Drunken monkeys offer fresh insight into the treatment of alcoholism

In a new study that must have required some impressive hoop-jumping to achieve ethical clearance, a team of international researchers has made ground-breaking inroads into the treatment of alcoholism – by studying a group of drunken monkeys.

The study, published in Cell Metabolism, describes how the drunkards in question, a captive population of vervet monkeys, were offered free choice between plain water and water spiked with ethanol. After sorting out which monkeys were partial to a tipple and which opted to abstain, the researchers administered an experimental treatment using an analogue of a hormone produced in the liver, called fibroblast growth factor 21 (FGF21), to those they’d identified as “alcohol-preferring”.

The results were a very promising 50% reduction in alcohol consumption.

Recent genome-wide studies have shown that variants of the FGF21 hormone are linked to alcohol consumption in humans, and pharmacological administration of FGF21 is known to reduce alcohol consumption in rodents, but this is the first study to document the effect in primates – a crucial step towards applications in human treatment.

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FGF21 is a hormone produced in the liver, and a pharmaceutical analogue can greatly reduce alcohol consumption by altering neural transmission in the nucleus accumbens and besolateral amygdala regions of the brain. Credit: Flippo, K.H. et al. / Cell Press

Interestingly, this study also found that FGF21 reduces sugar intake in mice, and the researchers wondered if our appetites for sugar and alcohol might be linked through evolution.

“Mammals were primarily exposed to alcohol from fermenting fruits, which possess high levels of simple sugars,” says senior study author Dr Matthew Potthoff of the University of Iowa Carver College of Medicine, in the US.

But by digging deeper into mechanistic pathways, the team found that this link didn’t hold up.

By studying the brain circuits through which FGF21 inhibits alcohol consumption in vervet monkeys and sugar consumption in mice, the team discovered the hormone acts on entirely separate neural pathways, likely having developed “independently and not in response to a shared selective pressure”, says Potthoff.

Progress towards developing novel treatments for alcoholism is desperately needed. Excess alcohol consumption is a major health and social issue across the globe, and efforts to therapeutically target pathways that regulate alcohol consumption have been limited in their ability to effectively treat alcohol use disorder.

Why is it so difficult to treat alcoholism in humans?

Although many mammals are drawn to the scent of alcohol, humans may be uniquely susceptible to its fickle charms.

Around 10 million years ago, roughly coinciding with the transition to bipedalism, a single-point mutation in our ancestors’ genes enabled a 20-fold increase in the ability to metabolise alcohol – likely a response to obtaining greater access to alcohol-laced fermenting fruits on the forest floor. In other words, our ability to get about on two legs went hand-in-hand with our proclivity to get legless.

Initial advantage aside, our propensity to partake has now become a major part of human culture, and alcohol is used and abused widely. With our drinking behaviour at least partially motivated by deeply rooted reward pathways in our brains, effective treatments for alcoholism rely on finding ways to target these circuits.

By narrowing in on the specific areas of the brain involved in the action of FGF21, the researchers have taken great strides towards its use in clinical treatments.    

They found that the hormone alters neural transmission in the nucleus accumbens, a brain region that plays a complex role in reward and addiction and suppresses alcohol consumption through a sub-population of neurons in the basolateral amygdala. Previous studies have shown that this pathway is involved in reward-seeking behaviour.

According to the authors, the next step is to investigate the specific effects of FGF21 on the activity of these neurons during alcohol consumption in animal models.

“Our results provide a mechanism for a liver-to-brain endocrine feedback loop that presumably functions to protect the liver from damage,” says co-first author Dr Kyle Flippo, also of the University of Iowa. “The central molecular and cellular effects of FGF21 represent an opportunity for future research, and the present data indicates that FGF21 analogues may provide a potential treatment option against alcohol-use disorder and related diagnosis.”

Cheers to that!

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