The Cerebellar GABAR System as a Potential Target for Treating Alcohol Use Disorder.

In the brain, fast inhibitory neurotransmission is mediated primarily by the ionotropic subtype of the gamma-aminobutyric acid (GABA) receptor subtype A (GABAR). It is well established that the brain's GABAR system mediates many aspects of neurobehavioral responses to alcohol (ethanol; EtOH). Accordingly, in both preclinical studies and some clinical scenarios, pharmacologically targeting the GABAR system can alter neurobehavioral responses to acute and chronic EtOH consumption. However, many of the well-established interactions of EtOH and the GABAR system have been identified at concentrations of EtOH ([EtOH]) that would only occur during abusive consumption of EtOH (≥40 mM), and there are still inadequate treatment options for prevention of or recovery from alcohol use disorder (AUD, including abuse and dependence). Accordingly, there is a general acknowledgement that more research is needed to identify and characterize: (1) neurobehavioral targets of lower [EtOH] and (2) associated brain structures that would involve such targets in a manner that may influence the development and maintenance of AUDs.Nearly 15 years ago it was discovered that the GABAR system of the cerebellum is highly sensitive to EtOH, responding to concentrations as low as 10 mM (as would occur in the blood of a typical adult human after consuming 1-2 standard units of EtOH). This high sensitivity to EtOH, which likely mediates the well-known motor impairing effects of EtOH, combined with recent advances in our understanding of the role of the cerebellum in non-motor, cognitive/emotive/reward processes has renewed interest in this system in the specific context of AUD. In this chapter we will describe recent advances in our understanding of cerebellar processing, actions of EtOH on the cerebellar GABAR system, and the potential relationship of such actions to the development of AUD. We will finish with speculation about how cerebellar specific GABAR ligands might be effective pharmacological agents for treating aspects of AUD.