Compulsive drinking in rats stopped cold by flipping neurons like switches
Researchers have discovered that deactivating neurons in the brains of alcohol-dependent rats completely stopped their compulsive drinking behavior. While the usual caveats around animal research apply, the study offers hope that drug therapy might one day help people gain control over alcohol dependence.
The research from The Scripps Research Institute, a non-profit US medical research facility, built on previous studies that found that frequent alcohol use activates small numbers of neurons in the central amygdala, an effect that scientists believe is connected with learned associations. "Activated" neurons can be recognized by the proteins they express when learning happens. The Scripps researchers observed that the more a rat drinks, the more it activates a neuronal ensemble that seems to reward and reinforce further alcohol drinking, which seems to ultimately carve a pathway of sorts to addiction.
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For years, it was not known whether these activated neuronal ensembles played cause or effect roles in learned behaviors such as alcohol use.
The scientists divided rats into different groups and taught them different drinking behaviors – some were made alcohol dependent, some were taught to binge drink, others drank only sugared water, etc.
They then observed that two groups of rats significantly changed their drinking behavior after a period of abstinence – rats that were made alcohol dependent, and nondependent rats that binged on alcohol. In both groups, they found that abstinence was associated with a natural switching off the activated neuronal ensemble.
The researchers then injected the prodrug Daun02 into the rats. In the last several years, scientists have been experimenting with using Daun02 to change the state of neurons activated by learned behavior back to their usual, inactive state.
Research Associate Giordano de Guglielmo, who was the study's first author, says he was surprised to see the alcohol-dependent rats completely stop their compulsive alcohol drinking, a change that continued for as long as the rats were monitored.
"We've never seen an effect that strong that has lasted for several weeks," he says. "I wasn't sure if I believed it."
After running the experiment a second and then a third time, the researchers saw the same result – the dependent rats stopped drinking compulsively when the neurons were switched back.
"It's like they forgot they were dependent," says Assistant Professor Olivier George, who led the study. The rats also showed no sign of the physical symptoms of alcohol withdrawal, such as shakiness.
The research may also have something to tell us about the difference between compulsive alcoholism and binge drinking. In the rats that binged on alcohol but were not made alcohol dependent, targeting the alcohol-linked neurons had little impact on future drinking. When binge drinking, the rats' brains simply switched on a new group of neurons, as if the long-lasting pathway that linked alcohol and reward was not yet formed.
As further proof of concept, the rats were still motivated to drink sugar water, indicating that the scientists had successfully reached only alcohol-activated neurons, not the brain's overall reward system.
The next step will be to track the formation of alcohol-activated neuronal circuits over time and find a way to translate this research to humans. The results suggest that focusing on neuronal ensembles in the amygdala may pave the way towards better treatments of alcohol dependence.
You can read the study in The Journal of Neuroscience.