50 million Americans smoke cigarettes. Although smoking has decreased in recent years, 24% of Missourians still light up. I learned to smoke from a schoolyard friend, Anton Schuszler, who died 21 years ago of lung cancer. All through high school (running on the track team!), college, and graduate school I smoked, never able to kick the habit. Only in my 30s did I succeed, and to this day I am grateful. Why did it take me 17 years to quit? Why do millions of other smokers find it impossible to “kick the habit?” Most studies indicate a “quitting” success rate — at least two year’s abstinence — of only about 20 percent. These millions of smokers cannot quit because they have become addicted to a chemical in the cigarettes they smoke, nicotine.
This month researchers reported that some of us are far more likely than others to become addicted to smoking and to develop lung cancer as a consequence. Over the last two years, a new approach called “genome wide association studies” has allowed scientists to identify specific sites within the human genome associated with increased risk for “lifestyle” diseases such as diabetes, colon cancer, and heart disease — diseases associated with how you live your life. Studying lung cancer in this way, three different studies have identified a location on the long arm of chromosome 15 where genetic variation greatly increases or decreases the likelihood of smokers becoming addicted to nicotine and of developing lung cancer (the researchers disagree wether the two liklihoods are linked).
Said simply, a small cluster of genes on Chromosome 15 seem to be able to lessen our addiction to nicotine. People lucky enough to inherit certain versions of these genes can smoke up a cloud and never become addicted. Others receiving a less fortunate set of genetic variants from their parents become addicted to nicotine after smoking only a few packs of cigarettes. With a quarter of Missourians smoking, it is important to take a closer look at this genetic lottery. Is there really a way to beat the game? Could drugs mimic what genes do? To answer these questions, it is necessary to step back and take a closer look at how drug addiction works.
How Psychoactive Drugs Affect the Brain
To understand the nature of nicotine addiction, you must focus your attention on how nerves in the brain communicate with one another, because it is in altering this process that chemicals like nicotine have their effect. Unlike electrical wires in a house, the nerve cells in the brain are not physically connected to one another. They are separated from one another by tiny gaps. For a signal to pass from one nerve cell to another within the brain, it must cross the space that separates the two cells. How is this achieved? By shooting chemicals across the gap! Called neurotransmitters, these chemicals bind to specific receptor proteins embedded within the cell membrane on the far side of the gap. The binding of a neurotransmitter to a matching stimulatory receptor promotes the generation of a new signal in the receiving nerve cell, thus successfully transferring the signal across the gap.
Investigators studying mind-altering drugs soon learned that mood, pleasure, and other mental states are determined by particular groups of nerves in the brain that use special sets of neurotransmitters and receptors. Much of the early work was driven by attempts to understand and treat depression. Researchers found that the mood-elevating nerve pathways of depressed individuals appeared to have too little of the neurotransmitter seratonin to function effectively. With too little seratonin in the gaps between nerve cells, the target receptors on the receiving nerve cells don’t fire enough to keep the mood-elevating pathway active, and depression results. Attempts to treat depression by administering extra seratonin failed — there were too many side effects.
Success was finally achieved with drugs that magnify the effects of the seratonin molecules already present. After each seratonin molecule has had a chance to transmit the signal across the gap by hitting a target receptor, it is either destroyed or reabsorbed by the nerve cell that released it. Antidepressant drugs like Prozac (c) block the reabsorption of seratonin. If it is not removed from the gap, the seratonin neurotransmitter molecules just keep smashing into receptors on the far side, triggering them to fire the nerve cell receiving the signal again and again.
From this research into depression a general rule emerged: Mind-altering drugs often work by prolonging the time the neurotransmitter persists in the gaps between nerves. They increase the number of “hits” of target receptors by simply allowing the neurotransmitter molecules to keep on shooting. Just as in a basketball game, the score increases if the game goes into overtime.
Search for the Chemical Nature of Addiction
The deep lesson learned from the studies of depression is that it is possible to understand mind-altering events in the brain at a molecular level. Part of a wave of research into the chemistry of the brain in recent decades, it sparked new investigations into many problems, one of them the chemical nature of drug addiction.
An immediate focus of research was the highly addictive drug cocaine. Cocaine affects nerve cells of the brain’s pleasure pathways (the so-called limbic system). These cells transmit pleasure messages using the neurotransmitter dopamine. Each cell communicates with the next by releasing dopamine into the gap, like pellets from a shotgun blast; the cell receiving the signal possess targets (the receptor proteins) that the pellets hit. The more receptor targets present on the surface of the receiving cell, the more likely a hit will occur, passing the signal to the receiving cell.
Investigators soon learned how cocaine stimulates the pleasure pathways to increase their rate of firing. Using radioactively-labelled cocaine molecules, they found that cocaine binds tightly to recycling proteins in the gap between nerves that normally remove the neurotransmitter dopamine after it has acted. Like a game of musical chairs in which all the chairs become occupied, there are no unoccupied recycling proteins available to the dopamine molecules, so they stay in the gap, firing the receptors again and again. As new signals arrive, more and more dopamine is added, firing the pleasure pathway more and more often.
