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. 2018;248:113-156.
doi: 10.1007/164_2018_109.

The Cerebellar GABA A R System as a Potential Target for Treating Alcohol Use Disorder

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Free PMC article

The Cerebellar GABA A R System as a Potential Target for Treating Alcohol Use Disorder

David J Rossi et al. Handb Exp Pharmacol. .
Free PMC article

Abstract

In the brain, fast inhibitory neurotransmission is mediated primarily by the ionotropic subtype of the gamma-aminobutyric acid (GABA) receptor subtype A (GABAAR). It is well established that the brain's GABAAR system mediates many aspects of neurobehavioral responses to alcohol (ethanol; EtOH). Accordingly, in both preclinical studies and some clinical scenarios, pharmacologically targeting the GABAAR system can alter neurobehavioral responses to acute and chronic EtOH consumption. However, many of the well-established interactions of EtOH and the GABAAR 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 GABAAR 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 GABAAR system, and the potential relationship of such actions to the development of AUD. We will finish with speculation about how cerebellar specific GABAAR ligands might be effective pharmacological agents for treating aspects of AUD.

Keywords: AUD; Addiction; Alcohol; Cerebellum; Ethanol; GABA.

Figures

Fig. 1
Fig. 1
Phasic and tonic GABAAR currents and modulation by EtOH, as exemplified by cerebellar granule cells. (a) Schematic diagram showing GABAARs in the synaptic cleft (blue) and outside of the synaptic cleft (green). Synaptic GABAARs are typically comprised of two α subunits (with α1 dominating at most synapses), two β subunits, and a γ subunit. Extrasynaptic GABAARs replace the γ subunit with a δ subunit which is crucial for anchoring the receptor complex extrasynaptically, and at most synapses is paired with either the α4 (hippocampus and thalamus) or α6 (cerebellum) subunit [as in (b), bottom panel], although other permutations also exist. (b) Immunocytochemistry for the α1 (top) and α6 (bottom) subunit of the GABAAR receptor. Note, the α6 subunit is exclusively expressed in granule cells. (c) Phasic IPSCs (left) are mediated by synaptic GABAARs (as evidenced by their sensitivity to the GABAAR antagonist, GABAzine) that are rapidly activated by the high concentrations of vesicular GABA released into the synaptic cleft, and their decay time is dictated by receptor desensitization and inactivation as GABA is cleared from the synaptic cleft by diffusion and uptake by GABA transporters. Tonic GABAAR-mediated currents (right; steady state current blocked by GABAzine; downward deflections superimposed on the tonic current are phasic IPSCs that are also blocked by GABAzine) are mediated by extrasynaptic GABAARs that have a higher affinity for GABA and do not readily desensitize, and so generate a steady state current that varies in accordance with the concentration of ambient extracellular GABA. Note, because GABA released into the synaptic cleft diffuses out of the cleft where it can activate extrasynaptic GABAARs, the magnitude of the tonic GABAAR current increases or decreases in parallel with changes in vesicle release rate, either from the presynaptic neuron or from neighboring synapses not directly connected to the recorded cell. (d) Example voltage-clamp recording (left) showing that EtOH (52 mM) increases sIPSC frequency and tonic GABAAR current magnitude in a granule cell in a slice of cerebellum from a low EtOH consuming Sprague Dawley rat (SDR). EtOH dose–response plot (right) shows the mean enhancement of sIPSC frequency (black) and tonic GABAAR current magnitude (red), without affecting sIPSC amplitude (gray). Images are adapted with permission from Mohr et al. (2013) and Pirker et al. (2000)
Fig. 2
Fig. 2
Circuitry of the cerebellar cortex. Circuit diagram of the cerebellum, showing the two excitatory/glutamatergic afferent inputs to the cerebellar cortex (mossy fibers and climbing fibers), the connectivity of the interneurons, which include the glutamatergic granule cells and GABAergic Golgi cells and Molecular Layer interneurons (MLIs), and the sole output of the cerebellar cortex, the GABAergic Purkinje cells. The Purkinje cells synapse onto a variety of cells distributed into three cerebellar nuclei, which in turn send mono- and polysynaptic efferents to most of the rest of the brain
Fig. 3
Fig. 3
Response of granule cell tonic GABAAR current to EtOH varies in parallel with and influences EtOH consumption phenotype. (a, b) Example recordings showing that EtOH (52 mM) enhances the tonic GABAAR current in low EtOH consuming rodent genotypes (SDRs and D2 mice; a), but suppresses the tonic GABAAR current in high EtOH consuming rodent genotypes (Prairie Voles and B6 mice; b). (c) Plot of mean EtOH-induced change in magnitude of granule cell tonic GABAAR current across mammalian genotypes with divergent EtOH consumption phenotypes. Note, EtOH consumption values are rough estimates of average amount consumed across a 24 h period for each mammalian genotype, without consideration for consumption pattern across the day. (d) Example recordings and bar chart of mean responses to varying doses of EtOH in SDRs and B6 mice showing that opposite action of EtOH is preserved at low to high [EtOH]. (e) Bar chart depicts the mean amount of EtOH consumed by B6 mice during a 2 h 2 bottle choice (water and 10% EtOH) session, under control conditions and after a local injection of the GABAAR agonist, THIP, into lobe 3 of the cerebellum. Adapted with permission from Kaplan et al. (2013, 2016a, b)

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