Group I metabotropic glutamate receptors: involvement in drug-seeking and drug-induced plasticity

L-glutamate is the principal excitatory neurotransmitter at fast synapses in the mammalian central nervous system, and signals though a number of ionotropic and metabotropic receptors. Among the latter are the group I metabotropic glutamate (mGlu1 and mGlu5) receptors that upon activation elevate intracellular calcium levels through activation of the phospholipase C pathway. The role of glutamatergic transmission in both the development of addiction and the phenomenon of relapse that may occur after prolonged abstinence, has come under intense scrutiny in recent times. While both mGlu1 and mGlu5 receptors have been implicated in certain aspects of the addictive state, the exact roles these receptors play in this process is, as yet, unclear. This review will introduce contemporary theories on drug addiction, including neural circuitry, before critically assessing the current body of knowledge on group I metabotropic glutamate receptors in this regard. This will involve an in-depth discussion of the distribution of these receptors in the brain, their presence in neural pathways known or postulated to be involved in addiction and their involvement in drug-related behavioral paradigms. The effect of acute and chronic drug administration on the activity and expression of group I metabotropic glutamate receptors will be investigated, as will the effect these receptors have on behavioral and biochemical responses to drugs of abuse. Finally, there will be a brief discussion on current and future therapeutic applications using our knowledge of these receptors, and the direction that future studies will need to take to close the gaps in our understanding.