Researchers at the University of California, San Francisco (UCSF) and New York University have discovered a gene mutation in fruit flies that alters sensitivity to crack cocaine and also regulates their internal body clock. The findings, reported in the December issue of Public Library of Science (PLoS) Biology, may have implications for understanding innate differences in sensitivity to cocaine in humans, potentially providing targets for development of drugs to treat or prevent addiction.

Headed by UCSF's Ulrike Heberlein, the research team discovered a mutation of the Drosophila LIM-only (Lmo) gene. Normal fruit flies increase their activity when exposed to low doses of crack cocaine over a one-minute period. At medium levels, fruit flies exhibit frenzied, jerky motions. At high doses, the flies become immobile. However, flies with the Lmo gene mutated were much more sensitive to crack cocaine and became immobile at much lower levels than normal fruit flies.

Heberlein's group also showed that Lmo is normally produced in the pacemaker neurons that control 24-hour--or circadian--rhythms of sleep/wake cycles in flies. Comprising about 10 cells per hemisphere, these neurons provide the fly with an internal clock, driving circadian rhythms of behavior even in the absence of light. While Lmo is found throughout the body, it is enriched in the brain. By expressing normal Lmo in over-sensitive mutants, the researchers discovered that Lmo's cocaine-related effects were localized to the circadian pacemaker neurons.

The researchers then asked if the Lmo mutations also affect the normal rhythms in circadian behavior. Subsequently, NYU's Justin Blau, an assistant professor of biology, found that many Lmo mutant flies no longer had clear rhythms of sleep/wake cycles. Together, the two sets of findings showed that the new gene modulates sensitivity to cocaine within the cells of the fruit fly's internal clock.

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Contact: James Devitt
james.devitt@nyu.edu
212-998-6808
New York University
22-Nov-2004

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