In Rats and Men, Nicotine Withdrawal Casts Similar Pall

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Efforts to quit smoking tend to end in failure. Almost half of smokers attempt to quit each year, but only 4 to 7 percent succeed on any given attempt without medicines or assistance, according to the American Cancer Society, and less than 25 percent of smokers who use medicines remain smoke-free for more than six months. Relapse is especially common within 48 hours of quitting when nicotine withdrawal symptoms are most acute.

In a set of novel experiments involving both humans and rats, researchers at the University of California, San Diego School of Medicine, Florida Atlantic University (FAU), University of Pittsburgh, Washington University and Harvard Medical School report that the brain’s response to reward – its ability to recognize and derive pleasure from natural stimuli such as food, money or sex – is measurably reduced after nicotine withdrawal.

The findings, published this week online in JAMA Psychiatry, suggest that nicotine withdrawal significantly impacts the ability to modulate behavioral choices based on the expectancy of reward. This deficit is seen often in people who suffer from depression.

“What we saw in both humans and rats was decreased responsiveness to reward,” said Athina Markou, PhD, professor and vice-chair of research in the Department of Psychiatry at UC San Diego. “During acute nicotine withdrawal, both people and animals attended less to positive rewards. That’s a hallmark of depression. And there is evidence that people who already express depressive symptoms and quit smoking are more likely to become clinically depressed and stay that way. These findings have an obvious bearing on how we approach cessation treatment.”

The study authors say the breadth of the findings involving similar results in two different species offer a strong translational framework for future studies that will allow development of clinical treatments focusing on reward responsiveness during early nicotine withdrawal.

“The fact that the effect was similar across species using this translational task not only provides us with a ready framework to proceed with additional research to better understand the mechanisms underlying withdrawal of nicotine, and potentially new treatment development, but it also makes us feel more confident that we are actually studying the same behavior in humans and rats as the studies move forward,” said Michele Pergadia, PhD, associate professor of clinical biomedical science in the Charles E. Schmidt College of Medicine at FAU.

The experiments reported in JAMA Psychiatry assessed reward responsiveness based upon the propensity to modulate behavior according to prior experience. In human testing, conducted at Washington University, participants were asked to repeat a computer task, with “correct” responses earning a modest financial reward. In testing at UC San Diego, rats were trained to press a lever upon hearing a specific tone to earn a food reward.

Results were similar. Human participants who were smokers but who had abstained from smoking for 24 hours prior to testing and rats chronically exposed to nicotine but deprived for 24 hours also prior to testing both performed less effectively than non-smokers and rats with no nicotine experience. That is, both humans and rats withdrawing from nicotine failed to display a bias toward maximizing their rewards.

Markou’s team, which included co-authors Andre Der-Avakian, PhD, and Manoranjan D’Souza, MD, PhD, subsequently re-exposed rats to nicotine and re-tested them. This time, the animals showed a heightened reward response, stronger than before.

“This finding indicates that after the initial withdrawal, if a relapse occurs, it will produce a more pleasurable effect. That’s why smokers who have a single cigarette after quitting often find it triggers a full relapse and they’re soon back to smoking as much as before.”

Markou and Pergadia say the findings open up two avenues of future research: Studying the neurobiology of the reward response phenomenon to pinpoint where in the brain it occurs and which circuits or neurons are involved; and assessing potential medications on rats during reward response testing. Promising drugs, if approved by the FDA for human administration, could then be tested on humans in similar experiments – an approach that could provide both new insights and speed the drug development process.

Co-authors include Pamela A.F. Madden and Andrew C. Heath, Washington University; Saul Shiffman, University of Pittsburgh; and Diego A. Pizzagalli, Harvard Medical School.

Funding support for this research came, in part, from the National Institutes of Health (grants DA019951, MH078979, DA011946, DA012854 and AA017688).