Genetics of Alcohol-Induced Behaviors in Drosophila

Alcohol Research & Health,  Fall, 2000  by Ulrike Heberlein

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Researchers frequently study the fruit fly Drosophila melanogaster as a model system for mammalian development and behavior. Drosophila appear resistant to alcohol's toxic effects and display many behaviors resembling intoxication (e.g., impaired motor control) when exposed to alcohol vapors. Accordingly, investigators have begun to measure alcohol sensitivity in Drosophila and to identify genetic mutations associated with increased or decreased sensitivity. One mutant called cheapdate affects a signaling system that plays a role in many regulatory processes in a cell and which involves the compound cyclic adenosine monophosphate (cAMP). Additional Drosophila mutants with altered alcohol sensitivity carry mutations in other components of the cAMP signaling system. Because the cAMP system also is affected in human alcoholics, these results indicate that studies using Drosophila as a model system may identify genetic changes relevant to human alcoholism. KEY WORDS: animal model; Drosophila melanogaster; AOD sen sitivity; cAMP; mutation; adenylate cyclase; genetic trait; animal strains

The fruit fly Drosophila melanogaster is one of the most widely used and successful genetic model systems for studying development and behavior. The usefulness of this model system is based on the fact that the genes and biochemical pathways underlying development and behavior have largely been conserved during evolution. As a result, many genes first identified in Drosophila have provided major insights into human and other vertebrate development and disease. Drosophila has a relatively sophisticated nervous system and is capable of many complex behaviors. For example, the flies can learn to associate certain events and to remember that association (Davis 1996; Dubnau and Tully 1998). Furthermore, they have sophisticated courtship behaviors (O'Dell and Kaiser 1997). Another advantage of Drosophila is that they are easy to rear and have a generation time of only approximately 2 weeks, allowing researchers to explore the heritability of certain traits or behaviors over many generations in a short period of time.

Nearly a century of intense genetic research on Drosophila has generated innumerable and sophisticated genetic tools, such as chromosomes that carry mutations resulting in visible traits (i.e., phenotypes) that can be used to map novel mutations. Subsequently, such genetic techniques as germ-line transformation [1] (Rubin and Spradling 1982), use of transposable elements as mutagens (Engels 1983), transposon tagging (Bingham et al. 1981), and targeted gene disruption (Rong and Golic 2000) have allowed researchers to conduct molecular and reverse genetic analyses. Finally, the sequence of the Drosophila genome has recently been published, and its analysis has revealed further similarities between flies and mammals (Adams et al. 2000).

Drosophila have been used extensively to investigate developmental processes and to study nervous system function. In doing so, researchers have identified many Drosophila gene products for whom the corresponding mammalian gene products (i.e., the mammalian homologs) have been implicated as potential targets for alcohol. For example, flies carry homologs of the mammalian receptors for the brain chemicals (i.e., neurotransmitters) gamma-aminobutyric acid, serotonin, dopamine, and glutamate (Littleton and Ganetzky 2000), all of which have been implicated in alcohol's actions (Tabakoff and Hoffman 1996). Consequendy, Drosophila may be a suitable animal model to study alcohol's effects on brain function and alcohol-related behaviors, such as sensitivity and tolerance to alcohol's effects. This article describes experimental designs to measure alcohol sensitivity and reviews the initial results of alcohol-related genetic research in Drosophila.

MEASURING ALCOHOL SENSITIVITY IN Drosophila

The natural habitat of Drosophila includes fermenting plants, which often contain high alcohol levels (i.e., 3 or more percent). Accordingly, fruit flies are resistant to alcohol's toxic effects and can metabolize alcohol efficiently for use as an energy source or as a starting material (i.e., substrate) for the production of lipids (Geer et al. 1993). To test whether a particular Drosophila strain is resistant to alcohol's toxic effects, researchers add alcohol to the culture medium serving as the flies' food (Geer et al. 1993). Such analyses found that Drosophila strains isolated from the wild differ in their resistance to alcohol (Kamping and van Delden 1978; David and Van Herrewege 1993). In addition, researchers found that they could quickly and substantially increase a Drosophila population's resistance to alcohol in the laboratory. For example, resistant strains were obtained by selectively breeding flies that survived exposure to high alcohol levels in their food (Chambers 1991) or were resistant to t he effects of alcohol vapor (Cohan and Hoffman 1986; Weber and Diggins 1990).

When exposed to alcohol vapor, adult Drosophila display many behaviors resembling acute intoxication in mammals, such as impaired motor control. To measure alcohol's effects on locomotion, researchers place flies into a small chamber that is covered with grid lines. Locomotor behavior is measured by counting the number of lines of the grid crossed as a function of time (Bainton et al. 2000; Singh and Heberlein in press). Within a few minutes of exposure, the flies become hyperactive and disoriented and then uncoordinated and sedated. After approximately 20 minutes of exposure, they become immobile, but recover 5 to 10 minutes after the alcohol is withdrawn (Singh and Heberlein in press).