With Christmas just behind us and New Year's around the corner, many of us will be familiar with the effects of alcohol, but exactly how it works in the brain is still shrouded in mystery. Now, scientists at the Scripps Research Institute have discovered a new step in the intoxication process – by getting flies drunk.

You're probably familiar with the experience. After a cocktail or two you start to feel "buzzed," but then after a few too many brews you just get sleepy. This effect, of going from hyperactive to anaesthetic, is well known, but what isn't entirely understood is how it happens. It has long been thought that alcohol affects the nervous system directly – but the new study shows that there are other molecules in the middle of the chain.

To investigate the process the Scripps researchers got fruit flies tipsy, and observed how it affected their systems. While they may seem very different to us, fruit flies are similar enough that they're often used in these kinds of studies as simple biological and genetic models. In this case, they got drunk the same way humans would.

The flies were kept in vials and occasionally given ethanol, then their behavior was monitored with cameras. First the flies became more erratic, which the team said was equivalent to the "buzzed" stage, before the sedation kicked in. Nobody asked them afterwards, but we're sure the flies woke up with pretty bad hangovers.

So what's going on in there? On closer inspection, the team uncovered the molecular mechanism of intoxication, which seems to use the same system that anesthesia works through. It turns out that the ethanol molecules don't act on the nerve cells directly – instead, once they get there an enzyme called phospholipase D2 (PLD2) links the ethanol molecules to lipids, creating a fatty alcohol metabolite called phosphatidylethanol (PEtOH).

The PEtOH metabolite tends to build up and makes it easier for nerves to fire, which is what causes the hyperactive buzzed phase. To test out the idea, the researchers then engineered flies that were missing the gene that encodes for PLD2, and sure enough the alcohol didn't make those flies any more active.

It's not yet known whether the PEtOH metabolite also plays a role in the sedation stage, or the hangover that all too often follows on the other side of the "buzzed" coin. Future work will investigate those questions.

The team says this is the first time this pathway has been linked to alcohol sensitivity, and the discovery could lead to a few new developments. Pinpointing alcohol's molecular targets could eventually lead to drugs that cancel out intoxication or even prevent hangovers. We'll drink to that.

"The fatty alcohol is known to linger in the brain for more than 16 hours making it a likely target," says Scott Hansen, corresponding author of the study. "Also, understanding this pathway could give insight as to why people use alcohol for pain management. It has definitely led to some different ways of thinking about alcohol intoxication at the molecular level. Most scientists thought alcohol had a direct effect. Blocking the enzyme in flies shows that's not likely true."

The research was published in the Journal of Molecular Biology.

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