This is your brain on cigarettes

>> A McGill pharmacologist tries to take the pleasure out of smoking

by PHILIP PREVILLE

If you smoke a pack of cigarettes a day, you will take an average of 100,000 puffs per year.

For tobacco industry executives, that statistic surely makes 100,000 dollar-signs dance in their heads. For those in the anti-smoking movement, it probably symbolizes 100,000 small steps closer to death's door. For physiotherapists, it probably represents a strong likelihood of a repetitive-stress injury.

But for Paul Clarke, a professor of pharmacology at McGill University, it means something entirely different. For the past 18 years, Clarke has been studying the physiological effects of nicotine addiction, how each one of those 100,000 drags gives smokers a tiny high. And Clarke thinks it's the sheer magnitude of hauls that makes quitting so difficult.

In a sense, he likens smokers to Pavlov's dogs. "Over 100,000 puffs, a smoker's body learns that one puff equals a small nicotine high. Even if they use nicotine gum or the patch, even if they manage to quit, they've learned over the years that puff equals pleasure. That's hard to shake." Which explains why, even after a smoker has quit, a lit cigarette leaning on the edge of an ashtray looks so very tempting.

Clarke's answer to the problem: smokers need to un-learn the association between puff and pleasure. He and his research team claim they may have figured it out. At the very least, they seem to have figured out a large part of it.

Clarke has discovered that chlorisondamine, a drug first developed in the 1950s to control high blood pressure, actually blocks the nicotine receptors in the brain--effectively taking all the fun out of the habitual haul. They've published articles in a number of academic journals, including Lancet, detailing the results of their experiments.

Clarke is the first to admit that chlorisondamine is not yet ready for human consumption as an aid for people who want to quit smoking. But he notes that a similar drug has undergone a first round of clinical testing in the United States, and believes his drug is even closer to the cutting edge. Says Clarke: "This may well be the way of the future for people who want to quit smoking."

Happy neurotransmitters

Nicotine has two main physiological effects on the body. First, it increases the flow of adrenaline in the muscles. Second--and more importantly, in so far as Clarke is concerned--it stimulates the production of dopamine in one of the pleasure centres of the brain. "I would never use the term 'pleasure centre' in an academic journal," says Clarke, "but that's basically what it amounts to." Dopamine is a neurotransmitter, which means it helps send signals between nerve cells. For all intents and purposes, it could be called the "happy neurotransmitter."

The body actually has two separate dopamine pathways. One leads from the brain to the rest of the body and helps with basic muscle movement; people with Parkinson's Disease suffer from a deterioration of this pathway. The second pathway--the "pleasure centre"--runs between two parts of the brain. (For those who want to consult Gray's Anatomy, it's the path that runs from the ventral tegmental area to the nucleus accumbens.)

Pick a pleasure, any pleasure: at the moment when you feel it most, chances are your brain's dopamine levels are rising. Dopamine levels rise when people eat a good meal or when they have sex. Or when they take cocaine, or amphetamines, or nicotine. The addictiveness of any drug depends on how much dopamine it produces, and how quickly. All forms of cocaine stimulate dopamine production, but smoking crack delivers the hit faster than injecting it. (Cocaine also blocks the pathways that pull dopamine back out of the pleasure centre, effectively flooding it.) Nicotine, by contrast, stimulates considerably less dopamine--but it delivers the hit within 15 seconds.

Pharmacologists have known about dopamine since the 1950s. But it is the 43-year-old Clarke, during a stint at the National Institute of Mental Health (NIMH), who is credited with discovering the existence of nicotine receptors in the brain: the sockets where nicotine attaches itself to the brain's dopamine-producing cells. That particular discovery was made in 1985. Since 1987, Clarke has been working at McGill, trying, among other things, to turn those receptors off.

He's not the only one to attempt such a thing: Jed Rose, a pharmacologist at Duke University in North Carolina, also discovered a way to block the brain's receptors using mecamylamine (also a 1950s blood pressure drug), and has conducted preliminary clinical tests on humans. The problem with Rose's drug is that it also blocks the nicotine receptors outside of the brain, and when those receptors are blocked, the body experiences all kinds of side effects: dry mouth, constipation, difficulty urinating. (For these reasons, both mecamylamine and chlorisondamine were eventually abandoned as blood-pressure drugs.) Rose's clinical trials actually included both his drug and a nicotine patch, in an effort to mitigate the negative effects in the body.

Cigarette sterilization

For Clarke, the challenge has been to shut down the brain's nicotine receptors without shutting down those in the rest of the body. Earlier this year--somewhat by chance, he admits--he succeeded. He fed chlorisondamine to laboratory rats, then injected them with nicotine (he never forced the rats to actually smoke, which would be impossible anyway) and monitored their dopamine levels. To his pleasant surprise, the rats' dopamine levels stopped rising when injected with nicotine. And his research appears to have a step up on Rose's: Clarke's rats experience only three days' worth of side effects. After that, the bodily discomforts disappear, but the brain-blockers keep working.

In many ways, his success has left him with more questions than answers. For one thing, chlorisondamine's effect appears to be permanent--a form of nicotine sterilization. "The drug sticks in the nicotine receptor like gum in a lock. It doesn't come out." Clarke is still trying to figure out what side effects, if any, might be caused by chlorisondamine's non-stop nicotine goaltending. His rats still produce high levels of dopamine when they eat. But, as he says: "I haven't let them screw yet to see if sex still produces higher dopamine levels.

"Nor have I asked them to drive a car or operate heavy machinery." There are some questions that the rats simply can't answer.

Nevertheless, both Clarke's and Rose's research is ground-breaking, because it represents a totally different philosophy for helping smokers quit. The idea behind both the patch and Nicorettes is to keep delivering the hit without using a cigarette, and then to gradually reduce the nicotine dosage. In other words, first you wean smokers off the cigarette, then you wean them off the nicotine. The problem with this approach, as Clarke sees it, is that both smoking and nicotine remain fun. The trick, as he sees it, is to take the pleasure out of the habit. "I don't want to push my research as a cure for smoking," he says, "but I do with to push it as an alternative. I think it's better than indulging people with other forms of nicotine."