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Aldosterone, a hormone produced in the adrenal
glands, may contribute to alcohol use disorder (AUD).
A new study led by scientists at the National
Institute on Alcohol Abuse and Alcoholism (NIAAA),
part of the National Institutes of Health, conducted
in collaboration with a team of investigators in the
United States and Europe, appears in the journal
Molecular Psychiatry.
“This intriguing work – conducted in humans as well
as two other species — demonstrates how interactions
between the brain and the endocrine system may serve
as potential targets for the development of new AUD
medications” said NIAAA Director George F. Koob,
Ph.D., a co-author of the study.
Aldosterone, a hormone produced in the adrenal
glands, may contribute to alcohol use disorder (AUD)
by binding to mineralocorticoid receptors in the
brain, particularly in the amygdala – a key brain
area involved in the development and maintenance of
AUD. NIAAA
Aldosterone helps regulate electrolyte and fluid
balance by binding to mineralocorticoid receptors (MRs),
which are located throughout the body.
In the brain, MRs are mainly located in the amygdala
and the prefrontal cortex, two key brain areas
involved in the development and maintenance of AUD.
In AUD, amygdala dysfunction heightens activation
of brain stress systems resulting in anxiety and
other negative emotions, while disruption of the
prefrontal cortex impairs executive control systems
involved in the ability to make decisions and
regulate one’s actions, emotions, and impulses.
“Previous studies, including a pilot clinical study
that we published in 2008, illustrate the possible
role for aldosterone in AUD,” said senior author
Lorenzo Leggio (M.D., Ph.D., chief of the Section on
Clinical Psychoneuroendocrinology and
Neuropsychopharmacology, a NIAAA intramural
laboratory jointly funded with the National
Institute on Drug Abuse, also part of NIH).
“Our overall hypothesis has been that aldosterone
may play a role in AUD via its MR receptor and that
this neuroendocrine pathway may be particularly
important in anxiety, stress and stress-induced
alcohol drinking.”
The new report describes three separate studies,
conducted with non-human primates, rats, and humans,
that investigated the potential contribution of the
aldosterone/MR pathway to AUD.
In a study conducted with non-human primates, the
researchers found that animals which
self-administered alcohol every day for six to 12
months had significantly higher blood aldosterone
concentrations, compared with the concentrations
measured prior to alcohol administration.
In fact, the aldosterone increase observed at six
months remained high after 12 months of continued
drinking, and did not increase further, suggesting
that blood aldosterone concentrations become
regulated at a new set-point under daily alcohol
consumption.
Furthermore, the researchers found that in the
amygdala, lower MR gene expression – the process of
making functional MR protein from the MR gene – was
associated with increased alcohol drinking in the
animals.
Similar results were not found in the prefrontal
cortex.
In a study conducted in a rat model of AUD, the
researchers found that lower levels of MR gene
expression in the amygdala (but not in the
prefrontal cortex) were associated with increased
anxiety-like behavior and compulsive drinking,
compared to rats not exposed to alcohol.
Conversely, higher levels of MR gene expression in
the amygdala were associated with decreased anxiety
and less compulsive alcohol drinking.
Overall, these findings suggest that higher MR gene
expression in the amygdala may protect against
compulsive drinking or, conversely, that lower
levels of MR gene expression may increase
vulnerability for anxiety-related compulsive
drinking in the rat AUD model.
“The amygdala is a key regulator of emotion and
stress and its adaptation to aldosterone signaling
due to chronic alcohol drinking illustrates
fundamental adaptations across organ systems that
underlie the pathological state associated with AUD,”
said Kathleen Grant, Ph.D., study co-author (and
head of the Division of Neuroscience, Oregon
National Primate Research Center at Oregon Health &
Science University, Portland).
In a human study of about 40 individuals undergoing
treatment for AUD, the researchers found that blood
aldosterone concentrations were higher in
individuals who continued drinking during the
12-week period, compared with those who were
abstinent during the same time frame.
For those who drank, the researchers found that
aldosterone concentrations correlated with the
amount of alcohol consumed during the study – higher
drinking levels were associated with higher
aldosterone concentrations.
The researchers also found that increasing blood
aldosterone concentrations correlated with
increasing levels of both alcohol craving and
anxiety.
Taken together, the researchers conclude that the
findings provide support across three different
species for a relationship between alcohol misuse,
AUD, and specific changes in the aldosterone/MR
pathway marked by increased circulating aldosterone
and decreased mineralocorticoid receptor gene
expression in the amygdala.
“Future studies should further investigate the
mechanisms underlying the relationship between
alcohol drinking and the aldosterone/MR pathway and
whether this pathway might be targeted for the
development of new pharmacotherapies for AUD,” said
Dr. Leggio.
For more information
A relationship between the aldosterone-mineralocorticoid
receptor pathway and alcohol drinking: preliminary
translational findings across rats, monkeys and
humans.
Aoun EG, Jimenez VA, Vendruscolo LF, Walter NAR,
Barbier E, Ferrulli A, Haass-Koffler CL, Markarian
P, Lee MR, Addolorato G, Heilig M, Hitzemann R, Koob
GF, Grant KA, Leggio L.
Mol Psychiatry. Online May 2, 2017. PMID: 28461696
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The National Institute on Alcohol Abuse and
Alcoholism (NIAAA)
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