Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity

The molecular mechanisms that mediate genetic variability in response to alcohol are unclear. We find that alcohol has opposite actions (enhancement or suppression) on GABA(A) receptor (GABA(A)R) inhibition in granule cells (GCs) of the cerebellum from behaviorally sensitive, low-alcohol consuming Sprague Dawley rats and DBA/2 mice and behaviorally insensitive, high-alcohol consuming C57BL/6 mice, respectively. The impact of alcohol on GC GABA(A)R inhibition is determined by a balance between two opposing effects: enhanced presynaptic vesicular release of GABA via alcohol inhibition of nitric oxide synthase (NOS), and a direct suppression of the activity of postsynaptic GABA(A)Rs. The balance of these two processes is determined by differential expression of neuronal NOS (nNOS) and postsynaptic PKC activity, both of which vary across rodent genotypes. These findings identify opposing molecular processes that differentially control the magnitude and polarity of GABA(A)R responses to alcohol across rodent genotypes.