Metabotropic glutamate receptors, which include the subtypes mGluR2 and mGluR3, have been known targets for addiction treatment. Unfortunately, mGluR2/3 agonists studied to date have shown important limitations, including development of tolerance and decreasing food intake along with drug intake.
Recent issue of Biological Psychiatry presents the results of three studies implicating metabotropic glutamate receptor 2 (mGluR2) as a new molecular target for the treatment of addiction.
The first study investigated whether non-neuronal glial cells regulate the activity of brain circuits that mediate relapse to cocaine. They used a molecular switch called Gq-DREADD to activate glial release of the chemical messenger glutamate in a key reward center of the brain, the nucleus accumbens.
The authors found that activating glutamate release prevented relapse to cocaine use in rodents who previously self-administered this drug. They also found that the effect of glial activation was mediated by stimulating mGluR2 and mGluR3.
The second and third studies reported encouraging anti-addiction effects of AZD8529, an AstraZeneca drug, which works by selectively enhancing the stimulation of mGluR2.
2nd study reported that AZD8529 reduced nicotine self-administration and prevented relapse to nicotine seeking following withdrawal in squirrel monkeys. They also showed that this drug decreases the ability of nicotine to stimulate dopamine release in brain regions implicated in reward in rodents.
A different research team discovered that AZD8529 reduced cravings to self-administer methamphetamine in rodents following voluntary abstinence.
Dr. John Krystal, Editor of Biological Psychiatry, summarized, "It is unusual to have three papers supporting a new treatment mechanism emerge at the same time. Enhancing mGluR2 function may hold promise for the treatment of addiction."