Divergent Selection for Pentobarbital-Induced Sedation Times in Mice

Abstract

Divergent selection for pentobarbital sedation-time response was practiced in mice for 9 generations. At the end of 9 generations of selection, the long-sedation-time line (LST) slept an average of 433 min; the short sedation time line (SST) slept an average of 29 min. The control line (C) slept an average of 71 min. These differences represent an almost 15-fold increase in sedation time for the LST compared to the SST line and a 6-fold increase compared to the C line. The SST line slept about 40% less than the C line after 9 generations of selection (measured in tenth generation progeny). Analysis of selection differentials and realized heritabilities indicated that selection response did not diminish after 9 generations of selection. Realized heritabilities for sedation time ranged from 0.43 to 0.83 for the LST line and from 0.55 to 0.81 for the SST line. Realized heritabilities did not decrease in magnitude due to selection progress, indicating that more progress can still be achieved. Comparing corrected (for environmental factors) to uncorrected heritabilities showed the importance of including a control line in selection experiments. Crossing of lines to study gene action responsible for this trait revealed that this trait was controlled by a number of genes with additive gene action without dominance, overdominance, epistasis, or maternal effects.

Addiction and Dose Response: The Psychomotor Stimulant Theory of Addiction Reveals That Hormetic Dose Responses Are Dominant

“…This approach has been highlighted in the work of Stino (1992) with NIH Swiss mice, employing mass selection to create a line of mice with long loss of righting reflex, that is, sleep time [i.e., long sleep time (LST)], and a comparison group with short sleep time (SST) after pentobarbital (PB) injection. Such efforts lead to the conclusion that at least half of the phenotype was due to genetic factors (Stino et al, 1998). Follow-up investigations revealed that LST mice had a greater response for sensitivity to ethanol-induced hypothermia, implying a commonality in the gene influencing these two endpoints.…”

Genetic determinants of sensitivity to pentobarbital in inbred mice

“…Starting with NIH Swiss mice, Stino (1992) used mass selection to create a line of mice with long loss of righting reflex, or "sleep time" (LST) and a parallel line with short "sleep time" (SST) after IP injection of PB (50 mg/kg). Heritability of drug response was ≥0.50 indicating that at least half the phenotypic variance was due to genetic sources (Stino et al 1998). When these animals were tested for sensitivity to ethanolinduced hypothermia, LST mice had a greater response (Mizinga et al 1995), suggesting overlap in the genes affecting these two responses.…”

Anxiety and Sensitivity to Ethanol and Pentobarbital in Alcohol Withdrawal Seizure‐Prone and Withdrawal Seizure‐Resistant Mice

“…The degree of response to the sedative effects of alcohol and pentobarbital is genetically determined (Deitrich et al, 1989;Stino et al, 1998). Furthermore, it is likely that some common genes determine severity of withdrawal, as measured by handling-induced convulsions, from ethanol and from pentobarbital (Metten and Crabbe, 1999;Metten et al, 1998).…”