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Vol. LXVI, No. 14
July 4, 2014
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Fruit Fly Walks into a Lab
Heberlein Reviews Fly Model in Alcohol Research

On the front page...

Dr. Ulrike Heberlein
Dr. Ulrike Heberlein

Did you hear about the fruit flies that got so drunk they couldn’t climb the walls?

“That’s Drosophila melanogaster,” said Dr. Ulrike Heberlein in her recent Wednesday Afternoon Lecture “Drosophila as a Model for Alcoholism: An Interplay of Nature and Nurture.” Heberlein, who spoke in Masur Auditorium, is scientific director and lab head at the Howard Hughes Medical Institute, Janelia Farm Research Campus.

Human studies are difficult and costly, but widely used rodent models have provided important insights into the mechanisms underlying the effects of alcohol. Why use fruit flies to study alcohol?

Continued...

Drosophila was the model we decided to use about 20 years ago to try to understand both the genetics and the physiology related to alcohol,” Heberlein said, “and at the time it was a pretty crazy idea. But we took on the challenge.”

She reminded the audience that “flies are the premier model organism for genetics due to the work of T.H. Morgan and colleagues at Columbia in the early 1900s. Much of what we know about genetics comes from work on Drosophila. Flies are easy, fairly inexpensive to raise in the laboratory in large numbers…and the generation time is short.”

For decades scientists have used Drosophila to study genetics and illnesses such as Parkinson’s, Huntington’s and Alzheimer’s disease.

You have probably met this red-eyed critter with its loopy flight pattern and its thing for ripe fruit. In the presence of yeast, sugars are fermented to produce ethanol, the drinkable alcohol, for millennia one of the most widely used and abused drugs in the world. The fruit fly is not immune to its charms.

“Drosophila was the model we decided to use about 20 years ago to try to understand both the genetics and the physiology related to alcohol,” Heberlein said, “and at the time it was a pretty crazy idea. But we took on the challenge.”

Drosophila was the model we decided to use about 20 years ago to try to understand both the genetics and the physiology related to alcohol,” Heberlein said, “and at the time it was a pretty crazy idea. But we took on the challenge.”

Photos: Bill Branson

We and Drosophila have more in common than a taste for tangy peaches. About 75 percent of known human disease genes have a recognizable match in the fruit fly genome, first sequenced in 2000. Most molecular, cellular and neurobiological processes are conserved—carried over—between the fly and mammals.

Interestingly, the fruit fly has a “fat body,” thought to be homologous to the human liver (similar in construction and evolutionary origin) where most of the ethanol is metabolized.

In humans, alcohol use disorders are a big problem, Heberlein said, affecting more than 17 million Americans, around 8.5 percent of people in the U.S. “And not just as individuals; there are many, many innocent people, bystanders, killed or maimed or injured as a consequence of some people drinking too much.”

It is also an expensive problem. The most recent estimated annual cost of alcoholism to the U.S. economy is “about $200 billion,” she said.

And it’s tricky to study. “Alcohol is a very nonspecific drug,” she continued. Other drugs of abuse have a specific receptor in the brain and act in micro concentrations. Yet alcohol has multiple targets in the brain and acts in fairly high concentrations.

“The challenge has been to figure out how [alcohol] leads to changes in the brain that ultimately lead to addiction.”

As in all addictions and many other diseases, the genetics are complex: “Genetics contributes approximately 50 percent of the risk factors; the other 50 percent comes from environmental interactions that are equally complex,” Heberlein noted. “Alcoholism is likely a very old problem; when the first primates walked the earth they consumed fruits containing alcohol.”

During acute ethanol exposure, how did the flies behave?

  • Adult flies showed locomotor hyperactivity followed by motor incoordination and sedation. They flew around in a tizzy until they got too sloppy to climb.

  • In adult flies, repeated ethanol exposure induced either tolerance or sensitization. Tolerance means an increasing dose is required to get the same effect; in sensitization, a lower dose has an increased effect. Both effects are evidence of worsening disease.

  • Chronic exposure induced alcohol dependence, withdrawal symptoms and relapse-like behavior.

  • Flies also exhibited more complex addiction-like behavior, including a lasting attraction for a cue that predicts ethanol intoxication and a preference for consuming ethanol-containing food even if it’s unpalatable.

Heberlein also described an experiment to distinguish genetic from environmental factors that contribute to alcohol-induced behaviors. Her team focused on neuropeptide F (NPF) signaling; NPF is the Drosophila homologue of neuropeptide Y in humans. (Neuropeptides are molecules that transmit information in brain tissue.)

Her team compared brains of males rejected by females to males who had mated.

  • Rejected males had low levels of NPF and high ethanol preference.

  • Mated males had high levels of NPF and low ethanol preference.

She saw a causal relationship.

“We know rejection [of males by females], through some mechanism that we would like to get our hands on, reduces the level of NPF and that leads to increase in ethanol consumption. Mating, on the other hand, increases the level of NPF and this reduces ethanol preference and consumption.

“So this is an example, I think, where we now have encountered a mediator between a social experience and a drinking behavior; where this mediator is sensitive to the social experience and it’s causally related to the changes in behavior that occur after the social experience.”

Here’s the validity of using Drosophila as a model: “You can use the power of genetics in flies to do unbiased screens,” she said, “end up with a gene that you have no clue what it does and find a potential pre-clinical rat model for alcoholism with an FDA-approved drug. We’re starting to understand the molecular mechanism through which experiences in the environment affect ethanol consumption.”

The videocast is archived at http://videocast.nih.gov/summary.asp?Live=14146&bhcp=1.


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