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Neuroscientists Identify Brain Circuitry Responsible for Increased Anxiety in Smoking Cessation

In a promising breakthrough for smokers who are trying to quit, neuroscientists at The Scripps Research Institute (TSRI) and UMass Medical School (UMMS) have identified circuitry in the brain responsible for the increased anxiety commonly experienced during withdrawal from nicotine addiction.

“While increased anxiety is a predominant and troublesome withdrawal symptom for smokers trying to quit—and one that contributes to relapse—until now it has been very difficult to identify a specific neuronal circuit that can be switched off to prevent nicotine withdrawal,” said TSRI Assistant Professor Olivier George. “Our new study identified this circuit. It’s a game-changer for the development of new compounds to help quit smoking.”

The research yielded 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 especially troublesome symptom.

Experiments leading to the multiple, related findings were conducted over several years by George’s group (which last November reported the discovery of a new population of neurons involved in nicotine intake and aversion to nicotine withdrawal) and the UMMS laboratories of Andrew Tapper, associate professor of psychiatry who was senior author of the new study, and Paul Gardner, professor of psychiatry.

Published online by Nature Communications on April 21, the new study’s main finding is that a brain region called the interpeduncular nucleus is activated and appears to cause anxiety during nicotine withdrawal. Investigators were intrigued to learn that the sub-region of the interpeduncular nucleus, which is activated and linked to anxiety during withdrawal, is distinct from another sub-region, previously identified by Tapper, where physical nicotine withdrawal symptoms such as headaches, nausea and insomnia originate.

Anxiety is an affective symptom often likely to thwart smokers’ attempts to quit. The newly discovered sub region offers a distinct target for dampening the affective symptoms of nicotine withdrawal.

Also newly identified is the fact that input from neurons in two other brain regions converge onto the interpeduncular nucleus to stimulate anxiety-provoking neurons. Surprisingly, the ventral tegmental area, which is traditionally associated with the rewarding or pleasurable effects of abused drugs, activates neuron receptors through corticotropin releasing factor, a protein neurotransmitter released in response to stress. Also surprising, neurons in the medial habenula stimulate interpeduncular nucleus neurons by releasing glutamate, the major excitatory neurotransmitter in the brain, an effect that is increased by corticotropin releasing factor receptor activation.

“Both of these inputs are important,” said Tapper. “We could alleviate anxiety during nicotine withdrawal by either preventing corticotropin releasing factor synthesis in the ventral tegmental area, or by silencing the medial habenula inputs into the interpeduncular nucleus.”

Investigators were able to alleviate anxiety in mice by quieting the activity of those activated neurons, suggesting the same might be possible for humans. 

“There are already drugs that block the CRF receptor that contributes to activation of these anxiety-inducing neurons,” Tapper noted. “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. 

Other authors of the paper, “Increased CRF signaling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal,” were Rubing Zhao-Shea (first author), Steven R. DeGroot, Liwang Liu, Markus Vallaster, Xueyan.

Pang, Qin Su and Guangping Gao and Oliver J. Rando of UMMS. For more information, see

The research was supported by the National Institute’s of Health National Institute on Drug Abuse (grants F32DA034414, R01DA035371 and R01DA033664).

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“It’s a game-changer for the development of new compounds to help quit smoking.”
—Olivier George