One of the many challenges with battling alcohol addiction and other substance abuse disorders is the risk of relapse, even after progress towards recovery, said researchers from Brown University in the US. Just a few drinks in an evening may change how memories are formed at the fundamental, molecular level, a study suggests. Even pesky fruit flies have a hankering for alcohol, and because the molecular signals involved in forming flies’ reward and avoidance memories are much the same as those in humans, they are a good model for study, they said.
The study, published in the journal Neuron, in flies found that alcohol hijacks this memory formation pathway and changes the proteins expressed in the neurons, forming cravings. Researchers uncovered the molecular signalling pathways and changes in gene expression involved in making and maintaining reward memories.
“One of the things I want to understand is why drugs of abuse can produce really rewarding memories when they’re actually neurotoxins,” said Karla Kaun, an assistant professor at Brown University. Led by Emily Petruccelli, who is now an assistant professor at Southern Illinois University in the US, the team used genetic tools to selectively turn off key genes while training the flies where to find alcohol. This enabled them to see what proteins were required for this reward behaviour.
One of the proteins responsible for the flies’ preference for alcohol is Notch, the researchers found. Notch is the first “domino” in a signalling pathway involved in embryo development, brain development and adult brain function in humans and all other animals. Molecular signalling pathways are not unlike a cascade of dominos — when the first domino falls (in this case, the biological molecule activates), it triggers more that trigger more and so on.
One of the downstream dominos in the signalling pathway affected by alcohol is a gene called dopamine-2-like receptor, which makes a protein on neurons that recognises dopamine, the “feel-good” neurotransmitter. “The dopamine-2-like receptor is known to be involved in encoding whether a memory is pleasing or aversive,” Petruccelli said. Alcohol hijacks this conserved memory pathway to form cravings. In the case of the alcohol reward pathway studied, the signalling cascade didn’t turn the dopamine receptor gene on or off, or increase or decrease the amount of protein made, Kaun said.
Instead, it had a subtler effect — it changed the version of the protein made by a single amino acid “letter” in an important area. “We don’t know what the biological consequences of that small change are, but one of the important findings from this study is that scientists need to look not only at which genes are being turned on and off, but which forms of each gene are getting turned on and off,” Kaun said. “We think these results are highly likely to translate to other forms of addiction, but nobody has investigated that,” she said.
Kaun is working with John McGeary, assistant professor at Brown, to look at DNA samples from patients with alcohol abuse disorders to see if they have genetic polymorphisms in any of the craving-related genes discovered in flies. “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 said.
“After three glasses, with an hour break in between, the pathway doesn’t return to normal after 24 hours. We think this persistence is likely what is changing the gene expression in memory circuits,” said Kaun. “Just something to keep in mind the next time you split a bottle of wine with a friend or spouse,” she said.