Initial sensitivity and tolerance to ethanol in mice genetically selected for diazepam sensitivity.
The benzodiazepine (BZ) receptor is coupled with a GABA-receptor chloride-ionophore complex. The BZs augment the GABA-induced increase in chloride conductance, which leads to postsynaptic inhibition. This effect is believed to be responsible for antianxiety, sedative, muscle relaxant, and anticonvulsant effects, but the mechanisms underlying these behavioral effects are poorly understood. Various other sedative-hypnotics, including ethanol and barbiturates, interact with this system, probably contributing to their behavioral effects. We have recently conducted a selective breeding program to develop lines of mice which are diazepam-resistant (DR) and sensitive (DS) (Gallaher EJ, Hollister LE, Gionet SE, Crabbe JC. Psychopharmacology, 93:25-30, 1987); when tested for the duration of rotarod impairment after 20 mg/kg diazepam the DR line was impaired for 71 +/- 13 min compared with 200 +/- 18 min in the DS line. In the current study we tested mice from the DR and DS lines to determine if BZ sensitivity generalized to ethanol. DS mice became ataxic with lower brain ethanol concentrations, and recovered at later times and with lower blood ethanol concentrations, than did DR mice, indicating that sensitivity differences did extend to ethanol. Following a series of sequential doses over 5 to 6 hr DS mice developed minimal rapid tolerance, whereas DR mice developed considerable tolerance. By the end of the day DS mice were therefore much more sensitive to ethanol than were DR mice; this difference was greater in males than in females. High dose ethanol toxicity was studied by assaying brain ethanol concentrations at the cessation of respiration; no differences were found between lines or sexes.
Gallaher
E J
EJ
Veterans Administration Medical Center, Palo Alto, California.
Gionet
S E
SE
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004361:Drug Tolerance; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology*; D005838:Genotype; D051379:Mice; D008815:Mice, Inbred Strains; D009048:Motor Skills / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000187:drug effects
D011963:Receptors, GABA-A; D000431:Ethanol; D003975:Diazepam