By Matt Windsor

If you want to get inside a smoker’s head, try this experiment: Crack open an egg, toss it into a frying pan, and stir. That’s how UAB neuroscientist Robin Lester, Ph.D., explains the transformative power of nicotine.

“When I give a talk, I remind people of that old ‘This is your brain/this is your brain on drugs’ commercial,” Lester says. “It is a good example of the problem that we’re working on in nicotine research: Once you’ve smoked, can you get your brain back to its normal state? Can the egg, once it’s fried, get back in the shell? Does it stay a fried egg? Or does it change into something else, like a soufflé?”

Lester specializes in the neurobiology of nicotine—how the drug alters the intricate layers of neural machinery to reshape our minds. The current money, he says, is on the soufflé. “Many people in the field argue that once you’ve smoked, basically you’re a smoker or an ex-smoker for life,” Lester says. “You’ve changed your brain.”

Never Let You Go

More than a billion people worldwide are affected by nicotine—including Lester himself, who has tried several times to break the habit. Smokers, especially in the developed world, have plenty of rational reasons to quit. Yet even though statistics indicate that more than two thirds of smokers want to give up cigarettes, 80 percent of those who try can’t manage it for a year or more.

One roadblock is withdrawal, the often agonizing period when the body reacts to the loss of nicotine in the system. But research by Lester and other scientists indicates that the initial discomfort may not be the biggest hurdle. Instead, it’s the deep-seated craving for nicotine that recedes over time but never seems to go away completely.

“I know people who have quit smoking for 20 years and say ‘sometimes I just really want a cigarette,’” Lester says. His current theory is that withdrawal is a two-phase process—a short-term neurochemical battle that resolves into a long-term problem. But he sees cause for hope: Understanding the neurobiology of withdrawal could lead to new ways to break nicotine’s grip.

Strange Addiction

Nicotine, says Lester, is just plain weird. It “doesn’t produce euphoria, like heroin or cocaine,” he observes. “In fact, when they first try it, it makes many people sick. But it’s one of the hardest drugs to quit.”

One reason is that nicotine is remarkably adaptable. “If you’re feeling down, it can raise your mood, and if you’re feeling too hyper, it can calm you,” Lester says. This is a peculiar property of nicotine, he notes, and may be why “many major mental illnesses are associated with an increased rate of smoking—especially schizophrenia, where 80 percent of patients smoke.”

Chemically, nicotine resembles the neurotransmitter acetylcholine. Like its more well-known cousins dopamine and serotonin, acetylcholine stimulates brain cells. So does nicotine, which can latch onto many of the cell receptors designed to process acetylcholine. But while acetylcholine is quickly cleared away from its receptors, nicotine can linger for up to two hours, giving it far more stimulating power.

Nicotine generates a frenzy of activity in the body’s reward systems; at the same time, it is setting off warning bells elsewhere. The brain is constantly monitoring body temperature, acid levels, blood sugar, and hundreds of other factors to keep itself in balance—a concept known as homeostasis. “Your reward level is part of that as well,” Lester says—and each surge of nicotine threatens to upset this delicate equilibrium.

Some scientists, Lester notes, theorize that constantly activating the reward system causes the body to strengthen its natural “anti-reward” system, which inhibits the same cells that the reward system energizes. (This system’s job would be to shut down appetitive behavior—such as eating, or in this case smoking—before it goes too far.) Eventually, the theory goes, the nicotine wears off, but the anti-reward system is still active. That drives the user to crave a new wave of reward—a craving that can only be satisfied by lighting another cigarette.

Smoke Gets in Your Nerves

Lester’s research indicates that regular use of nicotine brings significant, rapid changes as the brain battles to return to its original homeostatic range. In a 2011 paper, Lester and graduate student Rachel Penton reported evidence of long-term changes caused by only a few days of exposure to the drug. In less than 48 hours, for example, there is an increase in nicotinic receptors, particularly in the dentate gyrus of the hippocampus. (The hippocampus is a seahorse-shaped structure, lodged deep in the midbrain, which plays a prominent role in learning and memory.) “We speculate that there are also changes in neurons in this region that lead to increased inhibition” of reward signals, Lester adds.

