the study. Future research could look for ways to further characterize the addiction signal pathway, she said. The prevention method would be more clinically viable if nor-BNI could act on stress after it occurred instead of preemptively, she added.

Kauer emphasized the importance of studying basic synaptic properties. “We could never have come up with this drug target if we had not first worked it out in the basic lab,” she said.

It is unclear how well the study’s findings will translate to human subjects. Addiction processes have similar effects on humans and testing animals, but the brain works in mysterious ways, Graziane said. “We know that this system is in humans, and studies have shown people who have addictions often have changes in the kappa opioid system.”


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