Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction

Drug addiction is characterized by maladaptive decision-making and dysfunctional brain circuitry regulating motivated behaviors, resulting in loss of the behavioral flexibility needed to abstain from drug seeking. Hence, addicts face high risk of relapse even after prolonged periods of abstinence from drug use. This is thought to result from long-lasting drug-induced neuroadaptations of glutamate and dopaminergic transmission in the mesocorticolimbic and cortico-striatal circuits where group II metabotropic glutamate receptors (mGlu(2/3) receptors) are densely expressed. mGlu(2/3) receptors presynaptically control glutamate as well as dopamine release throughout the mesocorticolimbic structures involved in reward processing and drug seeking, and their function is reduced after prolonged exposure to drugs of abuse. In pre-clinical models, mGlu(2/3) receptors have been shown to regulate both reward processing and drug seeking, in part through the capacity to control release of dopamine and glutamate respectively. Specifically, mGlu(2/3) receptor agonists administered systemically or locally into certain brain structures reduce the rewarding value of commonly abused drugs and inhibit the reinstatement of drug seeking. Given the ability of mGlu(2/3) receptor agonists to compensate for and possibly reverse drug-induced neuroadaptations in mesocorticolimbic circuitry, this class of receptors emerges as a new therapeutic target for reducing relapse in drug addiction.