The Fruit Fly: A Model Organism to Study the Genetics of Alcohol Abuse and Addiction?

It is interesting to compare the observations described by Moore et al. 1998xMoore, M.S, DeZazzo, J, Luk, A.Y, Tully, T, Singh, C.M, and Heberlein, U. Cell. 1998; 93: 997–1007Abstract | Full Text | Full Text PDF | PubMed | Scopus (307)See all ReferencesMoore et al. 1998 with our current knowledge of cAMP pathways and addiction. It is striking that all the genes thought to be required for the modulatory up-regulation of the cAMP pathway, amnesiac (PACAP), rutabaga (AC), and DCO (PKA-C) were previously implicated in learning and memory. The proteins encoded by rutabaga (AC) and DCO (PKA-C) are known to be expressed at significantly higher levels in the mushroom bodies of the flies than in other brain cells. These organized neuronal structures are the centers for olfactory learning and memory (Davis 1996xDavis, R.L. Physiol. Rev. 1996; 76: 299–317PubMedSee all ReferencesDavis 1996) but do not seem to be the locus of increased sensitivity to ethanol. Indeed, flies that lack mushroom bodies do not display an increased sensitivity to ethanol (Moore et al. 1998xMoore, M.S, DeZazzo, J, Luk, A.Y, Tully, T, Singh, C.M, and Heberlein, U. Cell. 1998; 93: 997–1007Abstract | Full Text | Full Text PDF | PubMed | Scopus (307)See all ReferencesMoore et al. 1998). Hence, other neurons or cells of the fly are probably involved in the acute response to ethanol. Since many of the genes involved in cAMP regulation are expressed in many tissues, those that may be expressed in specific cells of the nervous system, e.g., amnesiac (PACAP), may provide very useful information about the site of action of the cAMP pathway.A PACAP-like neuropeptide has been shown to be involved in synaptic transmission in Drosophila. This peptide coactivates the Ras/Raf and rutabaga (AC) pathways, suggesting that upon activation of a G protein–coupled receptor, two pathways are activated. The pathways then converge to modulate K+ channel activity, leading to an efflux of K+ (Zhong 1995xZhong, Y. Nature. 1995; 375: 588–592Crossref | PubMedSee all ReferencesZhong 1995). Since amnesiac encodes a PACAP-like peptide, it will be of interest to determine if the gene product of amnesiac activates these two pathways, and if the Ras/Raf pathway plays a role in ethanol sensitivity as well. If amnesiac (PACAP) is indeed involved in regulating K+ efflux in specific neuronal populations, it may play a key neuromodulatory role.The cAMP pathway has been implicated in forms of addiction other than alcoholism. Chronic administration of opiates leads to up-regulation in the cAMP pathway in cultured cells, whereas acute exposure inhibits the cAMP pathway (Nestler and Aghajanian 1997xNestler, E.J and Aghajanian, G.K. Science. 1997; 278: 58–63Crossref | PubMed | Scopus (975)See all ReferencesNestler and Aghajanian 1997). Hence, the same pathway seems to respond differently to chronic administration of opiates and alcohol. McClung and Hirsh 1998xMcClung, C and Hirsh, J. Curr. Biol. 1998; 8: 109–112Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesMcClung and Hirsh 1998 have recently initiated studies to determine the effects of cocaine in flies. Cocaine administered in volatile form induces multiple responses that resemble the behaviors seen in rodents, including sensitization. These authors also propose to initiate genetic screens to isolate mutants with altered responses to cocaine. It will be interesting to see how all these fly mutants respond to different addictive drugs, and if common pathways are involved.While the study by Moore et al. 1998xMoore, M.S, DeZazzo, J, Luk, A.Y, Tully, T, Singh, C.M, and Heberlein, U. Cell. 1998; 93: 997–1007Abstract | Full Text | Full Text PDF | PubMed | Scopus (307)See all ReferencesMoore et al. 1998 focuses on the acute responses to ethanol, it is likely that chronic exposure to lower levels of ethanol, or intermittent exposure to acute doses of ethanol, induces pathophysiological changes that can also be measured in flies. In vertebrates, chronic exposure of cells to ethanol causes the opposite effect as the acute response: i.e., a down-regulation of the cAMP pathway. If so, the same genes that affect the cAMP pathway in the acute response may play an important role in chronic responses, and the inability to modulate the cAMP levels in the mutants may affect various behaviors. For example, dunce (PDE) females have been shown to cause sexual hyperactivity in males, and dunce (PDE) flies exhibit reduced longevity in both sexes (Bellen and Kiger 1987xBellen, H.J and Kiger, J.A Jr. Genetics. 1987; 115: 153–160PubMedSee all ReferencesBellen and Kiger 1987). In addition, one would predict that dunce (PDE) flies would be more resistant than other mutants to chronic exposure to ethanol as their cAMP levels may only be partially down-regulated. It will thus be of interest to compare some of the behavioral phenotypes displayed by the cAMP mutants upon chronic exposure to ethanol.Finally, this study provides an important glimpse at the potential genetic factors that may be implicated in alcoholism. Previous studies with wild-type fruit flies had shown that using the inebriometer, one can select for flies that are much more resistant to ethanol knock-down, e.g., from a mean elution time (MET) of 12.6 min in generation 1, to a MET of 34.6 min in the 20th generation, an increase of a factor of 2.7 (Cohan and Hoffmann 1986xCohan, F.M and Hoffmann, A.A. Genetics. 1986; 114: 145–163PubMedSee all ReferencesCohan and Hoffmann 1986). Hence, it is likely that multiple genetic components underlie the sensitivity to ethanol. Similarly, humans are known to have very different abilities to resist ethanol, and as pointed out earlier, those who are more resistant are much more likely to become alcoholics (Schuckit 1994xSchuckit, M.A. Am. J. Psychiarty. 1994; 151: 184–189PubMedSee all ReferencesSchuckit 1994). In addition, alcoholism clearly has a hereditary component, but despite compelling evidence that genetic factors are involved in alcoholism, no genes responsible for this disease have been identified. Given the data presented by Moore et al. 1998xMoore, M.S, DeZazzo, J, Luk, A.Y, Tully, T, Singh, C.M, and Heberlein, U. Cell. 1998; 93: 997–1007Abstract | Full Text | Full Text PDF | PubMed | Scopus (307)See all ReferencesMoore et al. 1998, it will be interesting to sequence the genes encoding some of the ACs, PKAs, and PDEs in selected flies and specific humans, and to determine if polymorphisms exist that may correlate with the predisposition to become more resistant to ethanol intoxication or alcoholism.In summary, the most exciting feature of the study by Moore et al. 1998xMoore, M.S, DeZazzo, J, Luk, A.Y, Tully, T, Singh, C.M, and Heberlein, U. Cell. 1998; 93: 997–1007Abstract | Full Text | Full Text PDF | PubMed | Scopus (307)See all ReferencesMoore et al. 1998 is that it lays the foundation for a genetic approach to dissect the acute, and possibly the chronic, effects of ethanol in vivo. The fruit fly may pave the way for an in-depth study of many of the genes involved in acute and chronic effects of ethanol, as well as other drugs like cocaine (McClung and Hirsh 1998xMcClung, C and Hirsh, J. Curr. Biol. 1998; 8: 109–112Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesMcClung and Hirsh 1998). These studies are therefore likely to foster many other studies in other model organisms that are amenable to genetic analysis as well as studies with cultured cells. These novel data should increase our understanding of the molecular mechanisms causing drug abuse and addiction in the near future.