Alcohol and central glutamate activity: What goes up must come down?

Alcohol use disorders (AUD) are a serious public health concern. Clinical and preclinical research indicates that glutamate activity in the reward neurocircuitry of the central nervous system (CNS) is critical for the development and maintenance of AUD. Both ionotropic and metabotropic glutamate receptors, as well as associated transporters, are located in tripartite synapses throughout the CNS. Acute alcohol exposure functionally antagonizes glutamatergic activity and its receptors. Chronic alcohol exposure downregulates glutamate transporters, which leads to excessive glutamate levels and activity. Excessive glutamate activity, in turn, can lead to excitotoxicity/neurotoxicity. In addition, this excessive CNS glutamate activity alters synaptic plasticity, learning, memory, and stimulus conditioning associated with the development of alcohol and substance use disorders. These neuroplastic changes occur in multiple brain regions that mediate learning and memory. Research into alcohol’s effects on the glutamatergic system has provided initial glutamate-associated pharmacotherapies and novel molecular targets to treat AUD. Continued research in this area has identified, and will continue to identify, promising mechanisms to treat substance use disorders in general.