GENE STUDIES OF `INTERNAL CLOCK' OFFER CLUES TO DRUG ADDICTION

Genes that help regulate circadian activity -- the internal rhythms that
organize the day-night cycle in insects and animals -- could play a role in
drug-induced behavior, scientists said Thursday.

Researchers said they made the link after discovering that a fruit fly's
response to cocaine exposure changed when certain so-called ``clock'' genes
were damaged or missing.

``The last thing we would expect to affect cocaine sensitivity would be
genes that regulate circadian rhythms,'' said Dr. Jonathan Pollack, program
director of cell biology and genetics at the National Institute on Drug Abuse.

But that's what Jay Hirsh and his colleagues at the University of Virginia
said they found in research reported today in the journal Science.

When the genes were working correctly, cocaine prompted several behavioral
responses in the flies, the researchers said. Over time, animals and humans
become sensitized to the effects of the same dose of cocaine, and their
behavior changes. But when the genes were missing in the flies, there was
no change in the response to cocaine over time.

This is the first time that these clock genes have been implicated in any
behavior outside of circadian rhythm, Hirsh said.

Alan Leshner, director of the National Institute on Drug Abuse, said there
are many similarities in clock genes identified in fruit flies and humans,
and that these tiny flies can be a valuable model to study the complex
biological factors at play in drug abuse.

Hirsh said the finding offers further evidence that ``addiction is probably
a biological disease.''

Normally, repeated exposure to crack cocaine leads to increasingly severe
behaviors in fruit flies, including motor responses such as grooming,
circling and mouth movements. According to Hirsh's study, four of the five
known clock genes are involved with sensitization to cocaine.

The findings came to light as the result of some disparate work being
carried out under the same lab roof, the researchers said.

Rozi Andretic, a graduate student in Hirsh's lab, first identified
circadian rhythm effects in studying fruit flies' responses to dopamine, a
brain chemical implicated in reward, motivation and drug addiction. Then
Sarah Chaney, another colleague, found the same variation in
dopamine-receptor responsiveness during cocaine sensitization.

With two different behaviors sharing a link, the group decided to look at
the clock genes.

``Ninety-nine percent of the time when you try crazy experiments they don't
work,'' Hirsh said. ``This was quite surprising.''

The researchers delivered cocaine to fruit flies by infusing the drug into
a chamber. The drug is absorbed through the fly's trachea and spiracles.

``If there is a similar system (of clock genes regulation in cocaine
craving) in vertebrates, including humans, it opens up a whole new way to
think about treating drug addiction,'' Hirsh said.