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Done drinking? Try the GDNF solution!
12 JUNE 2008

Molecule moderates heavy-drinking rats
Researchers at the University of California at San Francisco have found that one dose of natural brain chemical can dampen a Plant with large, glossy green leaves bears small, smooth orange and green podsrat's desire to drown its troubles in alcohol. Ten minutes after injecting a tiny jolt of GDNF (glial-derived neurotrophic factor, if you must know) into the brain, guzzling rats turn into social drinking rats, if not ax-wielding Carrie Nations.

Ibogaine, from the African shrub Tabernanthe iboga, is a hallucinogen that also combats drug addiction.

Which is not to belittle the enormous toll of our most dangerous drug. Almost 10 million Americans abuse alcohol, based on a 2002 survey. Almost 40 percent of fatal traffic crashes were due to the drug in 2004.

The GDNF story begins with ibogaine, a compound derived from a West African shrub. "In the 1960s, ibogaine made its way to the illegal drug market in the United States because it is hallucinogenic, which is probably why it is also used for religious rituals in West Africa," says Dorit Ron, an associate professor of neurology at UCSF.

People who took the drug to get high "reported that ... it stopped all their desire to use other drugs," she adds. Since then, rodent studies have showed that ibogaine has "very desirable properties against various drug of abuse" that operate through a reward pathway based on the brain chemical dopamine.

Although ibogaine is used in some countries to treat addiction to heroin, cocaine and alcohol, "It is a dirty drug, it has nasty side effects," Ron adds, "hallucinations, tremors, heart arrhythmia, so it is not used in the United States."

Graphic shows flattened surface of receptor in pink, ready for uptake of  dopamine, shaped like blue shards
Dopamine is a "feel-good" neurotransmitter that conveys a reward for many behaviors, including taking drugs. Dopamine can bind to dopamine receptors on a neighboring neuron, transmitting a positive message down the neural telephone. National Institute on Drug Abuse

Making a mechanism
Even so, ibogaine is providing clues to combating drug abuse, Ron says. In 2005 and 2006, her lab showed that ibogaine seems to dampen a rat's urge to drink by raising the level of GDNF, a brain chemical that contributes to the growth of kidneys and the spinal cord.

In a study reported last week, Ron and colleagues found that one dose of GDNF, if injected into a region of the brain that is a critical enabler of addictive behavior, can attenuate the urge to drink in rats. (That region, called the ventral tegmental area, will not be on the test...)

The researchers plopped a rat into a cage equipped with a lever that supplied a drink of alcohol and water when pressed three times. To assess the rat's motivation to drink, they simply counted lever presses. ""The solutions are bitter, not something that any human would want to drink, unless they were hard core alcoholics. However, the rats are motivated to drink it because it is rewarding just like alcoholic beverages," says Ron, who is principal investigator at the UCSF's Ernest Gallo Research Center. The center is funded, appropriately enough, by a founder of Graph shows one white bar and three gray bars, descending from left to rightE&J Gallo, a giant wine maker that has for decades produced, among other products, a high-alcohol "bum wine" called Thunderbird that has long been a centerpiece on skid rows across the nation.

In one experiment, rats were offered at 10 percent solution of alcohol. Those that got the strongest dose of GDNF pressed the lever half as much as control rats, who got no GDNF injections.

Within 10 minutes, GDNF reduced the motivation to press a lever and obtain a slurp of 10 percent alcohol. Higher doses are more effective, indicating that GDNF did cause the change in behavior. Graph adapted from Carnicella et al...

A second experiment tested the effect of GDNF in a model that resembles excessive alcohol consumption. The rats drank a solution of 20 percent alcohol (which resembles the behavior of heavy drinkers) for a long period. Again, the GDNF-treated rats showed a massive reduction in drinking. Overall, Ron says, "The action of GDNF is rapid, but sustained, it lasts for quite a long time."

Graph shows one white bar above number 0 and two gray bars, above 5 and 10 respectively, descending from left to rightA single shot of GDNF affected the urge to drink 20 percent alcohol for at least three hours. Graph adapted from Carnicella et al...

Relapse city?
A third experiment concerned relapse, a common problem in many addictions. "Relapse can be evoked by one drink of alcohol," Ron says. "You think you are okay, you haven't been drinking for several years, you get one, and you relapse."

After training another group of rats to get booze by pressing a lever, the researchers shut off the alcohol and the rats, as miserable as a dead-broke wino, eventually gave up, returning to a lackadaisical level of lever-pressing that was due to boredom or to curiosity, but not any expectation of a boozy reward.

Suddenly, after two weeks, lever-presses again began to produce a slurp of booze. The control (untreated) rats immediately fell off the wagon and resumed a rapid rate of lever-pressing, but the rats that had received one shot of GDNF were much less diligent about pressing the lever, indicating less desire to drink.

Didn't do
Just as important was what GDNF did not do. Drugs that inhibit the urge to drink affect the dopamine pathway, which also rewards benign actions like eating sweets. After one dose of a natural brain chemical, rats were much less eager to drink alcoholThese drugs, including naltrexone, "reduce the pleasure system, and people don't feel good, so they don't take them," Ron says.

Treating rats with GDNF, however, did not affect their sweet tooth, as measured by sucrose consumption.

Ron sees many similarities between the regulation of drug intake in rats and people: "The genes are very similar, we know that alcohol and other drugs of abuse work through the same reward pathway, in the same brain region." Nevertheless, a rat study does not prove what will happen in people -- even the most rat-like ones.

Yet Ron seems to be holding an ace in the hole. "We have a follow-up study that suggests this may be used [in people] sooner rather than later, but we are not thinking of squirting GDNF into the brains of alcoholics."

- David Tenenbaum

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Prize-Winning Brains
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• GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse, Sebastien Carnicella et al, cgi doi 10.1073 pnas.0711755105, June 10, 2008.

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