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Researchers at the University of Toronto and The Scripps Research Institute have found that the brain’s stress and reward systems are linked during nicotine addiction and withdrawal.

The finding opens a new avenue for research into addiction treatment and relapse prevention in smokers and people addicted to other drugs.

Scientists have long known the brain’s stress and reward systems function independently. However, the new research shows our brain’s stress neurotransmitter, called corticotropin-releasing factor or “CRF,” is present in dopamine neurons in the reward system operating in the brains of drug addicts.

“We knew the two systems existed separately, but we didn't know how they interacted during drug withdrawal,” says Taryn Grieder, lead author of the study and staff scientist in the lab of Derek van der Kooy, a professor in U of T’s Donnelly Centre for Cellular and Biomolecular Research and the department of molecular genetics.

“If we can find a way to selectively activate CRF neurons when a person is in withdrawal, we can help ease their discomfort and help prevent them from relapsing,” she says.

The area of the brain where the scientists found CRF neurons – the ventral tegmental area (VTA) – had only been associated with feelings of pleasure and reward in drug addiction. Scientists knew that dopamine was critical to those feelings, but most did not suspect that stress neurons also played a role.

“These results shed light on why a smoker feels like they need a cigarette when they are stressed for any reason, and also why they have a hard time feeling any pleasure during drug withdrawal,” says Grieder.

The journal published the results.

Grieder and Olivier George, senior author on the study and an assistant professor at Scripps, knew they had discovered something special five years ago when they first saw the stress neurotransmitter in dopamine neurons of nicotine-dependent mice.

“No one believed us, and we hardly believed it ourselves. If you look in a textbook or at other studies, you won't see CRF neurons in the brain reward system,” Grieder says.

But no one had looked for the neurons in the brains of drug-dependent humans or rodents.

The researchers then examined the role of the neurons in nicotine addiction. They studied brain samples from rodents exposed to nicotine levels similar to a person who smokes two packs of cigarettes a day. They found the neurons were active during withdrawal, but when they inhibited CRF activity the animals did not feel the negative effects of withdrawal and did not take much nicotine. They also analyzed brain samples from nicotine-dependent people and found the neurons in the VTA.

The researchers believe the same neurons may be active in our brain’s response to other addictive drugs, such as heroin, cocaine and alcohol.

“Looking at these results, we are on the way to developing new treatments to help people addicted to nicotine and other drugs of abuse quit, and to prevent relapse during stressful situations,” says Grieder.

The study was funded by the Canadian Institutes of Health Research, U.S. National Institute on Drug Abuse, U.S. National Institute on Alcohol Abuse and Alcoholism, Tobacco-Related Disease Research Program, U.S. National Institute of Diabetes and Digestive and Kidney Diseases and the Clayton Medical Research Foundation.

Jim Oldfield is a writer with the Faculty of Medicine at the University of Toronto.