Researchers isolate target for therapies to treat cocaine addiction

A new study by researchers at Massachusetts General Hospital suggests a newly identified neural target is key in contributing to cocaine cravings following a period of abstinence.
A litany of genes and neural receptors have been implicated in the science of addiction. But in studying the behaviors of lab mice, scientists found that by simply changing a single amino acid in a subunit of a receptor protein that influences cravings -- a protein known as the AMPA receptor -- they could reduce cravings and the likelihood of a drug relapse.
"The critical role of the AMPA receptor in cocaine addiction is clear," Dr. Ghazaleh Sadri-Vakili, director of the NeuroEpigenetics Laboratory at Mass General and senior author of the new study, explained in a press release. "We have known that activation of the AMPA receptor in the nucleus accumbens -- an area of the brain important for drug addiction -- promotes the resumption of cocaine seeking in animal models, and this study identifies an increased contribution of calcium-permeable AMPA receptors to this process."
In most human brains, AMPA receptors are not calcium-permeable. But chronic cocaine use disrupts glutamate editing in the nucleus accumbens. Glutamate editing determines whether the subunits of AMPA receptors, particular subunit GluA2, are calcium-permeable or not.
In the latest study, mice were given cocaine for 21 days, then were withheld from the drug for 10 days. After their cocaine binge, the mice were found to have fewer edited GluA2 subunits than drug-free animals, as well as less of the enzyme responsible for editing the subunits.
The changes seem to have isolated one of the major neural components in the processes of addiction, self control and relapse. Researchers predicted that by reversing the damage to the AMPA receptors, they could mitigate the chance of relapse.
After the ten days of abstinence, researchers gave half the mice a GluA2-editing enzyme called ADAR2. The over-expression of this enzyme upped the presence of edited GluA2 in the mice's brains and reduced the resumption of cocaine.
"Our findings support the novel hypothesis that calcium-permeable AMPA receptors containing unedited GluA2 subunits contribute to cocaine seeking and that repairing the deficient editing of GluA2, possibly by regulation of ADAR2 expression, could be a treatment strategy for cocaine addiction," concluded Sadri-Vakili.
The findings were detailed in a study published this week in the journal Molecular Psychiatry.