The role of metabotropic glutamate receptors in drug reward, motivation and dependence

Addiction to drugs of abuse is a disorder that involves dysfunctions in motivational processes. Both the primary rewarding effects of drugs, as well as the acquired motivational properties of stimuli associated with drug-seeking and -taking, contribute to the perpetuation of dependence on drugs of abuse. Metabotropic glutamate (mGlu) receptors, which mediate slow glutamate neurotransmission, are located throughout limbic and cortical brain sites implicated in drug addiction. Preclinical evidence suggests that mGlu receptors play a crucial role in regulating behavioral effects of drugs of abuse relevant to drug addiction. Specifically, antagonists at excitatory postsynaptic mGlu5 receptors decrease drug self-administration without affecting motor behaviors, cognition or the reward value of natural rewards, while agonists at inhibitory presynaptic mGlu2/3 receptor agonists prevent reinstatement to drug-seeking and -taking after a period of abstinence. These findings have increased our understanding of the neuropathological processes associated with aspects of dependence on drugs of abuse and have provided new targets for pharmacological approaches to the treatment of dysfunctions in motivational processes characterizing the various phases of drug addiction.