Rodney C. Baker

Effect of pentobarbital and gaseous anesthetics on rats selectively bred for ethanol sensitivity.

Rats have been genetically selected to have a differential hypnotic response to an acute injection of ethanol. These high alcohol sensitive (HAS) and low alcohol sensitive (LAS) rats were used to investigate commonalities of the mechanism of action of several gaseous anesthetics, pentobarbital and ethanol. Similar studies have been carried out extensively with mouse lines also differentially sensitive to ethanol (short- and long-sleep mice). Like the mice, the rats are also differentially sensitive to the two gaseous anesthetics, enflurane and isoflurane. However, in contrast to results with these mice, we find that the HAS and LAS rats are differentially sensitive to halothane and pentobarbital in the same direction as their sensitivity to ethanol. In other studies, the rats also have been found to be differentially sensitive to phenobarbital as are SS and LS mice. These results show that, by the use of these anesthetics in combination with selectively bred rodent lines, many new opportunities for dissecting the molecular mechanisms of anesthetic agents present themselves.

Genetic brain polypeptide variants in inbred mice and in mouse strains with high and low sensitivity to alcohol

Twelve genetically determined brain polypeptide charge variants were identified by comparing cerebellar vermis of 7 inbred mouse strains and of mice selectively bred from 8 strains closely related to these 7 ancestral strains and one other for acute behavioral sensitivity to the sedative effects of ethanol. The selectively bred ethanol-sensitive (LS, long sleep) and insensitive (SS, short sleep) mice exhibited different allelic variants at 6 of these 12 gene loci expressed in the cerebellum. Variant polypeptide A1 (81 kdalton, pI 5.6) was shown to be associated with the membrane of synaptosomal mitochondria and to exhibit a basic variant in SS mice that is determined by a dominant allele. Other variant polypeptides showed codominant inheritance in F1 crosses. However, the phenotype of no single one of these brain polypeptides consistently correlated with the ethanol behavioral sensitivity of the 7 inbred mouse strains nor of 8 recombinant inbred (B X D, C57BL X DBA) strains. This finding supports the hypothesis that a substantial amount of inbreeding, leading to random fixation of alleles independent of selection for ethanol sensitivity, occurred during the breeding of the SS and LS mice. The present findings of a lack of a strong association between sleep time and a brain polypeptide variant do not preclude the existence of a major gene effect contributing to variation in acute sensitivity to ethanol but are consistent with reports that multiple loci are responsible for the difference in ethanol sensitivity between SS and LS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Ceramide composition of whole brain synaptosomal gangliosides from mice genetically bred for divergent ethanol sensitivities

A comparison of the two major ceramide molecular species (d18:1-C18:0 and d20:1-C18:0) of synaptosomal gangliosides GM1, GD1a+GT1a, GD1b, GT1b, revealed a difference between the ceramide composition of ethanol-sensitive LS and ethanol-insensitive SS whole brain synaptosomal gangliosides. In all comparisons, the ratio of the two major molecular species, (d18:1-C18:0/d20:1-C18:0) was less for LS than for SS mice.