As New Year’s Eve nears, many will anticipate the familiar buzz from enjoying a favorite cocktail or wine. Interestingly, the phenomenon of alcohol intoxication isn’t exclusive to humans. A recent study from Scripps Research has shed light on the intricate process of how alcohol affects living beings, revealing that even flies can get drunk, and importantly, how it happens at a molecular level.
Just like humans, fruit flies exhibit signs of intoxication when exposed to alcohol. According to Scott Hansen, PhD, an associate professor in the Department of Molecular Medicine at Scripps Research, flies serve as an excellent model for studying genetic activity due to their simpler genome, which is easier to manipulate compared to more complex animals. “They act just like people,” Hansen explains. “They start losing coordination. They literally get drunk.” This observable similarity in drunken behavior makes flies invaluable for understanding the effects of alcohol.
The research, published in the Journal of Molecular Biology, delves into the initial stages of alcohol intoxication. Scientists have discovered that alcohol, acting much like an anesthetic, first induces a hyper “buzzed” state before leading to sedation. The study pinpoints a crucial intermediary step in this process, one that was previously unknown. Focusing on an enzyme found on nerve cell membranes called phospholipase D2 (PLD2), the researchers traced alcohol’s effects. They observed that this enzyme facilitates the binding of ethanol molecules to lipids (fats) within the nerve cell membrane.
This binding action of PLD2 sets off a chain of reactions within the cell, acting as a catalyst. It results in the creation of a fatty alcohol metabolite known as phosphatidylethanol (PEtOH). As PEtOH accumulates, it causes nerve cells to become more easily excitable, leading to heightened activity in the flies. “With hyperactivity you see the flies run around more, and this is what we equate to being buzzed,” Hansen notes. To confirm this pathway, the scientists genetically modified flies to eliminate the gene responsible for producing the enzyme that creates PEtOH. Remarkably, these flies did not exhibit increased activity when exposed to alcohol, confirming the essential role of PLD2 and PEtOH in the initial buzz phase of intoxication.
This discovery marks the first identification of this specific pathway as a determinant of alcohol sensitivity. While the study clarifies the initial “buzz” stage, further research is underway to understand if PEtOH is also involved in the subsequent sedation phase and potentially the hangover effects experienced later. Understanding the precise molecular mechanisms of alcohol intoxication opens doors for developing potential antidotes for intoxication or even hangover remedies, according to Hansen.
The persistence of this fatty alcohol metabolite, PEtOH, in the brain for over 16 hours makes it a promising target for future interventions. Furthermore, unraveling this pathway could provide insights into why some individuals use alcohol for pain management. Hansen emphasizes the significance of this finding, stating, “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.” This research highlights a previously unknown, indirect mechanism of alcohol action, mediated by the PLD2 enzyme and the PEtOH metabolite, offering a fresh perspective on alcohol intoxication and its effects on the nervous system.
