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Looking into the smoker's brain
Researchers gleaning genetic, chemical clues about nicotine's powerful grip on its users
By Karin Jegalian
Jul 21, 1998
The Dallas Morning News
For one small molecule, people routinely risk death.

That molecule is nicotine. It beguiles people into irrational devotion by tweaking their nerves and changing their brains.

In recent months, several new studies have helped explain how nicotine secures such power. Scientists have found genetic differences that can make nicotine harder to resist for some people, and have learned more about how nicotine baits the emotional centers of the brain.

"The era of learning about nicotine is upon us," said Kenneth Kellar, a neuropharmacologist at Georgetown University in Washington, D.C.

Geneticists have recently related people's risks for becoming smokers to variations in a liver gene that digests nicotine, as well as to various forms of a gene that works in the brain. Scientists have also described racial differences in how nicotine is metabolized. And new reports have found evidence linking nicotine use with depression and other psychological problems.

Nicotine's influence on the emotional brain appears to be the key to its addictive power. Among other places, nicotine nestles against nerve cells in a minute region "maybe the size of the end of your pinkie" near where the spinal cord joins the brain, says Paul Sanberg, a neuroscientist at the University of South Florida in Tampa. Nerve cells from that area lead into another similarly small region in the bottom of the forebrain, behind the eyes. Nicotine provokes the release of the "feel-good" chemical dopamine in the forebrain.

"It seems that any drug that is addictive can release dopamine in that same area," Kellar noted.

In regular smokers, the parts of the nerves that recognize nicotine are overstimulated and become numb. Yet the same agents that recognize nicotine have another, more basic job -- responding to a key signaling molecule known as acetylcholine, which occurs naturally in the body. To compensate for the benumbed state of the nerve endings, the body needs to make more of the agents that recognize both nicotine and acetylcholine.

As the body adjusts for the presence of nicotine, smokers begin to need nicotine just to feel normal.

Nicotine's power over someone depends partly on genetics. Studies of twins long ago convinced scientists that heredity influences who smokes and who can easily quit. Now, researchers have found specific genes that affect smoking behavior. Last month in the British journal Nature, Canadian scientists described variations in a gene coding for a liver enzyme that chews up nicotine. What forms of the gene people have can sway whether and how much they smoke, reported Rachel Tyndale, a pharmacologist at the University of Toronto, and her colleagues.

People who break down nicotine more slowly are less likely to smoke regularly, and if they do, they tend to smoke fewer cigarettes, the Canadian researchers found.

Another gene linked to smoking codes for a protein in the brain that recognizes dopamine. People with particular forms of that gene, whose brains don't recognize dopamine as efficiently, are more likely to smoke; they're also more likely to be alcoholics, Margaret Spitz of the University of Texas M.D. Anderson Cancer Center and her colleagues reported in March in the Journal of the National Cancer Institute.

The liver enzyme Tyndale's group studied digests about 70 percent of the nicotine a smoker ingests. Other enzymes can also attack nicotine but far less efficiently, and the body excretes some without changing it at all.

Besides converting nicotine into a much less potent chemical called cotinine, the liver enzyme also converts chemicals in cigarettes known as nitrosamines into carcinogens.

"There isn't anything beneficial known that this gene (that codes for the liver enzyme) does," Tyndale said. She suggests that weakening the enzyme with drugs could be a way to curb people's appetite for nicotine.

Scientists often measure levels of cotinine in people to see how they assimilate nicotine. In a study published last week, government scientists reported that African-Americans who smoke the same amount as whites or Mexican-Americans have higher levels of cotinine in their blood. That finding suggests that African-Americans are more likely to become addicted to nicotine, Ralph Caraballo of the U.S. Centers for Disease Control and Prevention and his colleagues reported in the "Journal of the American Medical Association."

Earlier work had shown that African-Americans have more trouble quitting smoking and are more at risk of developing lung cancer; the new research suggests genetics may be at least partly to blame.

Unsurprisingly, given all the known health consequences of smoking, 80 percent of smokers say they want to quit.

"People who could quit have already succeeded," suggested Athina Markou, a neuropharmacologist at the Scripps Research Institute in La Jolla, Calif. "For those who haven't quit, the speculation is that a subpopulation of smokers are self-medicating pre-existing psychiatric disorders."

She and her colleagues wrote in Nature in May that rats undergoing nicotine withdrawal display symptoms of depression. They need far more brain stimulation to reach the same levels of pleasure that normal rats can achieve.

Many scientists suggest that smoking may ameliorate some of the effects of psychological problems. Slightly more than a quarter of the general population smokes in the United States, but half of depressed people smoke, and 90 percent of schizophrenics smoke. People with bipolar disorder, or manic-depressive illness, are also more likely to smoke, according to a report in the May issue of the Journal of Clinical Psychology. And so are people with attention deficit disorder.

Those prone to depression are more likely to continue smoking once they start, but as Markou said, "it is also possible that once you smoke, you tend to become depressive unless you smoke. This is particularly true for women, who have higher rates of depression."

One of the most effective aids for quitting smoking is Zyban, a drug that was initially used as an anti-depressant. Unlike most other anti-depressants, which target other chemicals, Zyban elevates dopamine levels between cells in the brain.

The regions in the brain where smoking exerts its effects are also related to diseases like Parkinson's, Alzheimer's, and Tourette's syndrome, which causes tics, particularly in children. Nicotine patches are being used to treat some people with these ailments.

So while scientists agree that smoking kills, and nicotine is a co-conspirator, the substance by itself may have some uses.

"The public has to appreciate the differences between the harmful effects of smoking and the harmful and beneficial effects of nicotine," Markou said.