Group III metabotropic glutamate receptors and drug addiction

Neuroadaptations of glutamatergic transmission in the limbic reward circuitry are linked to persistent drug addiction. Accumulating data have demonstrated roles of ionotropic glutamate receptors and group I and II metabotropic glutamate receptors (mGluRs) in this event. Emerging evidence also identifies Gαi/o-coupled group III mGluRs (mGluR4/7/8 subtypes enriched in the limbic system) as direct substrates of drugs of abuse and active regulators of drug action. Auto- and heteroreceptors of mGluR4/7/8 reside predominantly on nerve terminals of glutamatergic corticostriatal and GABAergic striatopallidal pathways, respectively. These presynaptic receptors regulate basal and/or phasic release of respective transmitters to maintain basal ganglia homeostasis. In response to operant administration of common addictive drugs, such as psychostimulants (cocaine and amphetamine), alcohol and opiates, limbic group III mGluRs undergo drastic adaptations to contribute to the enduring remodeling of excitatory synapses and to usually suppress drug seeking behavior. As a result, a loss-of-function mutation (knockout) of individual group III receptor subtypes often promotes drug seeking. This review summarizes the data from recent studies on three group III receptor subtypes (mGluR4/7/8) expressed in the basal ganglia and analyzes their roles in the regulation of dopamine and glutamate signaling in the striatum and their participation in the addictive properties of three major classes of drugs (psychostimulants, alcohol, and opiates).