Scientists hunt for neurons responsible for alcohol withdrawal
Suspected amygdala neurons may not be to blame after all, new mouse study shows
Date:
March 22, 2022
Source:
Scripps Research Institute
Summary:
When a heavy alcohol drinker tries to take a night off, their
body protests, with shaky hands, heart palpitations, anxiety
and headaches.
These acute symptoms of alcohol withdrawal -- but even more so
the enduring emotional distress that lingers into protracted
abstinence - - are one reason people with alcohol use disorders
have a hard time quitting. Now, scientists have made new headway
in understanding the basis of alcohol withdrawal in the brain.
FULL STORY ==========================================================================
When a heavy alcohol drinker tries to take a night off, their
body protests, with shaky hands, heart palpitations, anxiety and
headaches. These acute symptoms of alcohol withdrawal -- but even more so
the enduring emotional distress that lingers into protracted abstinence
-- are one reason people with alcohol use disorders have a hard time
quitting. Now, scientists at Scripps Research have made new headway in understanding the basis of alcohol withdrawal in the brain.
========================================================================== Previously, a signaling 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 the suspect CRF is produced by neurons in a brain area called the
central nucleus of the amygdala. But in the new study, published in
the journal Molecular Psychiatry in March 2022, the team found that --
at least in mice -- 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," says 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 as well
as in response to other psychological stressors. Pharmaceutical companies
are actively investigating how to target CRF signaling 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.
Contet's group wanted to test the hypothesis that cells in the central
amygdala produce the CRF necessary for alcohol withdrawal. In the new
study, the researchers 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. However, activating these CRF-producing neurons had no
effect on the drinking behavior of the mice, even though other experiments confirmed that CRF was getting released in the central amygdala. Next,
the team showed that blocking these neurons also had no effect on the
behavior 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 basically saw that activating these neurons within the central
amygdala is not sufficient nor necessary for the escalation of drinking
in mice," says 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," says Melissa Herman, a former Scripps Research
postdoctoral research associate and co-first author of the new paper.
When the team looked at the spatial patterns of organization of the
amygdala neurons they were studying, they made another unexpected
observation -- the CRF neurons weren't organized the same way in mice
brains as they are in rat brains. The observation, Contet says, suggests
that there might be some variation in CRF between species. This also
could explain why the amygdala neurons in question have been found to be 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.
This work was supported by funding from the National Institutes of Health (AA024198, AA026685, AA027636, AA027372, AA006420, AA021491, AA015566,
AA02300, and AA024952).
========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Max Kreifeldt, Melissa A. Herman, Harpreet Sidhu, Agbonlahor
Okhuarobo,
Giovana C. Macedo, Roxana Shahryari, Pauravi J. Gandhi, Marisa
Roberto, Candice Contet. Central amygdala corticotropin-releasing
factor neurons promote hyponeophagia but do not control alcohol
drinking in mice.
Molecular Psychiatry, 2022; DOI: 10.1038/s41380-022-01496-9 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220322141128.htm
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