mGlu2 Receptors in the Basal Ganglia: A New Frontier in Addiction Therapy

Glutamate is an important neurotransmitter in the mammalian brain. Among the receptors that glutamate interacts with is metabotropic glutamate (mGlu) receptor 2, a Gα_i/o-coupled receptor. These receptors are primarily located on glutamatergic nerve terminals and act as presynaptic autoreceptors to produce feedback inhibition of glutamate release. Abundant mGlu2 receptors are distributed in major glutamatergic pathways in the basal ganglia, especially the corticostriatal and thalamostriatal projections in the striatum. These receptors are involved in the regulation of motivation, reward processing, learning, motor, and cognitive functions. As an inhibitory presynaptic receptor, mGlu2 is linked to the addictive properties of drugs of abuse, a topic summarized in this review. Chronic exposure to multiple addictive drugs and alcohol causes the adaptive downregulation of mGlu2 receptors in their expression and function in the key regions of the limbic reward circuit. This downregulation contributes to the remodeling of limbic excitatory synaptic transmission and plasticity critical for enduring drug-seeking behavior. Normalization of mGlu2 activity by pharmacological or genetic approaches attenuates drug taking and seeking. Here, we highlight that recent progress in mGlu2 biology research demonstrates the pivotal roles of mGlu2 receptors in different aspects of drug addiction. mGlu2 subtype-selective agents (both orthosteric and allosteric compounds) thus have the potential to be developed into novel pharmacotherapies for addictive conditions.