Genetic covariation in low alcohol-sensitive and high alcohol-sensitive selected lines of rats: behavioral and electrophysiological sensitivities to the depressant effects of ethanol and the development of acute neuronal tolerance to ethanol in situ at generation eight.

Phenotypic differences in behavioral and initial neuronal sensitivities to acute ethanol (EtOH) administration were examined and compared among replicate lines of rats, which were selectively bred for low and high EtOH sensitivity. The eighth generation of HAS (EtOH-sensitive) and LAS (EtOH-insensitive) rats were significantly different in terms of sensitivity both to EtOH-induced loss of righting response (sleep time) and to EtOH-induced depressions of cerebellar Purkinje neuron firing rates. This study provides the first evidence for a significant correlation between behavioral and electrophysiological EtOH sensitivities among individual animals and between replicate selected rodent lines. These data support the hypothesis that a genetic correlation exists between these two phenotypes. In addition, the LAS rats expressed a significantly higher incidence of acute cellular tolerance to the depressant neuronal effects of repeated local applications of EtOH over a period of a few minutes. We have characterized this response and concluded that it may contribute to EtOH sensitivity. However, our data also suggest that the EtOH insensitivity of cerebellar Purkinje neurons in LAS rats is not only a consequence of acute neuronal tolerance to EtOH, but also due to low initial EtOH sensitivity of these neurons. Both behavioral and electrophysiological EtOH phenotypes of LAS and HAS rats have diverged with the application of selection pressure for behavioral EtOH sensitivity; these data suggest that the mechanisms underlying neuronal sensitivity and acute neuronal tolerance to EtOH are important in determining the behavioral EtOH sensitivities of these animals.