Alcohol Suppresses Tonic GABA_A Receptor Currents in Cerebellar Granule Cells in the Prairie Vole: A Neural Signature of High-Alcohol-Consuming Genotypes

Background: Evidence indicates that the cerebellum plays a role in genetic predilection to excessive alcohol (ethanol [EtOH]) consumption in rodents and humans, but the molecular mechanisms mediating such predilection are not understood. We recently determined that EtOH has opposite actions (enhancement or suppression) on tonic GABA_A receptor (GABA_AR) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABA_AR current responses to EtOH contributes to genetic variation in EtOH consumption phenotype. Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABA_AR currents in another high-EtOH-consuming rodent, prairie voles (PVs). Results: EtOH (52 mM) suppressed the magnitude of the tonic GABA_AR current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABA_AR current in 5% of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABA_AR currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABA_AR currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABA_AR-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABA_ARs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH enhancement of GABA release) demonstrated that nNOS expression in the GC layer of PV cerebellum was similar to the levels seen in B6 mice, both being significantly reduced relative to D2 mice and SD rats. Conclusions: Combined, these data highlight the GC GABA_AR response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABA_AR system as a contributing mechanism to high EtOH consumption.