GLT-1 and alcohol.

Glutamate transporter 1 (GLT-1) is responsible for the uptake of glutamate from the extracellular space, predominantly into astrocytes that insulate glutamatergic synapses. This transport is the primary method by which glutamate is removed from the synapse, as, unlike several other neurotransmitters, there is very little reuptake of glutamate by presynaptic neurons following release. As such, GLT-1 is crucial for homeostatic functioning of glutamatergic synapses, with disruptions such as excessive downregulation contributing to excitotoxicity. Alcohol is one example of an exogenous agent that can downregulate GLT-1 expression with chronic exposure in a brain region-specific manner, which is thought to underlie, in part, the dysregulated glutamatergic signaling observed in alcohol use disorder. This reduction in GLT-1 is thought to, in turn, modulate alcohol use behaviors. The pharmacological agents that restore GLT-1 expression and reduce alcohol intake, most notably the beta-lactam antibiotics, typically also modify peripheral systems, such as immune signaling and makeup of the gut microbiome, suggesting linkage between the central and peripheral effects of chronic alcohol. However, the direct role of GLT-1 in alcohol drinking, and how modulation of GLT-1 is driven by peripheral versus central mechanisms, is not completely understood. Here, we summarize the literature on effects of alcohol on GLT-1 across species and paradigms, how GLT-1 modulation impacts alcohol-related behaviors, and putative mechanisms including an emphasis on peripheral systems. We discuss the inconsistencies in GLT-1 effects between studies and the skewed distribution of experimental designs in this field. We highlight outstanding gaps in knowledge and potential clinical implications, particularly how modulation of GLT-1 expression, especially through peripheral mediators, may present treatment targets for disorders marked by glutamatergic dysfunction such as alcohol use disorder.