Scientists find brain circuitry that raises anxiety during nicotine withdrawal

22 Apr

A discovery about the brain may offer new hope to smokers finding it hard to

quit. Scientists writing in the journal Nature Communications describe how they

identified circuits in the brain that they believe are responsible for the anxiety that

often accompanies nicotine withdrawal.

anxious woman
Researchers found circuitry in the brain that appears to be specifically

wired to increase anxiety during nicotine withdrawal.

Senior author Andrew Tapper, associate professor of psychiatry at the University of

Massachusetts Medical School (UMMS), says:

“Increased anxiety is a prominent nicotine withdrawal symptom that contributes

to relapse in smokers attempting to quit.”

He and his colleagues found circuitry in the brain that appears to be specifically

wired to increase anxiety during nicotine withdrawal.

The team also discovered several other interconnected features in the brain that

trigger anxiety during nicotine withdrawal.

They suggest their findings may open the door to new treatments to relieve or even

prevent anxiety during nicotine withdrawal.

The new work builds on achievements accomplished over several years – both at UMMS and

at The Scripps Research Institute in La Jolla, CA.

It follows, for example, a study published in 2013 in the journal Current

Biology, where Prof. Tapper and colleagues had shown that a specific set of cells in

a region of the brain known as the interpeduncular nucleus causes physical nicotine withdrawal symptoms, such as headaches,

nausea and insomnia originate.

The team was

surprised to find that the area of the interpeduncular nucleus that is activated during withdrawal-related anxiety is distinct from the sub-region they had previously identified as being linked to nicotine withdrawal


The researchers were also surprised to find that signals from two other brain

regions come together at the interpeduncular nucleus to trigger anxiety-causing brain


One of the signals comes from the ventral tegmental area – a group of cells at the

very centre of the brain – which is normally linked with reward or pleasure. The study

shows that this area activates brain cells in the interpeduncular nucleus using

corticotropin releasing factor (CRF) – a brain chemical that is released in response to


The other signal comes from the medial habenula and triggers cells in the

interpeduncular nucleus by releasing glutamate – the chemical most used by brain cells to

send signals to each other. In this case, the arrival of CRF at the interpeduncular

nucleus cells appears to increase the effect of glutamate.

Reducing stimulation of interpeduncular nucleus cells alleviated anxiety in mice

In further tests, the researchers found they could alleviate anxiety in mice by reducing the

stimulation of the cells in the interpeduncular nucleus, and they suggest the same may be

possible in humans.

Prof. Tapper says both of the inputs – CRF from the ventral tegmental area, and glutamate from the medial habenula – appear to be important and offer potential

treatment targets:

“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.”

Drugs that block CRF receptors on cells

already exist, says Prof. Tapper. He also notes that these receptors have already been

linked to anxiety and depression, so their study findings could have implications for

anxiety disorders in general.

The team now plans to investigate interactions between anxiety, stress, reward and

withdrawal from addictive substances and explore whether the circuits they have

identified relate to stress-induced anxiety in general or just that induced by nicotine


In September 2014, Medical News Today learned how researchers found that nicotine withdrawal reduced reward responsiveness and

the effect was particularly strong in smokers with a history of depression.