Study Reveals Mechanism Behind Nicotine Dependency

By Gary Kuhlman and Mika Ono

Many more people try to quit smoking than succeed in giving up this nicotine-delivering habit. Now, a group of scientists at The Scripps Research Institute has identified one neurobiological mechanism that contributes to nicotine dependence, and to the anxiety and craving experienced upon withdrawal. The findings also suggest a new approach to developing drugs that could help smokers quit.

The research was published the week of October 1, 2007, in an advance, online issue of the journal Proceedings of the National Academy of Sciences(PNAS).

The new study reveals that, in rats, chronic nicotine use recruits a major brain stress system, the extrahypothalamic corticotropin releasing factor (CRF) system, which contributes to continued tobacco use by exacerbating anxiety and craving upon withdrawal. The researchers found that administering a compound that blocked the receptors involved in this stress system alleviated withdrawal symptoms.

"We reduced the need to take nicotine by blocking CRF-1 receptors in the brain," says Olivier George, a research associate in the Scripps Research Koob lab who conducted the study with Sandy Ghozland and other colleagues. "We were surprised by the compound's dramatic effectiveness. We don't know yet if the same mechanism is involved in humans with tobacco dependence, but it is very promising."

Tobacco addiction is the leading avoidable cause of disease and premature death in the United States, responsible for more than 438,000 deaths annually, according to the Centers for Disease Control and Prevention. Nicotine, the main psychoactive ingredient in tobacco, is a tough drug, with smokers continuing to crave it long after they've started withdrawal. Most smoking-cessation medication is based on nicotine replacement therapy, using nicotine gum or patches, that substitutes one source of nicotine for another. Roughly 80 percent of smokers who try to quit relapse within a year.

While nicotine can produce mildly pleasurable effects, the Scripps Research scientists believe a more important factor in the difficulty in quitting is the brain's adaptation to that reward, which produces an intense discomfort upon withdrawal.

"The key in nicotine addiction is that the positive pleasurable effects of nicotine are instantaneous and short lasting, while the negative effects are delayed and long lasting," George says. "Even if nicotine may transiently induce a relief from a negative emotional state, its long-term consequences are disastrous."

For years, scientists have wanted to know what changes in the brain occur in the transition from nicotine use to nicotine dependence. In the current study, the researchers set out to see if nicotine dependence is linked to changes in the CRF system in the amygdala, an area of the brain that plays a primary role in the processing and memory of emotional reactions. The CRF system is activated by CRF-1, an essential protein for coping with stressful events.

When the researchers induced nicotine withdrawal in rats, the nicotine-deprived group exhibited severe anxiety-like behavioral symptoms of withdrawal—such as burying and "freezing" (becoming motionless)—compared with controls. In addition, withdrawal whetted the rats' appetite for even greater quantities of the drug, a result the researchers call the "nicotine deprivation effect."

"Rats exhibited drug-loading behavior following a cycle of abstinence, attaining an amount of nicotine in roughly six hours that previously took 12 hours," George says. "This is like the light smoker becoming a chain smoker after trying to quit."

Measurements showed this behavior was indeed matched by hyperactivity in the CRF system, and that these withdrawal effects lasted a surprisingly long time. In addicted rats, these effects developed in under a week and maintained a hold for at least two months.

"That's a long time for a rat, considering its life expectancy is two years," says George. "These results suggest long-lasting neuroadaptations of the CRF system, possibly through gene regulation, that may help explain why many cigarette smokers relapse even after a long abstinence from smoking."

Importantly, the researchers were able to moderate the effects of nicotine deprivation. When addicted rats were injected with a CRF receptor antagonist, the injected rats showed less anxiety-like behavior during withdrawal and self-administered less nicotine compared with an addicted controls.

The Scripps Research scientists hope their work will lead to new nicotine-free pharmacological treatments, as well as shedding light on questions such as what makes some people more likely than others to become addicted in the first place.

In addition to George and Ghozland, authors of the paper, titled "CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine dependent rats," are Marc R. Azar, Pietro Cottone, Eric P. Zorrilla, Loren H. Parsons, Heather N. Richardson, and George F. Koob of The Scripps Research Institute; and Laura E. O'Dell of the University of Texas, El Paso.

The research was supported by the Tobacco Related Disease Research Program of the State of California, the National Institutes of Health, the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute, and the Tobacco Etiology Research Network of the Robert Wood Johnson Foundation.

Send comments to: mikaono[at]scripps.edu

"The key in nicotine addiction is that the positive pleasurable effects of nicotine are instantaneous and short lasting, while the negative effects are delayed and long lasting."

—Olivier George