WASHINGTON: A new study has uncovered the mechanism behind smokers' persistent dependency on nicotine.

Researchers at the Scripps Research Koob lab found that, in rats, chronic nicotine use recruits the extrahypothalamic corticotropin releasing factor (CRF) system, a major brain stress system, which contributes to continued tobacco use by intensifying anxiety and craving upon withdrawal.

The researchers pointed out that their findings might help explain why many cigarette smokers relapse even after a long abstinence from smoking.

They also suggested that administering a compound that blocked the receptors involved in this stress system could alleviate withdrawal symptoms.

"We reduced the need to take nicotine by blocking CRF-1 receptors in the brain. 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," said Olivier George, a research associate in the Scripps Research Koob lab who conducted the study with Sandy Ghozland and other colleagues.

"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. Even if nicotine may transiently induce a relief from a negative emotional state, its long-term consequences are disastrous," he added.

In the current study, the researchers set out to perceive 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. This is like the light smoker becoming a chain smoker after trying to quit," George said.

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. 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," he said.

Significantly, 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 that 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.