Targeting norepinephrine to treat alcoholism

The norepinephrine neurotransmitter 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 norepinephrine goes awry with alcohol dependence and addiction. Their findings, published in the journal Biological psychiatrysuggest that blocking certain brain cells from sensing norepinephrine could help treat alcohol use disorders.

“Understanding the many brain mechanisms that contribute to alcohol use disorders is important in order to develop new treatments,” says Marisa Roberto, PhD, Schimmel Family Chair in Molecular Medicine and Professor of Neuroscience at Scripps Research. “Our results point to drugs already approved by the FDA that could be repurposed for this disorder.”

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

In the new paper, Roberto and his colleagues focused on the role of norepinephrine in alcohol dependence in the amygdala, a brain region associated with stress, negative emotions, and motivation.

In a series of experiments, scientists compared norepinephrine signaling in alcohol-dependent rats, which drink a large amount of alcohol, with signaling in non-dependent control animals, which consume a more moderate level similar to drinkers. human social. Specifically, they looked at how different brain receptors that sense norepinephrine – called α1, β1 and β2 – regulate the activity of neurons in the amygdala and how they contribute to alcohol consumption. The team found that α1 receptors in the amygdala are required for moderate levels of alcohol consumption, similar to social drinking in humans. Blocking these receptors decreased alcohol consumption in nondependent “social drinker” rats, but not in alcohol-dependent rats. However, in alcohol-dependent animals, blocking β receptors in the amygdala significantly reduced alcohol intake, while blocking α1 had no effect.

“These results are really exciting because they help us understand the distinct role that each norepinephrine receptor may play in determining the level (excessive versus moderate) of alcohol consumption during the development of alcohol use disorder. alcohol,” says Florence Varodayan, 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 the levels of the three norepinephrine receptors in the brains of deceased adult men who had been diagnosed with alcohol use disorder, as well as controls. . Levels of α1 receptors, they found, were higher in the amygdala of male alcoholics. This indicates similar changes in how the brain senses norepinephrine.

Various drugs targeting both the α1 and β norepinephrine receptors are already FDA-approved for a number of other conditions, including blood pressure regulation. Additionally, based on previous studies linking norepinephrine to alcohol consumption, there are already active clinical trials investigating the use of these drugs in the treatment of alcohol use disorders. ; the new evidence adds weight to these lines of inquiry.

Taken together, this study suggests that blocking norepinephrine receptors could be a valuable target for the treatment of alcohol use disorders. Both repurposed and new drugs should be screened for this use, the researchers say.

Roberto’s team plans future studies to better understand how noradrenergic receptors are involved in alcohol use disorders, including expanding the research to women, since the rats and humans included in the current study were all men.

Reference: Varodayan FP, Patel RR, Matzeu A, et al. The noradrenergic system of the amygdala is compromised by an alcohol use disorder. Biol. Psychiatry. 2022. do: 10.1016/j.biopsych.2022.02.006

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