Novel findings show a link between the steroid hormone aldosterone and a risk for alcohol use disorder, underscoring the role of neuroendocrine mechanisms in alcohol cravings and in potential treatments, new research shows.
"The aldosterone pathway and its mineralocorticoid receptor may represent a novel target to develop pharmacological treatments for patients with alcohol use disorder," Lorenzo Leggio, MD, PhD, chief of the Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland, told Medscape Medical News.
"We believe that this target might be particularly promising for those individuals who drink excessive amounts of alcohol to cut their stress and anxiety – this is technically what we refer to as the 'withdrawal/negative affect stage,' [and] it is a domain for which we do not have approved targeted medications."
Produced by the adrenal glands, aldosterone regulates electrolyte and fluid balance by binding to mineralocorticoid receptors. The receptors, which are located throughout the body, are present in brain regions linked to alcohol use disorder ― the amygdala and the prefrontal cortex.
In 2008, Dr Leggio and colleagues published research supporting the thesis that aldosterone plays a role in alcohol use disorders.
In new research published online May 2 in Molecular Psychiatry, the authors describe further evidence that supports that thesis with findings from three studies. One of the studies was conducted in humans; the other two were conducted in animals.
The clinical study included 42 alcohol-dependent patients who were part of a project examining secondary endocrine-related outcomes from a larger study involving a baclofen intervention. In that study, baclofen was not found to have an effect on primary drinking outcomes or blood aldosterone levels.
Patients were asked to abstain from alcohol for at least 3 days prior to enrollment and to try to remain abstinent during the 12-week study. Medical treatment was provided to help reduce drinking. Some of the participants were able to maintain abstinence or reduce their alcohol intake; others were not able to reduce their drinking at all.
No differences were seen at baseline between aldosterone levels of the patients who were and those who were not abstinent. After 12 weeks, however, those who did not maintain abstinence showed significantly higher aldosterone levels (232 ± 57 pg ml−1) compared to those who were abstinent (134 ± 13 pg ml−1 ; P = .04).
In addition, a positive correlation was seen between plasma aldosterone levels and the number of drinks consumed during the course of the 12-week study period (P = .0007).
Measures of alcohol craving were also linked to aldosterone levels, with higher aldosterone levels associated with higher alcohol craving at week 12, as measured by obsessive disorder and compulsive disorder subscales (for both, P = .02).
Correlations with higher plasma aldosterone levels were also observed in measures of anxiety at week 12 (P = .03).
The study is a continuation of the team's 2008 study, which involved patients who were abstinent from alcohol for 12 weeks. The new study included a larger sample, with patients who were and others who were not able to abstain from alcohol for the 12 weeks.
The previous study showed aldosterone levels to be increased in patients with alcoholism during early alcohol withdrawal. Levels normalized during recovery.
In the new study, "we confirmed the relationship between aldosterone concentrations in the blood and craving and anxiety, but also expanded with a new hypothesis, that is, the relationship between aldosterone and alcohol drinking," Dr Leggio said.
"And in fact, we found that aldosterone concentrations were higher in those people who drank alcohol vs those who were abstinent. Furthermore, we found that the more alcohol they consumed, the higher aldosterone concentrations measured," he added.
The team's two animal studies provide further insight into the relationship between aldosterone and alcohol use. The first showed significant increases in aldosterone levels in monkeys at 6 months that received ethanol; aldosterone levels remained high after 12 months. No increases were observed in monkeys that received only water.
"These data suggest that aldosterone levels become regulated at a new set-point under daily ethanol consumption, consistent with the hypothesis that chronic ethanol produces an allostatic shift of brain stress systems," write the investigators.
That study further showed a negative correlation between expression of the mineralocorticoid receptor gene NR3C2 in the central nucleus of the amygdala and average ethanol intake during the 12-month period.
In the second animal study, rats with low levels of expression of the NR3C2 gene showed greater vulnerability to anxiety-related ethanol drinking compared to those with high levels of expression.
"These findings suggest that high NR3C2 levels in the central nucleus of the amygdala may be protective against compulsive ethanol drinking or, conversely, that low levels of NR3C2 expression may convey vulnerability for anxiety-related compulsive ethanol drinking," the authors write.
Study coauthor and NIAAA Director George F. Koob, PhD, agreed that the findings are compelling.
"This intriguing work — conducted in humans as well as two other species — provides a compelling example of how basic and preclinical research is translated into studies with direct relevance to humans," he said in an NIH press statement.
"Fascinating, Innovative" Research
Edward V. Nunes, MD, professor of psychiatry at Columbia University in New York City, noted that the studies provide important insights worthy of additional investigation.
"I think it's fascinating, and we need more work of this kind," he told Medscape Medical News.
"There have been efforts to target the cortisol system, with cortisone being the classic stress hormone that is also excreted by the adrenal system. But I think the focus on aldosterone for this is innovative."
Key questions that remain unanswered, including whether the changes in aldosterone are a cause or an effect of alcohol use. Further research into the use of aldosterone medications in hypertension may be useful in resolving such questions, he said.
"There are a lot of drugs used to treat high blood pressure that target the aldosterone system, so now it will be interesting to look at those drugs to see if they have any impact on behaviors such as alcohol use in humans," said Dr Nunes.
The studies were funded by the Swedish Research Council, the Pearson Center for Alcoholism and Addiction Research, the Division of Intramural Clinical and Biological Research of the NIAAA, the Intramural Research Program of the National Institute on Drug Abuse, the European Foundation for Alcohol Research, the National Institute of Mental Health, and the Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology of the NIH. The study authors and Dr Nunes have disclosed no relevant financial relationships.
Mol Psychiatry. Published online May 2, 2017. Full article
Medscape Medical News © 2017
Cite this: Aldosterone Hormone Linked to Alcohol Use, Cravings - Medscape - Jul 25, 2017.