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What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?
For a drug like ethanol, which exhibits low potency and speci-ficity, and modifies complex behaviors, the precise roles of its many direct and indirect targets are difficult to define. Increasingly, ethanol researchers are employing genetic approaches to complement standard neurobiologic experi-mentation. Three experimental animal systems for which pow-erful genetic techniques exist—mice, flies, and worms—have yielded intriguing results.
Strains of mice with abnormal sensitivity to ethanol were identified many years ago by breeding and selection programs. Using sophisticated genetic mapping and sequencing tech-niques, researchers have made progress in identifying the genes that confer these traits. A more targeted approach is the use of transgenic mice to test hypotheses about specific genes. For example, after earlier experiments suggested a link between brain neuropeptide Y (NPY) and ethanol, researchers used two transgenic mouse models to further investigate the link. They found that a strain of mice that lacks the gene for NPY—NPY knockout mice—consume more ethanol than control mice and are less sensitive to ethanol’s sedative effects. As would be expected if increased concentrations of NPY in the brain make mice more sensitive to ethanol, a strain of mice that overex-presses NPY drinks less alcohol than the controls even though their total consumption of food and liquid is normal. Work with other transgenic knockout mice supports the central role in etha-nol responses of signaling molecules that have long been believed to be involved (eg, GABAA, glutamate, dopamine, opioid, and serotonin receptors) and has helped build the case for newer candidates such as NPY and corticotropin-releasing hormone, cannabinoid receptors, ion channels, and protein kinase C.
It is easy to imagine mice having measurable behavioral responses to alcohol, but drunken worms and fruit flies are harder to imagine. Actually, both invertebrates respond to etha-nol in ways that parallel mammalian responses. Drosophila mela-nogaster fruit flies exposed to ethanol vapor show increasedlocomotion at low concentrations but at higher concentrations, become poorly coordinated, sedated, and finally immobile. These behaviors can be monitored by sophisticated laser or video tracking methods or with an ingenious “chromatography” column that separates relatively insensitive flies from inebriated flies, which drop to the bottom of the column. The worm Caenorhabditis elegans similarly exhibits increased locomotion atlow ethanol concentrations and, at higher concentrations, reduced locomotion, sedation, and—something that can be turned into an effective screen for mutant worms that are resis-tant to ethanol—impaired egg laying. The advantage of using flies and worms as genetic models for ethanol research is their relatively simple neuroanatomy, well-established techniques for genetic manipulation, an extensive library of well-characterized mutants, and completely or nearly completely solved genetic codes. Already, much information has accumulated about candi-date proteins involved with the effects of ethanol in flies. In an elegant study on C elegans, researchers found evidence that a calcium-activated, voltage-gated BK potassium channel is a direct target of ethanol. This channel, which is activated by etha-nol, has close homologs in flies and vertebrates, and evidence is accumulating that ethanol has similar effects in these homologs. Genetic experiments in these model systems should provide information that will help narrow and focus research into the complex and important effects of ethanol in humans.
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