The movie Trainspotting, with its horrific depictions of heroin withdrawal, might someday seem as outdated as steam locomotives. Researchers have found a neurotransmitter that alleviates many of these chilling symptoms in mice. That transmitter is a new clue for developing therapies to deal with drug withdrawal in humans.
Withdrawal symptoms, such as tremors, anxiety, and a racing heart, are due to signals from the neurotransmitter norepinephrine, which arouses these "fight or flight" urges in times of stress. Opiates such as morphine sedate neurons sensitive to norepinephrine, causing them to work harder to communicate with their neighbors. When the opiate is later removed, the neurons respond to norepinephrine with excessive gusto. Another piece of the puzzle is galanin, a brain chemical that reduces norepinephrine release. It's not clear how galanin interacts with these neurons, but because neurons near the so-called locus coeruleus--a brain region that fires wildly during withdrawal--have receptors for galanin, neuroscientist Marina Picciotto of Yale University in New Haven, Connecticut, and colleagues tested whether galanin was involved in withdrawal.
Injected galanin won't get past the blood-brain barrier into the brain, so the team took advantage of an engineered molecule called galnon that imitates the neurotransmitter. After addicting mice to morphine, the researchers stopped supplying the drug and measured various withdrawal symptoms. Giving the mice galnon significantly reduced many symptoms, including how much the animals trembled and scooted backwards in their cages. Then the team genetically engineered some mice to lack the galanin gene and others to overproduce galanin in the locus coeruleus. Mice without the gene had worse withdrawal symptoms than normal mice, and the administration of galnon eased their trauma, the team reports online this week in the Proceedings of the National Academy of Sciences. Animals that made more galanin than normal had an easier time kicking the opiate habit.
Together, the results place galanin square in the middle of the withdrawal syndrome. "This is a system that protects you" from the bad effects of getting off drugs, says Picciotto. The study "shows for the first time that galanin is involved in opiate withdrawal," says Francis White of Chicago Medical School. Neuronal galanin receptors might be a good target for drugs to alleviate withdrawal symptoms, he adds.