Independent of differences in taste, B6N mice consume less alcohol than genetically similar B6J mice, and exhibit opposite polarity modulation of tonic GABA_AR currents by alcohol

Genetic differences in cerebellar sensitivity to alcohol (EtOH) influence EtOH consumption phenotype in animal models and contribute to risk for developing an alcohol use disorder in humans. We previously determined that EtOH enhances cerebellar granule cell (GC) tonic GABA_AR currents in low EtOH consuming rodent genotypes, but suppresses it in high EtOH consuming rodent genotypes. Moreover, pharmacologically counteracting EtOH suppression of GC tonic GABA_AR currents reduces EtOH consumption in high alcohol consuming C57BL/6J (B6J) mice, suggesting a causative role. In the low EtOH consuming rodent models tested to date, EtOH enhancement of GC tonic GABA_AR currents is mediated by inhibition of neuronal nitric oxide synthase (nNOS) which drives increased vesicular GABA release onto GCs and a consequent enhancement of tonic GABA_AR currents. Consequently, genetic variation in nNOS expression across rodent genotypes is a key determinant of whether EtOH enhances or suppresses tonic GABA_AR currents, and thus EtOH consumption. We used behavioral, electrophysiological, and immunocytochemical techniques to further explore the relationship between EtOH consumption and GC GABA_AR current responses in C57BL/6N (B6N) mice. B6N mice consume significantly less EtOH and achieve significantly lower blood EtOH concentrations than B6J mice, an outcome not mediated by differences in taste. In voltage-clamped GCs, EtOH enhanced the GC tonic current in B6N mice but suppressed it in B6J mice. Immunohistochemical and electrophysiological studies revealed significantly higher nNOS expression and function in the GC layer of B6N mice compared to B6Js. Collectively, our data demonstrate that despite being genetically similar, B6N mice consume significantly less EtOH than B6J mice, a behavioral difference paralleled by increased cerebellar nNOS expression and opposite EtOH action on GC tonic GABA_AR currents in each genotype.