Selective breeding of rats for sensitivity to the anesthetic effects of ethanol is being carried out with rats derived from the genetically heterogeneous N/Nih stock. Thirteen generations of within family selection have been achieved with replicate high (HAS), low (LAS) and control alcohol sensitive (CAS) lines. Significant separation between lines on sleep time and blood ethanol concentration (BEC) at awakening following ethanol administration has been achieved. In general, the results obtained so far replicate the findings with short (SS) and long (LS) sleep mice. One exception is that the high alcohol sensitivity rats (HAS) also appear more sensitive to pentobarbital relative to LAS rats. This finding is opposite to that which occurs with SS and LS mice where the low ethanol sensitive SS mice appear more sensitive to pentobarbital than the LS mice.

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The results indicate that segregating populations derived from the IHAS and ILAS strains can be used for mapping ethanol sensitivity QTL. The chromosome 2 LORR QTL may confer variation in ethanol metabolism, whereas the chromosome 5 LORR/BECrrr QTL likely mediates central nervous system ethanol sensitivity. The small number or absence of QTL for BEC1, AFT, and NTR1 receptor density suggests that genetic variation for these traits is minimal in the IHAS/ILAS strains and/or the effect size of QTL for these traits is too small to be mapped efficiently in this sample of F(2) rats. The ultimate identification of genes underlying these alcohol sensitivity QTL will contribute to our understanding of the actions of alcohol in the central nervous system if not to a deeper understanding of the genetic risk factors for alcoholism.

In this study, we examined if differences in initial membrane sensitivity to ethanol were associated with development of membrane tolerance to ethanol. High Alcohol Sensitivity (HAS) and Low Alcohol Sensitivity (LAS) rats were administered a 15% ethanol solution in water as the sole source of fluid for 30 days. The amount of ethanol consumed per day did not significantly differ between the HAS and LAS rats. Development of membrane tolerance to in vitro effects of ethanol has been previously reported for bulk membrane fluidity and protein-lipid interaction. Our data expands the understanding of "membrane tolerance" phenomenon to protein distribution and bilayer interdigitation. We also introduce genotype-dependent and genotype-independent properties of the membrane tolerance to ethanol. ethanol treatment produced genotype-dependent and genotype-independent membrane tolerance to ethanol. The in vitro effects of ethanol on synaptic plasma membrane (SPM) protein distribution and lipid bilayer interdigitation were abolished or decreased in the SPM of chronic ethanol-treated HAS rats, as compared with the SPM of HAS control rats (genotype-dependent tolerance). Protein distribution and bilayer interdigitation were not affected by ethanol in vitro in either chronic ethanol-treated or control LAS rats. Genotype-independent tolerance to ethanol in vitro was observed for SPM annular and bulk bilayer fluidity in chronic ethanol-treated HAS and LAS rats. It is concluded that initial sensitivity to ethanol contributes to the development of membrane tolerance to ethanol in HAS and LAS rats.

Alcoholics are almost invariably heavy users of tobacco. Both alcoholism and smoking appear to be influenced by genetic factors but it is not known whether the same or different genes regulate the abuse of ethanol and nicotine. Recent studies have demonstrated that the long-sleep (LS) and short-sleep (SS) mouse lines, which were selectively bred for differences in ethanol-induced anesthesia ("sleep-time"), also differ in several effects of nicotine and the muscarinic agonist, oxotremorine. In order to determine whether or not these differences are due to chance, the relative sensitivities of rat lines which were selectively bred for differences in ethanol-induced sleep-time were determined. The high alcohol sensitivity (HAS) rat line was more sensitive to the locomotor and body temperature depressant effects of nicotine than was the low alcohol sensitivity (LAS) rat line. The control line (CAS) was intermediate in sensitivity. The rat lines did not differ in sensitivity to oxotremorine's hypothermia-producing effects. The numbers and affinities of two classes of brain nicotinic receptors were measured in eight brain regions. No differences among the rat lines were detected. These results suggest that ethanol elicits some of its depressant actions via an effect on brain nicotinic systems, but the differences in sensitivity to ethanol and nicotine are probably not due to differences in the number of brain nicotinic receptors. Perhaps this interaction explains the high correlation between alcoholism and smoking in humans.