Alcohol withdrawal causes a range of symptoms and scientists are now investigating how the brain reacts to abstinence.
Alcohol withdrawal causes a wide range of acute symptoms, from shaky hands to anxiety; however, the emotional distress associated with removal of alcohol is a key reason why alcohol-use disorders face difficulty when quitting.
Scientists from Scripps Research are addressing the unknown and aiming to understand the basis of alcohol withdrawal in the brain.
The study was published in the journal Molecular Psychiatry.
Linking alcohol withdrawal and brain activity
Previous studies found a signalling molecule called corticotropin-releasing factor (CRF) was linked to alcohol withdrawal. When researchers block CRF in rats or mice addicted to alcohol, the animals drink less. Scientists believed that suspect CRF is produced by neurons in a brain area called the central nucleus of the amygdala. But in the new study, the team found that in mice that these cells aren’t required for alcohol withdrawal or alcohol dependence.
“Understanding the basis of withdrawal is incredibly important for treating alcohol addiction in humans because this is one of the motivational drivers of excessive alcohol drinking,” said Candice Contet, PhD, associate professor in the Department of Molecular Medicine at Scripps Research. “These findings weren’t what we expected but help us get closer to understanding alcohol addiction and the role of CRF.”
Many studies have established that CRF levels increase in the central nucleus of the amygdala of rats and mice during alcohol withdrawal and response to other psychological stressors. Pharmaceutical companies continue to actively explore how to target CRF signalling to treat a variety of psychological diseases, including alcohol addiction. But results in humans have been inconclusive, and scientists have not been able to pin down which cells in the brain release CRF during alcohol withdrawal.
Testing the hypothesis
Contet’s group tested the hypothesis that cells in the central amygdala produce the CRF necessary for alcohol withdrawal. In the new study, the scientists activated and blocked these amygdala-residing neurons in mice dependent on alcohol.
First, they activated the neurons in various patterns designed to replicate cycles of repetitive drinking and withdrawal. But the researchers found that activating these CRF-producing neurons did not affect the drinking behaviour of the mice, even though other experiments confirmed that CRF was getting released in the central amygdala. Moreover, the team showed that blocking these neurons also did not affect the behaviour of mice with alcohol dependence, which was surprising because it meant that the CRF known to signal in the amygdala to promote alcohol drinking wasn’t being produced in that area.
“We saw that activating these neurons within the central amygdala is not sufficient nor necessary for the escalation of drinking in mice,” said Contet. “So it means that the CRF is coming to the central amygdala from somewhere else in the brain.”
Other neurons in the brain are known to produce CRF, but the team doesn’t yet know which might be involved in alcohol dependence.
“These findings were surprising but highlight the complexity of the CRF system and the changes in brain circuitry that occur following chronic alcohol exposure,” said Melissa Herman, a former Scripps Research postdoctoral research associate and co-first author of the new paper.
The team made another unexpected observation – the CRF neurons weren’t organised the same way in mice brains as they are in rat brains. The observation, Contet said, suggests that there might be some variation in CRF between species. This also could explain why the amygdala neurons in question are necessary for alcohol withdrawal in rats but, according to the new data, not in mice.
“Our data has to be taken with a grain of salt when it comes to implications for humans,” she says. “Since there’s this important difference between rats and mice, more work is definitely needed to figure out the relevance to humans.”
The group is planning experiments to further understand the differences in CRF between rats and mice, as well as pin down which other neurons in the brain might be involved in its production during alcohol withdrawal.