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Translational Findings: What drunk fruit flies can tell us about alcohol addiction

A study in 2012 found that approximately 7.2% of adults in the United States have an alcohol use disorder (a term that covers any person for whom their drinking causes distress or harm). That adds up to approximately 17 million Americans! Treatments for alcoholism, such as behavioral therapies or medications, can often be ineffective in the long-term due to changes that happen in the brain as a result of addiction. Improved treatment for alcoholism therefore requires an understanding of how and why addiction forms.

Cartoon of the alcohol geneFigure 1. Genes can account for about 50% of the risk for alcoholism. Image by Addiction Blog

Research has shown that genes are responsible for about 50% of the risk for alcoholism, which can explain why alcoholism seems to run in families. Although genes alone don’t determine whether someone will become an alcoholic, they can influence a person’s sensitivity and tolerance for alcohol. Environmental or social interactions account for the remainder of the risk.  A person with increased sensitivity to the stimulant effects of alcohol (increased energy, lowered inhibition) and/or decreased sensitivity to its depressant effects (motor impairment, sedation) might have a more pleasant experience with it, making them more likely to use it regularly. On the other hand, someone who finds the taste or side effects more aversive is unlikely to become addicted. For example, some people of Asian descent carry a gene variant that causes them to metabolize alcohol too fast, and they experience symptoms like flushing, nausea, and rapid heartbeat when they drink.

Studying the genes that increase the risk of alcoholism in animal models could lead to better preventive measures in at-risk families. Alcohol addiction also causes neuronal changes in the brain that can be studied in animal models to gain a better understanding of how the brain is changing and how to reverse it. Such an understanding will inevitably lead to better treatments for alcohol addiction.

Cartoon of fly addictFigure 2. Fruit flies can serve as a model for alcohol addiction. Drawing by the Heberlein Lab

Wait, isn’t this a fruit fly blog?  How can they possibly have anything to do with alcohol addiction? You may have heard the old adage, “You catch more flies with honey than vinegar”, but in truth, fruit flies are more attracted to the smell of vinegar and fermenting fruit. Fruit flies like to feed off of the microbes (such as yeast) that are found in fermenting fruit, and they have evolved to develop a tolerance for the alcohol produced by fermentation.  In fact, researchers have found that fruit flies even prefer to feed and lay their eggs on substances with about 4-5% alcohol—the concentration of an average beer.

One of the reasons fruit flies have learned to love alcohol is because it protects them from parasitic wasps, one of their most dangerous predators. Parasitic wasps inject their eggs into fruit fly larva. Although the larva’s immune system can sometimes resist the wasp growing inside it, most often the wasp larva eats the fly from the inside out, later bursting from it as a mature wasp. But while fruit flies have evolved a resistance to alcohol, the parasitic wasps have not. When a larva has been injected by one of these predators, it will consume almost toxic levels of alcohol in an attempt to kill off the parasite within it. In fact, female fruit flies that have detected the presence of parasitic wasps nearby will seek out the most alcohol-laden foods she can find before laying her eggs, giving her offspring their greatest chance to survive the predators.

But what happens when fruit flies are exposed to levels of alcohol not normally found in their natural environments? Stronger alcohol concentrations than what they have evolved to tolerate can actually be harmful to fruit flies. Does that mean fruit flies are smart enough to avoid such concentrations?

Fruit fly drinking alcohol from a capillary tubeFigure 3. A fruit fly drinking alcohol from a capillary tube during a test for whether flies prefer food laced with alcohol. Photo by G. Shohat-Ophir, UCSD

Researchers have found that fruit flies seem to treat intoxicating levels of alcohol in the same way that some humans do—as a reward they just can’t get enough of. Fruit flies that have never been exposed to alcohol before will initially show a slight preference for it over a non-alcoholic food source, likely because it instinctively knows that alcohol signals food and safety. But with each exposure their preference for the alcohol-laden food gets stronger and stronger, despite its bitter taste and aversive side effects such as motor incoordination and sedation (sound familiar?). Eventually, these fruit flies show signs of alcoholism: they regularly drink until they’re “drunk”, build up a tolerance over time and drink more and more to compensate, and continue drinking despite increasingly dangerous side effects. They’ll keep drinking even if researchers add an aversive stimulus to the alcohol-laden food, such as a repulsive chemical or an electric shock. Fruit flies will also experience symptoms of withdrawal when the alcohol is taken away, and relapse to previous levels of drinking when it’s returned. Perhaps even more surprising is that drunk fruit flies lower their standards when looking for suitable sexual mates, and flies that have been sexually rejected will turn to alcohol to cope. These parallels between human and fruit fly drinking behavior are amazing! Scroll down to see a breakdown of the many ways fruit flies show signs of alcohol addiction.

