Piece of puzzle unlocked in what drives alcohol addiction

By Sally Robertson, B.Sc.Mar 19 2019

Researchers at the Scripps Research Institute have made an important discovery that may help to explain the neural mechanism that drives alcohol consumption in cases of addiction.

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In a rat model of alcohol-dependency, the team found they could reverse the urge to drink by inactivating a specific subset of nerve cells called corticotropin-releasing factor (CRF) neurons. The technique, which used lasers to inactivate the neurons, also reduced physical symptoms of withdrawal in the animals.

Senior author of the study, Olivier George, says that although the laser treatment is far from ready for clinical use in humans, it could pave the way for new drug or gene therapies to treat alcohol addiction: "We need compounds that are specific to this neuronal circuitry," he says.

Previous work by the Scripps researchers had shown that the transition from casual drinking to alcohol dependence occurs alongside fundamental changes in neuronal signaling.

In 2016, George and colleagues found a possible source of the brain cells that drive the desire to drink in a rat model of alcohol addiction. They identified a group or “ensemble” of connected cells in an area of the brain called the central nucleus of the amygdala (CeA). Although mapping of this brain region was a major step forwards, they still needed to characterize the neurons involved in the ensemble.

As reported in the journal Nature Communications, the group has now found that 80% of the ensemble is made up of CRF neurons, which led them to investigate whether these cells are the drivers of alcohol cravings.

To study the neurons, the researchers used optogenetics – a technique that uses light to control the activity of genetically-defined cells. They surgically implanted rats with optic fibers that would mean they could shine light onto the CRF neurons to immediately inactivate them.

First, the team established a baseline for how much alcohol rats could drink without becoming alcohol-addicted, which began with the equivalent of a glass of wine or beer for a human. The amount of alcohol consumption was then increased over several months until the rats became dependent.

The researchers then cut-off the alcohol supply, which induced withdrawal symptoms that were only alleviated when alcohol was re-introduced. At this point, the CeA neuronal ensemble was activated and the rats drank more than at any point previously.

Next, the team used lasers to shine light on the CRF neurons and inactivate them. The animals immediately reverted to their pre-dependent alcohol consumption and there was also a reduction in physical withdrawal symptoms such as shaking and abnormal gait. The effect was also reversible: when the lasers were turned off, the alcohol-dependent behaviour returned.

"In this multidisciplinary study, we were able to characterize, target and manipulate a critical subset of neurons responsible for excessive drinking," says first author Giordano de Guglielmo.

Establishing the neuronal wiring that drives a specific, destructive behavior is a huge scientific breakthrough. George says the next step is to translate the work to humans by finding a way to specifically inhibit the CRF neurons. This may involve using a novel or repurposed compound that could be identified using high-throughput screening of large libraries of compounds.