The Down Side of Nicotine and Environmental Stimuli

By Jason Socrates Bardi

In the classic 1980 movie "Airplane," actor and comedian Lloyd Bridges plays a harried air traffic controller who is faced with having to talk an airlines passenger through an emergency jumbo jet landing. At some point during the chaos he quips, "Looks like I picked the wrong week to quit smoking." 

In an article appearing in a recent issue of The Journal Neuroscience, Associate Professor Athina Markou and Research Associate Paul Kenny in the Department of Neuropharmacology at The Scripps Research Institute are reporting data that adds another twist to Lloyd Bridges' line. The study suggests that otherwise neutral stimuli in an environment the person associates with smoking can induce a withdrawal-like state, even long after that smoker has quit and the withdrawal signs have dissipated.

These feelings of withdrawal are significant because ex-smokers may then relapse into smoking or may suffer the negative effects of acute nicotine withdrawal, one of which is believed to be depression. In the case of Lloyd Bridges' character, the pressure of pushing tin as an air traffic controller—in the tower where he was used to smoking—was enough to cause him to smoke again.

These findings may have significant implications for people who are trying to quit smoking because the data that Markou and Kenny collected also suggests that quitting itself can be a conditioning stimulus. The behaviors and cues a person associates with the very act of quitting, they say, can amplify withdrawal.

"When smokers go into an environment where they have undergone withdrawal before, they can immediately experience this feeling of withdrawal," says Kenny.

A Major Health Problem

Though the plight of smoking relapse as portrayed by the fictional Lloyd Bridges character is humorous, the reality is much less funny.

Nicotine is one of thousands of chemical components of cigarette smoke, and it is the main ingredient in tobacco that leads to addiction. This nicotine addiction fuels cigarette smoking, which is a major health problem in the United States. The latest report of the U.S. Surgeon General on the health effects of smoking calls smoking the leading preventable cause of death in American Society. And, according to the U.S. Centers for Disease Control and Prevention (CDC), one in five deaths in the United States is related to smoking, and more than 400,000 Americans die each year from it—through cancers, cardiovascular diseases, and respiratory diseases.

In the last few years, Markou and her colleagues at Scripps Research and at Novartis Pharma AG have been funded by a multi-year, $3.45 million grant from the National Institute of Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA) to design new ways to treat depression and nicotine addiction. One of the goals of this grant is to look at the connection between cigarette smoking and depression, which could shed light on what makes nicotine so addictive, and how the same sorts of compounds used to treat depression could be used to treat nicotine addiction.

The pairing of depression and nicotine addiction in the grant is not arbitrary. Markou has been working for several years in the area of drug dependence and withdrawal and has found evidence of depression-like states in withdrawal from amphetamines and from nicotine. When people stop smoking, a large number exhibit depressive symptoms—sometimes severe—and tobacco use may be higher among people suffering from depression because they are using it to self-medicate depressive symptoms.

"Fifty percent of depressed people smoke, versus 30 percent in the U.S. general population and 14 percent in California," says Markou.

This observation is bolstered by clinical evidence that treating people for depression during smoking cessation can help them quit smoking. In fact, one type of antidepressant, bupropion, is approved by the U.S. Food and Drug Administration (FDA) for use in smoking cessation—this is the only non-nicotine based therapy for smoking cessation approved by the FDA.

Push and Pull

The new findings of Markou, Kenny, and their colleagues may lead to new smoking cessation strategies. Using a rodent model, the scientists paired nicotine withdrawal (simulated through the administration of a nicotine receptor antagonist) with neutral stimuli that had no effects in control rodents—in this case, flashing lights and a sound.

After a few sessions pairing nicotine withdrawal with the stimuli, the stimuli were used alone. "[The data showed that the stimuli] induced a withdrawal-like state without the subjects actually being in withdrawal," says Markou.

These findings have interesting implications for people who are trying to give up smoking, suggesting that long after a person quits, exposure to familiar cues may induce a withdrawal-like state. In other words, says Markou, nicotine addiction is a bit of push and pull. The pull comes from the drug itself, and the push comes from the negative affective state that is induced when a person stops smoking. The environment in which he/she previously smoked can cause him/her to start smoking again.

This suggests that efforts to stop smoking may benefit by explicitly addressing not only the positively rewarding aspects of nicotine, which is generally done through nicotine replacement therapy, but by also addressing these negatively reinforcing states induced by the person's habitual environment—although exactly how this can best be done is yet to be determined.

Significantly, Markou and Kenny also found that pairing acute withdrawal from nicotine with the neutral stimuli like the flashing lights makes the immediate acute stage of withdrawal much worse. This suggests that, ironically, the more times people try to quit smoking, the harder it may be.

The article, "Conditioned Nicotine Withdrawal Profoundly Decreases the Activity of Brain Reward Systems" by Paul J. Kenny and Athina Markou is printed in the June 29, 2005, (6208-6212) issue of The Journal of Neuroscience. See: http://dx.doi.org/10.1523/JNEUROSCI.4785-04.2005

More information:

1) The Health Consequences of Smoking, a report of the U.S. Surgeon General: http://www.cdc.gov/tobacco/sgr/sgr_2004/index.htm

2) Cigarette Smoking-Related Mortality, statistics compiled by the CDC: http://www.cdc.gov/tobacco/research_data/health_consequences/mortali.htm

3) Related Story, "NIH Funds Scripps Research-Novartis Collaboration To Target New Treatments for Depression and Nicotine Addiction." See: http://www.scripps.edu/newsandviews/i_20031208/markou.html

Send comments to: jasonb@scripps.edu