Drugs of choice: Science tackles smoking addiction

Faster than an injection, more reinforcing than crack cocaine: Smoking a cigarette speeds nicotine to the brain faster than any other delivery method, giving smokers precise control over their exact nicotine dose with each puff they take. It turns out that those two attributes– speed and control– greatly enhance nicotine's addictive effect on the brain.

"It's not just the drug, but how you take it," says Timothy Baker, associate director of the University of Wisconsin's Center for Tobacco Research and Intervention.

"Cigarette smoking introduces nicotine to the pulmonary beds of the lungs," he continues, "which means it gets to the brain in seconds, without achieving general venous circulation."

Nicotine mimics the neurotransmitter acetylcholine, binding to and activating a subset of receptors. Nicotine affects the brain in much the same way as cocaine, opiates, and amphetamines do; it's hard to say which drugs are more addictive.

Animals can be trained to self-administer nicotine, just as they do other drugs; and even though nicotine can be fatal, animals will not dose themselves to death, as they will with cocaine. But once hooked, people cling to their cigarettes: Researchers have asked people with multiple addictions which drug is hardest to give up; nicotine is often the answer. "They all activate key brain regions that seem to be involved in addiction," says Baker.



Once it reaches the brain, nicotine quickly spreads the love– the activated brain regions are part of a reward, memory, and learning center. Nicotine stimulates nicotinic acetylcholine receptors in the brain where the firing receptors cause the release of dopamine, a neurotransmitter associated with pleasure and addiction.

Smoking may also keep brain dopamine levels high by reducing enzymes that break it down. Nicotine also influences a host of other brain molecules that control mood, energy level, and memory, just to name a few. Furthermore, nicotine increases the number of its own receptors.

"The brain becomes used to having nicotine on board, which is why when people quit smoking they experience withdrawal symptoms," says Caryn Lerman, Department of Psychiatry, University of Pennsylvania.

Withdrawal symptoms are not the only thing that makes a substance addictive: Long-lasting neurological changes also play a role. An effect called reinstatement increases an ex-addict's desire for drugs after re-exposure to just a small amount. Researchers say that it's usually the relentless long-term cravings– rather than the relatively short-term withdrawal symptoms– that catch up with addicts and lure them back.

In other words, smoking is a remarkably difficult habit to kick. Researchers are using knowledge about the biology of addiction to study specific genes that might predispose or protect people from getting hooked, with the hope of keeping future generations from inhaling.



"Many studies suggest that as much as 50 percent of the variability in smoking initiation, and 70 percent of the variation in nicotine dependence, may be attributable to genetic factors," says Lerman. "There may be genes ... that may increase risk for drug dependence ... [there may be] other genes that play a role in the metabolism of specific drugs or brain receptors for the drugs," she adds.

For example, genes in the dopamine pathway could predispose to addiction in general, whereas variants in enzymes that metabolize nicotine could predispose specifically to nicotine addiction.



Besides nicotine replacement therapy, the only FDA-approved drug for treating nicotine dependence is the antidepressant bupropion (Zyban). But Zyban's effectiveness doesn't come from simply curing depression–Zyban clinical trials were conducted on nondepressed people.

Furthermore, Zyban seems to help schizophrenics, among whom nicotine addiction rates are very high, quit smoking. "You don't see a lot of smoking-naïve schizophrenics," says Gregory Dalack, a Michigan associate professor of psychiatry. The relationship is complex, but people with schizophrenia seem to respond differently to nicotine. Unlike others, they do not puff less when supplemented with nicotine patches, and one (unconfirmed) study showed that their brains have fewer nicotinic acetylcholine receptors.

Although its mechanism of action is largely unknown, researchers think Zyban could help treat a broad array of addictions. "We're testing Zyban in cocaine addiction, and it is also in Phase I [trials] ... for methamphetamine dependence," says Vocci. "There's a lot of speculation about what it's doing. It may directly involve some nicotine receptor effects, and there may be other effects too."

At a descriptive level, Zyban may dull the negative emotions associated with quitting. In addition to depression, these can include anxiety, sadness, anger, and irritability.

"The worse the mood, the more likely the person is to go back to using tobacco," says Baker. People with a history of depression (but who are not so when they try to quit) tend to experience more severe emotional symptoms, making it harder to avoid cigarettes.

"Smoking may have a certain ability to mask or ameliorate negative moods," says Baker.

Despite the relational complexity between smoking and depression, a link exists. Smokers with a history of depression are about half as likely to quit as others; smokers are more apt to be depressed than nonsmokers; and depressed teens are more susceptible to cigarette ads than their counterparts. For example, one recent study showed that depressed teens are more likely to have a favorite cigarette ad or own clothing with cigarette logos.



Two companies, Xenova Group and Nabi Biopharmaceuticals, are taking a vaccine approach to block nicotine's action on the brain. "Using a vaccine as a treatment rather than a preventive is a slightly different way of thinking about vaccines," says Doreen Wood, product manager at Xenova.

Rather than generating an immune response that clears away nicotine, both companies' vaccines create antibodies that bind nicotine in the blood and prevent it from crossing the blood-brain barrier. The result: Nicotine can't stimulate the brain's reward centers– no buzz. Thus, there is little, if any, reason to smoke.

In preclinical studies, vaccinated animals were interested less in self-administering intravenous nicotine. However, it's unclear if the vaccines will work against the faster and stronger effect of nicotine delivered by smoking. So far, human trials have measured only safety, yet both companies are hopeful.

"We think this will be very helpful to somebody who ... needs protection from falling off the wagon," says Naso.

Xenova is developing a similar vaccine against cocaine addiction, although Vocci is concerned that a vaccine might not sweep up the large amounts of cocaine that users get into their system. "Average [blood] nicotine levels are 1/10th to 1/100th the concentration of cocaine levels," he says.

Whether used against cocaine or nicotine, the vaccines could be especially helpful in blocking reinstatement. With a vaccine, even if an ex-smoker stumbles a bit, if that nicotine doesn't reach the brain, then the reinstatement molecules that normally would ratchet up cravings may not be activated. They may have smoked lettuce for all the reward they'll get.

As long as nearly 33 million smokers in the United States alone want to quit, interest in nicotine addiction therapies is likely to remain high.

Both Dalack and Lerman think future studies– such as comparing schizophrenic patients who smoke with those who do not, or stratifying smokers according to their biological response to nicotine on brain scans or blood tests– will provide finer resolution of the smoking phenotype.



This is an abbreviated version of an article originally published in The Scientist, March 24, 2003 .