These findings have led scientists to develop fruit flies as a model organism for alcohol addiction, because although fruit flies and humans may seem very different, many genes and cellular processes are shared between them (and in fact among most species!). Fruit flies are fantastic for genetic research, and could tell us a lot about genetic risks for alcoholism and why alcohol addiction forms. They can even be used to study the changes that occur in the brain as a result of addiction, since fruit flies exhibit many “alcoholic” behaviors.

What have fruit flies taught us so far? Fly scientists have already identified several genes that contribute to the risk of alcoholism (listed below). Despite their funny names, they could provide some very serious information about why some individuals have higher sensitivity or tolerance for alcohol and how these genes can be targeted by drugs to prevent or treat alcoholism.

  • Krasavietz – Researchers have found that fruit flies with a mutation in this gene are completely uninterested in alcohol. They showed that mutations in krasavietz reduced flies’ sensitivity to the “sedation” effect of alcohol, causing flies to quickly become sedated after intoxication, skipping all the fun stimulating side-effects.
  • Cheapdate – Flies with a mutation in this gene experienced increased sensitivity to alcohol, such that much lower doses were able to cause “intoxicated” behaviors.
  • Happyhour – A mutation in this gene causes flies to be less sensitive to the sedative effects of alcohol while maintaining normal sensitivity for the stimulating effects. A mutation in this gene in humans might increase the risk of addiction, because they will have a more pleasant experience when drinking and are more likely to drink regularly.
  • Hangover – Flies with a mutation in the hangover gene don’t develop a tolerance for alcohol. Instead of needing increased doses to achieve the same behavioral effects over time, the same dose always affects them the same way. Because increased consumption over time leads to dependence and addiction, human with a mutation in this gene may be at lower risk of alcoholism.

Researchers have also learned that a desire for alcohol in flies depends upon a certain chemical in the brain called neuropeptide F (NPF), which is very similar to neuropeptide Y (NPY) found in mammals. NPY signaling in mammals has been linked to stress, alcohol consumption, sexual motivation, and sugar satiety, among other things. In flies, reduced NPF levels led to increased alcohol intake. Sexual fulfillment was found to increase NPF levels, while sexual rejection decreased them. NPF levels could therefore indicate general “reward satisfaction”, and reduced levels causes flies to seek out something rewarding, whether it’s sex, drugs, or rock and roll. It is very likely that NPY in mammals plays the same role, which means manipulating NPY levels in humans could be a possible treatment for addiction.

Finally, fruit fly researchers have found that dopamine, a chemical that some neurons in the brain use for communication, was also involved in alcohol addiction. Dopamine has also been implicated in addiction in mammalian research because of the role it plays in the mammalian “reward system”, a brain region that gets hijacked in addiction. Further research in this area in flies may provide clues as to how dopamine signaling can lead to changes in “reward” structures.

No animal model will ever be a perfect model for alcoholism, because it is a largely a human phenomenon influenced by social, cultural, and cognitive factors. But animal models can be used to model important physical and behavioral facets of addiction, and to determine the genetic basis for withdrawal and tolerance. These findings will lead to the development of better medications for the prevention and treatment of alcoholism.

 

Fruit flies exposed to high levels of alcohol show behaviors that indicate they could be “tipsy” and/or “drunk”

Image of the booze-o-matFigure 4. The “booze-o-mat” is where fruit flies are placed in tubes with alcohol vapors to ensure consumption. Photo by the Heberlein Lab

While researchers sometimes provide fruit flies with alcohol by mixing it into their food, they can ensure consistency in their flies’ level of “drunkenness” by putting them in tubes filled with alcohol vapors so they breathe it in (Figure 4). This allows them to assess the behavioral effects of alcohol with less variation.  At lower doses, the alcohol acts as a stimulant and increases their level of activity (comparable to increased energy and lowered inhibitions in humans). This is thought to be the rewarding effects of the alcohol. But increase the dose, and flies start showing signs of motor incoordination. They actually seem to be tipsy—they fall over, bump into each other and the walls, and have difficulties climbing. Even higher doses have a sedating effect.

 

Fruit flies prefer to consume alcohol, even if they don’t need it for nutritional purposes

Cartoon of preference assayFigure 5. Fruit flies are given a choice of capillary tubes containing either regular food or alcohol-laden food. Modified from Devineni & Heberlein, 2009

When fruit flies that have never experienced alcohol before are given a choice between non-alcoholic food and alcohol-laden food, they initially show only a slight preference for it. But the next time they are given a choice, they will overwhelming choose the food laced with alcohol.  The flies will even consume enough alcohol to cause intoxication and alter its behavior as previously described. They will consume an intoxicating amount of alcohol time and time again with increased frequency, much like an alcoholic might.

