The Crux of a Craving?

Chronic cocaine users have a hard time just saying no, and scientists working with addicted rats may have found out why. Even after the animals no longer regularly get the drug, their brains are still buzzing with a protein that seems to maintain the craving. If the results hold up in humans, the protein might provide a novel therapeutic target to fight drug relapse.

In cocaine addicts, the prefrontal cortex, a region important for behavioral control, responds rapidly to thoughts of coke. Other stimuli, like thoughts of food or sex, become less important. Researchers thought this shift in priorities likely involves changes in neurons that use dopamine, the neurotransmitter of so-called reward pathways. To investigate, neuroscientist Peter Kalivas at the Medical University of South Carolina and colleagues tracked the activity of a key protein known as AGS3. When dopamine binds to receptors on the surface of a neuron, AGS3 helps relay the signal to the rest of the cell.The team injected rats with cocaine for a week--enough to get them addicted--and then cut off their supply of the drug. For up to 8 weeks afterward, levels of AGS3 were 30% to 100% higher in the addicted rats' brains than in those of nonaddicted rats. The protein was concentrated in two regions thought to be involved in addiction: the prefrontal cortex and the nucleus accumbens. To determine whether the elevated amounts of AGS3 ups the odds of relapse, the researchers injected nonaddicted rats with AGS3. When teased with a touch of cocaine, these rats suddenly began acting like addicts, frantically pressing a bar that dispenses the drug.On the other hand, blocking AGS3 seemed to cure addicted rats of their cravings. When proffered the cocaine tease, these rats didn't go nuts for more, just as if they had never sniffed cocaine. Taken together, the results suggest that high levels of AGS3 in cocaine addicts maintain craving for the drug during withdrawal, the team reports in the 22 April issue of Neuron. Kalivas adds that his laboratory is looking at whether AGS3 also plays a role in addictions to other drugs, such as alcohol.By showing that AGS3 stays abnormally high for months in the part of the brain needed for voluntary control over behavior, the study may explain why it's so hard to kick the habit, says behavioral neuroscientist Ann Kelley of the University of Wisconsin Medical School in Madison. Drugs that clear out the protein may prove to be very helpful, she says, but they're likely to be many years off.Related site
Cocaine information and resources from the National Institute on Drug Abuse