PRDM2: Could Targeting Addiction Enzyme Help Fight Alcoholism?

Research carried out on rats suggests that low levels of the PRDM2 enzyme could trigger self-destructive addictive behavior associated with alcohol dependency, leading people to continue to drink even though it is causing them physical and mental stress.

The studies showed that levels of this enzyme were lower in brain cells of the frontal lobe in rats that had previously been made dependent on alcohol, through being made to inhale alcohol vapor. These rats showed signs of addiction such as increased drinking of alcohol, even when it was mixed with bitter quinine, and seeking alcohol when stressed by being given electric shocks.

The researchers then found that rats which had not been exposed to alcohol vapor showed similar behavior, after being treated to prevent them from producing PRDM2. They say this shows that the enzyme is important in controlling impulsive behavior, which is difficult for people with alcohol addiction.

The obvious caveats about extrapolating animal research to humans apply.

The lead researcher said he hoped the findings would lead to medicines that can help people recover from alcoholism.

Current treatment options for alcohol dependency include talking therapies, group therapy, and medication that can help relieve cravings and prevent relapses. If you are worried about your alcohol consumption, speak to your GP to find out more about treatment options.

The Media And The Research

The study was carried out by researchers from Linköping University in Sweden, University of Miami Miller School of Medicine, National Institute on Alcohol Abuse and Alcoholism, and the University of Georgia, all in the US. It was funded by the National Institute on Alcohol Abuse and Alcoholism, the Swedish Research Council and United States Department of Defense.

The study was published in the peer-reviewed journal Molecular Psychiatry on an open-access basis so it is free to read online.

“Alcoholics are missing ‘vital chemical in their brain’ that helps control addiction,” the Daily Express reported. A story in TheTimes.co.uk says that cancer drugs “could help alcoholics give up drink.

The claims seem to be based on interviews with researchers, rather than anything in the study, which did not look at any medicines that might reverse the effects of the enzyme found to be lower in alcohol-dependent rats. The headline could raise hopes that a treatment for alcoholism is closer than it actually is.

The Daily Express fails to make it clear in its report that there is no direct evidence from this study that lack of PRDM2 is responsible for alcoholism in humans. This may be because the researchers’ press release was headed: “People with alcohol dependency lack important enzyme,” and doesn’t mention animal research until the seventh paragraph.

The study was a series of animal experiments on rats in a laboratory, including manipulation of genes responsible for producing the enzyme PRDM2. These types of studies are helpful to understand molecular pathways behind diseases like alcoholism, but they do not investigate cures.

Also, findings that apply to animals do not always translate to humans.

What Did The Research Involve?

Researchers did a series of experiments involving rats that had been exposed to breathing alcohol vapor for 14 hours a day over seven weeks. This makes them “dependent” on alcohol.

The researchers studied their behavior in a series of behavioral experiments, including seeing whether they continued to drink alcohol when it was mixed with bitter-tasting quinine.

The researchers examined brain tissue cells for production of enzymes including PRDM2 and carried out DNA sequencing to examine the function of nerve cells affected by these enzymes. They used DNA analysis and cell chemistry techniques to look at expression of PRDM2 and behavioral experiments to examine the effects of changing this enzyme expression.

They then carried out behavioral experiments on rats that had not been exposed to alcohol vapor, but which had been genetically manipulated not to produce PRDM2. The behavior of these rats was compared to rats with normal PRDM2 expression.

The researchers wanted to understand the role of different enzymes, and whether specific enzymes could be identified that affected alcohol addiction or produced behavior similar to that shown by rats dependent on alcohol.

Basic Results

Researchers found that rats with alcohol dependency, as shown by their behavior, had lower levels of the enzyme PRDM2 produced in their pre-frontal cortex cells, weeks after they had stopped receiving alcohol.

In the second series of experiments, rats engineered not to produce PRDM2 showed similar behavioral signs of alcohol dependency, despite not having been exposed to alcohol vapour. Compared to rats with normal PRDM2 production, they were likely to drink more alcohol, to drink compulsively despite the bitter quinine taste, and to drink alcohol in response to electric shock stress.

They were no more likely than normal rats to drink more sugar solution, suggesting that the effects of PRDM2 were specific to alcohol.

In their paper, the researchers said

“these observations suggest that long-term repression of PRDM2 is a key epigenetic mechanism contributing to a cluster of behaviours thought to be at the core of alcohol addiction.”

Epigenetics is the way in which genes are switched on and off, in response to external stimuli including enzymes.

They concluded that this gave a “strong rationale to explore PRDM2 or some of its downstream targets as candidate targets for novel alcoholism medications.” They say that reversing the changes seen in alcoholism where the cells stop producing PRDM2 might “promote a transition back to a pre-addicted state.”

Many Questions Remain

It seems likely that many factors influence why some people become addicted to alcohol and not simply a single enzyme. This new study shows that a change in enzyme production by brain cells of rats who have been forcibly exposed to alcohol vapor may be part of the process by which animals become dependent on alcohol.

But despite the claims in the press release, this study does not prove anything about human brain cells, enzymes or alcohol addiction.

One researcher expressed the hope that his findings would “do away with the stigmatisation of alcoholism,” by showing that it has a biochemical basis. While this is a laudable aim, the research published today does not show that the same mechanisms operational in rat brains operate in human brains.

We do not know whether PRDM2 expression is the key to developing alcohol addiction for humans, even if animal research suggests it may be.

The findings open up possibilities for future research in humans, and may even one day lead to new drugs to reverse people’s dependency on alcohol. That is still a way off, however, and much more research needs to be done before new drugs are likely to be available.

Barbier E, Johnstone AL, Khomtchouk BB, et al
Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2
Molecular Psychiatry. Published online August 30 2016

Analysis by Bazian. Edited by NHS Choices & Reliawire. Contains public sector information licensed under the Open Government Licence v3.0.

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