But the most significant changes seem to come about when the flow of nicotine stops. Lester’s lab is particularly interested in withdrawal effects on the hippocampus. “Our brains store most information in an associative manner, and the hippocampus is important for consolidating all types of associative information, including reward-based learning,” Lester says. “Think of Pavlov’s dog. He was trained to associate the sound of a bell with food arriving. It’s the same with drugs.” Studies using magnetic resonance imaging have found that the neurons in the hippocampus show a burst of activity when addicts see smoking-related cues, such as a pack of cigarettes or a lighter, Lester says.

“These systems are usually driven by natural rewards like food or reproduction,” Lester adds. “But they can get hijacked by drugs like nicotine. If something is constantly paired, like the smell of cigarettes and nicotine, the brain learns to respond to the smell of the cigarette, because that gives you an early warning that nicotine is coming.”

“These secondary cues become very strong reinforcers,” Lester adds—and this learned behavior is very hard to extinguish. “The hippocampus has stored all this contextual information, so when somebody who hasn’t smoked for awhile is exposed to those cues, they’ll trigger a craving; the body still associates those cues with the rewards of smoking.” Trying to break the association with nicotine causes mental distress with very real neurochemical underpinnings. “The smoker’s brain has found a way to get itself into balance with nicotine present,” Lester says. “If you pull the nicotine away, the brain falls out of balance, and that’s a stressful situation.”

The Sting in the Tail

The first week or more of withdrawal is marked by a “huge stress response,” Lester says. “Your body is releasing corticosteroids and many other stress-related compounds.” Several studies have suggested that these chemicals may in fact trigger the long-term reshaping of the brain.

Removing nicotine from the equation brings about “a rebound increase in excitability that permeates throughout the circuitry of the hippocampus,” Lester says. If the nicotine flow resumes (that is, if a person starts smoking again), the increase in excitability is reversed. After a few weeks of withdrawal, however, there seems to be a permanent change, as the source of the excitability shifts from the dentate gyrus “downstream” to another region of the hippocampus known as CA1. The number of nicotinic receptors, which went up during chronic nicotine use, goes back to normal, Lester adds—but the neurons of the hippocampus stay more excitable than they were before nicotine.

“It’s like the set point for nicotine has changed,” Lester says. “It may have been pushed out of range, and now the body can’t reset itself.”

These findings do suggest potential new treatment options. There are FDA-approved drugs on the market for other conditions that may be able to block key stress compounds, Lester says. Those drugs may help with the effects of withdrawal and reduce or prevent long-term brain changes.

Lester estimates that any patient-ready therapies are still five to 10 years away, hampered in part by our evolving knowledge of how nicotine works. “I don’t think there’s a completely coherent picture of what nicotine addiction is, at least at the neurobiological level,” Lester says. “A lot of people have their own little part of the story, but I don’t think it’s been all put together yet.”

Turkey Talk
Practical Advice on Breaking Nicotine’s Grip

Setting a “quit date” in your mind is an important part of kicking the smoking habit. But nicotine has such a powerful hold on the brain that going cold turkey is rarely an effective strategy, says UAB neuroscientist Robin Lester, Ph.D.

Lester doesn’t believe that we are powerless to fight back, however. “You’re not 100 percent an addict, in the way that a person who has epilepsy is 100 percent epileptic,” he says. “This is not the same type of disease. You can counteract addiction. There is willpower involved. Your prefrontal cortex, the part of your brain that makes conscious decisions, is still in control, although probably to a reduced extent. It’s just hard.”

Because a smoker’s brain has built up strong associations between smoking and related behaviors such as drinking a cup of morning coffee or finishing an evening meal, it’s important “to start dissociating smoking from your everyday behaviors before you quit,” Lester says. Don’t try to make the change all at once, he advises. “If you normally associate making your morning cup of coffee with lighting a cigarette, try and delay lighting up for five minutes, then a little bit more each day. Eventually, you will be able to have a cup of coffee without associating it with cigarettes.”