It’s Saturday morning. You wake up on a hot couch with a dry mouth and a headache. I’ll never drink again, you say, but that night, you do. New research in Neuron reveals an underlying basis for that endless cycle, showing the link between the brain’s relationship with alcohol and the pleasant memories formed under the influence.
Researchers have long known that addictive drugs like cocaine and alcohol mess with the way the brains’ reward pathways work, but this study shows just how that might happen. In the paper, published Thursday, Brown University researchers show that alcohol affects a specific cell signaling pathway in the brains of fruit flies (Drosophila melanogaster).
This pathway, called Notch, is shared by most multicellular organisms, including humans. Based on the changes the researchers observed in the fruit flies’ brains after they consumed alcohol, they suggest that alcohol’s effect on the Notch pathway could be a significant part of how animals — including humans — learn to pursue experiences that feel good.
Karla Kaun, Ph.D., an assistant professor of neuroscience at Brown University and the study’s corresponding author, says alcohol’s effect on the Notch signaling pathway contributes to the type of associative memory that can drive addiction.
“While you are drinking, you are forming memories for cues in your environment, like the feel of the glass or the bouquet of your wine, that become associated with the feeling of being intoxicated,” Kaun told Newsweek. “Our study provides genetic and biochemical evidence that fairly low doses of alcohol can activate a highly conserved cell-signaling pathway in the brain, leading to changes in expression of genes important for learning and memory.”
Alcohol’s effect on the brain’s reward and learning pathways seems to come in the form of altered gene expression in the Notch pathway. Early in life, the Notch signaling pathway plays a major role in the developing brain of an embryo. This study suggests that its significant impact on adult brains has been underestimated, though, and that could have a significant impact on how alcohol activates dopamine — a neurotransmitter frequently associated with good feelings and addiction — in the brain.
In the fruit flies who had been trained to seek out alcohol as part of the study, alcohol activated the Notch pathway. This activation had a cascade of effects down the line, which included a slight change to a gene that encodes cells’ dopamine receptors. Alcohol didn’t increase or decrease the production of dopamine receptors, nor did it activate the dopamine receptors, but it did slightly change the gene expression of the dopamine receptors that cells produced. This change, the study’s authors argue, suggests that alcohol is hijacking the way the brain’s dopamine pathways respond to pleasure and reward.
“If this works the same way in humans, one glass of wine is enough to activate the pathway, but it returns to normal within an hour,” Kaun told the Independent. But the more alcohol consumed, the longer it takes for it to return to normal. “After three glasses, with an hour break in between, the pathway doesn’t return to normal after 24 hours,” she said. “We think this persistence is likely what is changing the gene expression in memory circuits.”
Peter Giese, Ph.D., a professor of neuroscience at King’s College London who was not involved with the study, says that better understanding how alcohol — and other addictive substances — affect the brain on a microscopic level could help people who live with substance use disorders.
“[This study] suggests that drug addiction persists because memory mechanisms were hijacked by drug exposure,” Giese told the Independent. “The study not only provides a model for understanding the persistence of drug addiction, it also identifies potential pharmacological targets for treating addiction.”
Drugs of abuse, like alcohol, modulate gene expression in reward circuits and consequently alter behavior. However, the in vivo cellular mechanisms through which alcohol induces lasting transcriptional changes are unclear. We show that Drosophila Notch/Su(H) signaling and the secreted fibrinogen-related protein Scabrous in mushroom body (MB) memory circuitry are important for the enduring preference of cues associated with alcohol’s rewarding properties. Alcohol exposure affects Notch responsivity in the adult MB and alters Su(H) targeting at the dopamine-2-like receptor (Dop2R). Alcohol cue training also caused lasting changes to the MB nuclear transcriptome, including changes in the alternative splicing of Dop2R and newly implicated transcripts like Stat92E. Together, our data suggest that alcohol-induced activation of the highly conserved Notch pathway and accompanying transcriptional responses in memory circuitry contribute to addiction. Ultimately, this provides mechanistic insight into the etiology and pathophysiology of alcohol use disorder.