At the moment a former smoker catches a whiff of tobacco, glimpses the corner store where they used to buy cigarettes, or sees a stranger pull a pack of smokes out of their pocket, something happens in their brain that causes an intense craving, even years after they’ve quit. In a PNAS Early Edition paper published this week, scientists have now described the molecular events that happen in the brain at this precise moment that a former nicotine addict is faced with a cue to smoke.
“The big question is what’s the neurobiology of why people are vulnerable to relapse,” says Peter Kalivas of the Medical University of South Carolina. And in his latest work, Kavilas narrowed in on an area of the brain that he suspected might be involved in relapse based on previous knowledge on habits.
“We all go through life with a series of habits,” Kalivas explains. These habitual tasks are mediated by habit circuitry in the brain, which lets your brain go into a kind of auto-pilot to complete them. When a habit is disrupted, however–whether that means the road you normally drive home is closed or the coffee shop rearranges its milk and sugar–a part of the brain called the frontal cortex becomes involved, more actively planning out your actions. But if the frontal cortex repeatedly mediates this new behavior, it becomes a new habit, replacing the old one in the brain’s habit cortex and no longer requiring that active control.
For cigarette smokers, as well as cocaine and heroin addicts, the habit cortex doesn’t become reprogrammed when they quit, Kalivas says. “Unlike normal habits, where if you get enough new signals, it changes the behavior, they don’t seem to be able to change their smoking habit very effectively.”
The frontal cortexes of former smokers are fully functional, so Kalivas and his colleagues suspected that the signalling between the frontal cortex and the habit circuitry might be to blame for the stubborn cravings. To test their hypothesis, the scientists trained nicotine-addicted rats to associate a particular light and sound with receiving a dose of nicotine. Then, the animals were forced to quit nicotine, given no doses for two weeks–long enough that the drug would have fully left their body and a normal habit would have been reprogrammed in the brain.
Next, the scientists flashed the same light and sound that the rats had previously learned to associate with nicotine. The animals’ brains showed huge increases in activity, unlike any normal response to trained stimuli (they tested rats that had been trained to associate the same stimuli with sugar, and didn’t see the same massive response in the brain).
The researchers saw a rush of signalling molecules–one called glutamate, specifically–in an area of the brain called the nucleus accumbens, a key connection between the frontal cortex and the habit circuitry.
“Not only do you get this huge outpouring of signalling,” Kalivas says, “but the connection actually keeps getting stronger.” This overstimulation is likely what causes an intense craving when faced with a cue to smoke, he says.
The team went on to show that when they blocked the molecules in this part of the brain that respond to glutamate, the rats no longer wanted a dose of nicotine when faced with the sound and light (they chose not to press a lever in their cage that would give them the drug).
“Just these kinds of drug-associated stimuli alone are capable of producing very rapid changes in the brain that stimulate drug-seeking behavior,” says Kalivas. “By discovering what some of those changes are, I think we can find some very strong potential targets for treatments.”
The scientists are now moving toward an initial human clinical trial of a drug that can block the response to glutamate, hoping to see the same diminished nicotine craving observed in the mice.