 

Fruit flies will continue to consume alcohol even if they don’t like the way it tastes

Researchers have shown that while fruit flies like the way alcohol smells (it signals food and safety, after all), they don’t like the way it tastes. Nevertheless, just as humans consume alcohol despite its initially aversive bitter taste (and eventually develop a “taste for it”) fruit flies drink the alcohol anyway.  Even when researchers associate alcohol with an aversive stimulus, such as giving the flies an electric shock whenever they drink or lacing the alcohol with a repulsive chemical called quinine, they will continue to drink up. This shows that flies are willing to overcome an aversive stimulus in order to consume alcohol.

 

Fruit flies develop a tolerance to alcohol and consume more and more each time to compensate

Like humans, fruit flies build up a resistance to the effects of alcohol after repeated exposure, which is known as tolerance. Flies that have been previously exposed to alcohol show an increasing tolerance to its effects over time, and will drink more and more each time to produce the same behavioral effects.

 

Fruit flies develop a physiological dependence on alcohol and experience symptoms of withdrawal

In humans, withdrawal symptoms include dysphoria, anxiety, cognitive impairment, and seizures. Clinically, these symptoms are a sign of alcohol dependence. After flies were chronically exposed to alcohol, they showed some of these same symptoms when it was taken away.

In one study, researchers showed that flies experiencing withdrawal had a lowered threshold for seizures and had more seizures than flies that had never been exposed to alcohol.

Researchers have also shown that fruit fly larva experience cognitive impairment as a symptom of withdrawal. They found that larva who drank too much had difficulties learning at first, but after chronic exposure they adapted and were able to learn almost as well as larva that were not exposed to alcohol.  When the alcohol was taken away, their cognitive abilities were lost, and when the alcohol was returned, the larva also regained their learning abilities. These results suggest that the animals were dependent on alcohol not just physiologically, but also cognitively.

 

Fruit flies “relapse” after abstinence from alcohol

One characteristic of alcohol addiction is relapse, in which an individual will return to similar or greater consumption levels after a period of abstinence. In one study, fruit flies were chronically exposed to alcohol, followed by a period of abstinence. When the researchers provided them with alcohol again, the flies immediately began drinking at the same levels as before, without the gradual increase in preference that is seen when fruit flies are exposed for the first time.

 

Male fruit flies who have been sexually rejected turn to alcohol to cope

Researchers found that male fruit flies who had been unsuccessful in attempting to mate with a female drank more alcohol afterwards than males who were successful. They found that the desire to drink was dependent on levels of neuropeptide F (NPF), which were decreased after rejection but increased after successful mating. Alcohol consumption increased NPF levels again, suggesting that NPF acts as a “reward signal”. NPF is similar to mammalian neuropeptide Y (NPY), which has been linked to stress, anxiety, sexual motivation, alcohol consumption, and sugar satiety in mammals.

 

“Drunk” male fruit flies become hypersexual and lower their standards for suitable sexual mates

Image of courtship chainFigure 6. Drunk male fruit flies sometimes form a “courtship chain”, where male flies follow each other around trying to mate. Photo by Kyung-An Han laboratory, Penn State

Normally, male flies will only try to mate with females, but when they have been exposed to alcohol, they will not only step up their courting of females, but also even try to mate with other males. This effect got worse and worse with each exposure to alcohol. Unfortunately, just as humans have learned over the years, rates of successful mating actually decreased after getting tipsy. Even for fruit flies, getting drunk doesn’t necessarily lead to good sex.

 

 

References:

  1. Milan N. & Todd A. Schlenke (2012). Alcohol Consumption as Self-Medication against Blood-Borne Parasites in the Fruit Fly, Current Biology, 22 (6) 488-493. DOI: http://dx.doi.org/10.1016/j.cub.2012.01.045
  2. Kacsoh B.Z., N. T. Mortimer & T. A. Schlenke (2013). Fruit Flies Medicate Offspring After Seeing Parasites, Science, 339 (6122) 947-950. DOI: http://dx.doi.org/10.1126/science.1229625
  3. Shohat-Ophir G., R. Azanchi, H. Mohammed & U. Heberlein (2012). Sexual Deprivation Increases Ethanol Intake in Drosophila, Science, 335 (6074) 1351-1355. DOI: http://dx.doi.org/10.1126/science.1215932
  4. Lee H.G., Jennifer S. Dunning & Kyung-An Han (2008). Recurring Ethanol Exposure Induces Disinhibited Courtship in Drosophila, PLoS ONE, 3 (1) e1391. DOI: http://dx.doi.org/10.1371/journal.pone.0001391
  5. Robinson B., Anna Kuperman & Nigel S. Atkinson (2012). Neural Adaptation Leads to Cognitive Ethanol Dependence, Current Biology, 22 (24) 2338-2341. DOI: http://dx.doi.org/10.1016/j.cub.2012.10.038
  6. Devineni A.V. (2009). Preferential Ethanol Consumption in Drosophila Models Features of Addiction, Current Biology, 19 (24) 2126-2132. DOI: http://dx.doi.org/10.1016/j.cub.2009.10.070

General references:

1 Comment

  1. Nice job on the translational findings, Bethany!

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