Why's It So Hard to Quit Smoking? Neuroscience Has New Clues

Nicotine withdrawal activates anxiety-related brain circuitry.

Posted May 15, 2015

Pixabay/Free Image
Source: Pixabay/Free Image

Worldwide, 1 billion people are addicted to nicotine. A recent report published in the journal Addiction found that 11% of deaths in males and 6% of deaths in females are linked to tobacco use each year globally. 

Smoking is one of the hardest habits to kick. Anecdotally, you will often hear addicts say that kicking the cigarette habit can be harder than kicking a heroin habit. Are you a regular smoker who is addicted to nicotine? If so, the latest neuroscience may offer clues that will make quitting easier.

Recently, two separate neuroscientific studies pinpointed specific brain regions that make it difficult for some people to quit smoking and for others to succeed at smoking cessation. These regions are the interpeduncular nucleus and the insula respectively. 

Nicotine Withdrawal Activates Stress-Related Brain Regions 

A 2013 study from the University of Massachusetts Medical School pinpointed an isolated group of neurons within the interpeduncular nucleus in the base of the midbrain that trigger stress and anxiety during nicotine withdrawal.

For this study, Andrew Tapper and his colleagues conditioned mice in the laboratory to become addicted to nicotine. When they took away the nicotine, the mice started scratching and shaking uncontrollably like an animal that has the shivers from being cold and wet. When they examined the animals' brains they discovered increased activity in neurons within a specific brain region known as the interpeduncular nucleus.

When the researchers artificially activated those same neurons with light using optogenetics, the animals showed behaviors that mimicked nicotine withdrawal—regardless of whether the animal was actually withdrawing from nicotine. Conversely, light treatments that lowered the activity in those neurons alleviated the symptoms of nicotine withdrawal.

The interpeduncular nucleus receives connections from other areas of the brain involved in nicotine use and response, as well as feelings of anxiety. The interpeduncular nucleus is densely packed with nicotinic acetylcholine receptors that are the molecular targets of nicotine. There’s a possibility that the interpeduncular nucleus is linked to withdrawal from other forms of addiction.

In a press release, Tapper said, "Smoking is highly prevalent in people with other substance-use disorders, suggesting a potential interaction between nicotine and other drugs of abuse. In addition, naturally occurring mutations in genes encoding the nicotinic receptor subunits that are found in the interpeduncular nucleus have been associated with drug and alcohol dependence."

In a follow-up study on this research published in April 2015, Tapper and his colleagues at the University of Massachusetts Medical School teamed up with the Scripps Research Institute to expand on their initial findings that the interpeduncular nucleus triggers anxiety during nicotine withdrawal.

Their collaborative research resulted in several discoveries about interconnected brain mechanisms that induce anxiety during nicotine withdrawal and possible ways to derail these mechanisms in order to treat, or even prevent, the anxiety caused by nicotine withdrawal.

The neuroscientists discovered sub-regions within the interpeduncular nucleus that could be an effective target for dampening the negative symptoms of nicotine withdrawal. In a laboratory experiment, Tapper and his colleagues were able to alleviate anxiety in mice by quieting the activity of specific neurons. The researchers are optimistic that the same might be possible for humans. Andrew Tapper concluded:

There are already drugs that block the CRF receptor that contributes to activation of these anxiety-inducing neurons. These receptors have previously been linked to anxiety and depression, so our findings may also have implications for anxiety disorders in general. Next steps for this productive research collaboration will be expanding the scope of scientists' understanding of the interactions between anxiety, stress, reward, and withdrawal from addictive substances.

Optimal Brain Connectivity Can Hard-Wire Smokers for Success When Quitting

Courtesy of Duke Medicine
The top row represents the average brain connectivity among participants who successfully quit smoking, versus those who relapsed, shown on the bottom row.
Source: Courtesy of Duke Medicine

A recent study from Duke Medicine found that smokers who are able to quit smoking might actually be hard-wired for success in other areas of their lives. The May 2015 study, "Increased Functional Connectivity in an Insula-Based Network is Associated with Improved Smoking Cessation Outcomes," was published in the journal Neuropsychopharmacology.

The Duke neuroscientists found that people who were able to give up cigarettes showed greater connectivity between the insula and the somatosensory cortex which controls our sense of touch and motor control. This increased connectivity differentiated smokers who successfully quit smoking when compared to those who tried and failed.

The insula is a large region in the cerebral cortex that is typically viewed as the seat of addictive urges and cravings. The insula has been the subject of a wide range smoking cessation studies. The more connectivity between the insula and the somatosensory cortex in the Duke study was correlated with smokers who succesfully quit. Those who relapsed had less connectivity between these brain regions.

Merideth Addicott, Ph.D., assistant professor at Duke and lead author of the study said in a press release, "Simply put, the insula is sending messages to other parts of the brain that then make the decision to pick up a cigarette or not."

The insula is active when smokers are craving cigarettes and lights up during brain imaging when people think about smoking. Other studies found that smokers who suffer damage to the insula appear can spontaneously lose nicotine cravings or the desire to smoke cigarettes.

The Duke researchers analyzed MRI scans of 85 people taken one month before they attempted to quit. All participants stopped smoking and the researchers tracked their progress for 10 weeks. Forty-one participants relapsed. Looking back at the brain scans of the 44 smokers who quit successfully, the researchers found they had something in common before they stopped smoking which was better synchronization between the insula and the somatosensory cortex.

Joseph McClernon, Ph.D., associate professor at Duke and the study's senior author described the findings saying, 

There's a general agreement in the field that the insula is a key structure with respect to smoking and that we need to develop cessation interventions that specifically modulate insula function. But in what ways do we modulate it, and in whom? Our data provides some evidence on both of those fronts, and suggests that targeting connectivity between insula and somatosensory cortex could be a good strategy.

Conclusion: Targeting Specific Brain Areas Could Improve Smoking Cessation Outcomes

The latest neuroscientific research offers new clues about the role that the interpeduncular nucleus and insula play in smoking cessation outcomes.

In the future, pharmaceuticals that target specific brain regions could be developed to minimize the negative impact of nicotine withdrawal and the power of cravings. Mindfulnessmeditation, and neurofeedback are also treatment options that could be fine-tuned to modulate brain activity and targeted to help people quit smoking.  

Joseph McClernon from Duke concluded, "We have provided a blueprint. If we can increase connectivity in smokers to look more like those who quit successfully, that would be a place to start. We also need more research to understand what it is exactly about greater connectivity between these regions that increases the odds of success."


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