April 13, 2022

Scripps Research study suggests targeting noradrenaline to treat alcoholism Study indicates that drugs already targeting noradrenaline for other diseases may be useful in treating alcohol use disorder.

April 13, 2022

LA JOLLA, CA The neurotransmitter noradrenaline is one of the most abundant in the brain; it has a wide range of effects on attention, wakefulness, stress, blood pressure and heart rate. Now, Scripps Research scientists have shown in animal models and human brain tissue how the noradrenaline goes awry with alcohol dependence and addiction. Their findings, published in the journal Biological Psychiatry, suggest that blocking some brain cells from sensing noradrenaline could help treat alcohol use disorder.

It is important to understand the numerous brain mechanisms that contribute to alcohol use disorder in order to develop new treatments, says Marisa Roberto, PhD, the Schimmel Family Chair of Molecular Medicine and a professor of neuroscience at Scripps Research. Our results point toward drugs already approved by the FDA that might be repurposed for this disorder.

Noradrenaline, also called norepinephrine, is a signaling molecule that generally promotes arousal and attention. As part of the fight-or-flight response, noradrenaline levels rise in response to stress, causing increased heart rate, blood pressure, memory formation, and blood flow to muscles, among other changes. Broad differences in how the brain responds to noradrenaline have previously been linked to mood disorders, anxiety and alcohol dependence. But how noradrenaline functions within specific areas of the brain in people with alcohol use disorder has not been fully understood.

In the new paper, Roberto and colleagues homed in on noradrenaline's role in alcohol addiction in the amygdala, a brain region associated with stress, negative emotions and motivation.

In a set of experiments, the scientists compared noradrenaline signaling in alcohol-dependent rats, that drink a large amount of alcohol, with signaling in control nondependent animals that consume a more moderate level akin to human social drinkers. Specifically, they examined how different brain receptors that sense noradrenaline called 1, 1 and 2 regulate the activity of neurons in the amygdala and how they contribute to alcohol drinking. The team found that 1 receptors in the amygdala are required for moderate levels of alcohol intake similar to social drinking in humans. Blocking these receptors decreased alcohol consumption in the social drinker nondependent rats, but not in the alcohol-dependent rats. However, in animals that were alcohol-dependent, blockade of the receptors in the amygdala significantly decreased alcohol consumption, while blocking 1 had no effect.

These results are really exciting as they help us understand the distinct role each noradrenaline receptor can play in determining the level (excessive versus moderate) of alcohol intake during the development of alcohol use disorder, says Florence Varodayan, an assistant professor of psychology at Binghamton University and first author of the new paper, who carried out the work while a postdoctoral research associate at Scripps Research.

To test the relevance of the animal findings to humans, the scientists measured levels of the three noradrenaline receptors in the brains of deceased adult men who had been diagnosed with alcohol use disorder, as well as controls. Levels of 1 receptor, they discovered, were higher in the amygdala of the men with alcohol addiction. This points toward similar changes to how the brain is sensing noradrenaline.

Various drugs targeting both the 1 and receptors of noradrenaline are already approved by the FDA for a number of other conditions, including regulating blood pressure. In addition, based on previous studies linking noradrenaline to alcohol intake, there are already active clinical trials investigating the use of these drugs in treating alcohol use disorder; the new evidence adds weight to these lines of investigation.

Overall, this study suggests that blocking noradrenaline receptors could be a valuable target for treating alcohol use disorder. Both repurposed and new drugs should be examined for this use, the researchers say.

Roberto's team is planning future studies to better understand how the noradrenergic receptors are involved in alcohol use disorder, including expanding the research to females, since the rats and humans included in the current study were all male.

In addition to Roberto and Varodayan, authors of the study, Alcohol Use Disorder compromises the amygdala noradrenergic system, include Reesha R. Patel, Alessandra Matzeu, Sarah A. Wolfe, Sophia Khom, Pauravi Gandhi, Larry Rodriguez, Michal Bajo, Shannon D'Ambrosio and R mi Martin-Fardon of Scripps; Dallece E. Curley, and Carolina L. Haass-Koffler of Brown University; Lorenzo Leggio and Hui Sun of the National Institute on Alcohol Abuse and Alcoholism; and Tony M. Kerr, Rueben A. Gonzales and Luis A. Natividad of University of Texas at Austin.

This work was supported by funding from the National Institutes of Health (R00AA025408, R01AA015566, R01AA027700, R01AA013498, R01AA017447, R01AA021491, P60AA006420, T32AA007456, R01AA026999, R01AA028549, F32AA026765, R00AA025393, K01AA023867, R01AA027760, R21AA027614, ZIA-DA000635, ZIA-AA000218), the Merck Investigator Studies Program (MISP59371), the Austrian Science Fund (J-3942-B30), the Pearson Center for Alcoholism and Addiction Research, and the Office of the Clinical Director, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism.

Neuroscience Roberto, Marisa

LINK:	https://www.scripps.edu/news-and-events/press-room/2022/22020413-rober...
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