Protein that plays critical role in cocaine craving identified

Scientists have identified a protein that plays a critical role in the craving for cocaine and believe it could become an important target for treatments to prevent drug relapse.
Indiana University neuroscientists found that GLT1, a protein that clears glutamate from the brain, plays a critical role in the craving for cocaine that develops after only several days of cocaine use.
The study, published in The Journal of Neuroscience, showed that when rats taking large doses of cocaine are withdrawn from the drug, the production of GLT1 in the nucleus accumbens, a region of the brain implicated in motivation, begins to decrease.

However, if the rats receive ceftriaxone, an antibiotic used to treat meningitis, GLT1 production increases during the withdrawal period and decreases cocaine craving.
George Rebec, professor in the Department of Psychological and Brain Sciences, said drug craving depends on the release of glutamate, a neurotransmitter involved in motivated behaviour.
Glutamate is released in response to the cues associated with drug taking, so when addicts are exposed to these cues, their drug craving increases even if they have been away from the drug for some time.

The same behaviour can be modelled in rats. When rats, who self-administer cocaine by pressing a lever that delivers the cocaine into their bodies, are withdrawn from the drug for several weeks, their craving returns if they are exposed to the cues that accompanied drug delivery in the past; in this case, a tone and light.

But if the rats are treated with ceftriaxone during withdrawal, they no longer seek cocaine when the cues are presented.
Ceftriaxone appears to block craving by reversing the decrease in GLT1 caused by repeated exposure to cocaine.
In fact, ceftriaxone increases GLT1, which allows glutamate to be cleared quickly from the brain.
The researchers localised this effect to the nucleus accumbens by showing that if GLT1 was blocked in this brain region even after ceftriaxone treatment, the rats would relapse.
While an earlier paper of Rebec's group showed the effects of ceftriaxone on cocaine craving, the new paper was the first to localise the effects of ceftriaxone to the nucleus accumbens and was the first to show that ceftriaxone works after long withdrawal periods.

"The idea is that increasing GLT1 will prevent relapse. If we block GLT1, the ceftriaxone should not work. We now have good evidence that ceftriaxone is acting on GLT1 and that the nucleus accumbens is the critical site," Rebec said.