When the cells of your body are exposed to chemical signals for a prolonged period of time, they tend to loose their ability to respond to the stimulus with its original intensity. When you put on a wristwatch, how long are you aware you are wearing it? Nerve cells are particularly affected by this sort of loss of sensitivity. When receptor proteins on limbic system nerve cells are exposed to high levels of dopamine neurotransmitter molecules for prolonged periods of time, the nerve cells “turn down the volume” of the signal by lowering the number of receptor proteins on their surfaces. They respond to the greater number of neurotransmitter molecules by simply reducing the number of targets available for these molecules to hit, a feedback process that is a normal part of the functioning of all nerve cells. The cocaine user is now addicted. With so few receptors, the user needs the drug to maintain even normal levels of limbic activity.
Is Nicotine an Addictive Drug?
Investigators attempting to explore the habit-forming nature of nicotine used what had been learned about cocaine to carry out what seems a reasonable experiment — they introduced radioactively-labelled nicotine into the brain and looked to see what sort of recycling protein it attached itself to. To their great surprise, the nicotine ignored proteins in the between-cell gaps and instead bound directly to a specific receptor on the receiving nerve cell surface! This was totally unexpected, as nicotine does not normally occur in the brain — why should it have a receptor there?
Intensive research followed, and researchers soon learned that the “nicotine receptors” were in fact designed to bind the neurotransmitter acetylcholine, and it was just an accident of nature that nicotine, an obscure chemical from a tobacco plant, was also able to bind to them.
It will come as no suprise to you that the small cluster of genes on the long arm of chromosome 15 that researchers have recently shown to be associated with nicotine addiction and lung cancer are in fact genes encoding the three subunits (component parts) of this same nicotinic acetylcholine receptor.
What then is the normal function of these receptors? The target of considerable research, these receptors turn out to be one of the brain’s most important tools. The brain uses them to coordinate the activities of many other kinds of receptors, acting to “fine tune” the sensitivity of a wide variety of behaviors.
When neurobiologists compare the limbic system nerve cells of smokers to those of nonsmokers, they find changes in both the number of nicotine receptors and in the levels of RNA used to make the receptors. They have found that the brain adjusts to prolonged exposure to nicotine by “turning down the volume” in two ways: 1. by making fewer receptor proteins to which nicotine can bind; 2. by altering the pattern of activation of the nicotine receptors (that is, their sensitivity to neurotransmitter).
It is this second adjustment that is responsible for the profound effect smoking has on the brain’s activities. By overriding the normal system used by the brain to coordinate its many activities, nicotine alters the pattern of release into gaps between nerve cells of many neurotransmitters, including acetylcholine, dopamine, serotonin, and many others. As a result, changes in level of activity occur in a wide variety of nerve pathways within the brain.
Addiction occurs when chronic exposure to nicotine induces the nervous system to adapt physiologically. The brain compensates for the many changes induced by nicotine by making other changes. Adjustments are made to the numbers and sensitivities of many kinds of receptors within the brain, restoring an appropriate balance of activity.
Now what happens if you stop smoking? Everything is out of whack! The newly coordinated system requires nicotine to achieve an appropriate balance of nerve pathway activities. This is addiction in any sensible use of the term. The body’s physiological response is profound and unavoidable. There is no way to prevent addiction to nicotine with willpower, any more than willpower can stop a bullet when playing Russian roulette with a loaded gun. If you smoke cigarettes for a prolonged period, you will become addicted.
So what do you do, if you are addicted to smoking cigarettes and you want to stop? When use of an addictive drug like nicotine is stopped, the level of signaling along the many affected pathways will change to levels far from normal. If the drug is not reintroduced, the altered level of signalling will eventually induce the nerve cells to once again make compensatory changes that restore an appropriate balance of activities within the brain. Over time, receptor numbers, their sensitivity, and patterns of release of neurotransmitters all revert to normal, once again producing normal levels of signalling along the pathways. There is no way to avoid the down side. The pleasure pathways will not function at normal levels until the number of receptors on the affected nerve cells have time to readjust.
Many people attempting to quit smoking use patches containing nicotine to help them, the idea being that providing nicotine removes the craving for cigarettes. This is true, it does — so long as you keep using the patch. Actually, using such patches simply substitutes one (admittedly less dangerous) nicotine source for another.
Might study of the variant forms of the nicotine receptor that bind nicotine more poorly and so reduce the risk of addiction lead to treatments that lessen the risk of nicotine addiction? It is difficult to say, but for those already addicted it seems most likely that reducing the effectiveness of nicotine delivery in this way would simply lead to smoking more cigarettes, just as lowering the nicotine content of cigatette tobacco does.
If you are going to quit smoking, there is no way I know of to avoid the necessity of eliminating the drug to which you are addicted, nicotine. Hard as it is to hear the bad news, there is no easy way out. The only way to quit is to quit.
This column is an update of “Is smoking cigarettes addictive?” a past ON SCIENCE column which ran in June, 1998 in the Saint Louis Post Dispatch.