Stimulant and depressant properties of sedative-hypnotics in mice selectively bred for differential sensitivity to ethanol

Abstract

A genetic analysis of sedative-hypnotic response in selectively bred Long-Sleep (LS) and Short-Sleep (SS) mice showed LS mice to be more depressed by acetaldehyde, ethanol (ETOH), and t-butanol, but less sensitive to pentobarbital. Intermediate inheritance was shown by the two reciprocal F1 hybrids for the alcohols, but dominance to the LS genotype occurred for the aldehyde and the barbiturate. At several subhypnotic doses of ETOH in two experiments, LS mice showed less locomotor stimulation and greater disruption of coordination than the SS mice. The two reciprocal F1 hybrids did not differ from one another and had dose-response curves intermediate to the two parental lines. Study of the effects of t-butanol on locomotor activity revealed a pattern of line differences similar to that for ETOH. The genetic selection for LS and SS mice appears to have differentiated loci that pleiotropically influence a variety of behavioral responses to alcohols.

Distinctions among sedative, disinhibitory, and ataxic properties of ethanol in inbred and selectively bred mice

“…Twelve mice of each genotype/sex were tested. The dose and method of testing LRR were identical to that of earlier work with LS and SS mice (Dudek and Abbott 1984 a). Blood ethanol concentrations (BEC) were determined enzymatically from 5 gl blood samples taken from the retro-orbital sinus at the time when each mouse regained the righting reflex.…”

“…ETOH effects on motor coordination were evaluated with a grid apparatus previously described (Dudek and Phillips 1983;modified after Belknap 1975) and extensively used to characterize alcohol effects in LS and SS mice (Dudek and Phillips 1983;Dudek et al 1984). It consists of a 13 x 13 cm chamber with a floor of hardware cloth wire grid suspended 11 mm over a metal plate.…”

Genotype-dependent effects of GABAergic agents on sedative properties of ethanol

“…All mice were produced in our laboratory with standard genetic mouse colony procedures described elsewhere (Dudek and Abbott 1984;Dudek et al 1984a). LS and SS mice are currently maintained by random mating within each line, and the selection-produced difference in ETOH-induced LRR persists (Dudek and Abbott 1984;Dudek et al 1984a;Phillips et al 1984;Gilliam etal. 1985).…”

“…Doses of bicuculline and picrotoxin, and sample sizes can be found in Table 2. A dose adjustment procedure was also used for pentobarbital since SS mice are more sedated by this agent than are LS mice in our laboratory (Dudek et al 1984a). LS mice were given 60 mg/kg and SS mice 55 mg/kg.…”

“…One such set of tools is the Long-Sleep (LS) and Short-Sleep (SS) lines of mice bred for differential hypnotic response to ETOH (McClearn and Kakihana 1981). Duration of loss of the righting reflex (LRR) following ETOH administration (3.8 g/kg) is about 1 order of magnitude longer in LS mice than in SS mice (McClearn and Kakihana 1981 ;Dudek and Abbott 1984;Dudek et al 1984a). The major bases for this differential sensitivity appear to be central (i.e.…”