Short-term selection for the interaction between S-propranolol and ethanol in mice

Area of Science:

• Pharmacology
• Genetics
• Neuroscience

Background:

• Previous studies showed an interaction between S-propranolol and ethanol affecting hypnotic sensitivity in mice.
• This interaction was attributed to an additive hypothermic effect, decreasing ethanol metabolism.
• Genetic differences in response sensitivity between short-sleep and long-sleep mice suggested a genetic basis.

Purpose of the Study:

• To determine if the ethanol-S-propranolol interaction's hypnotic effects could be selectively bred in mice.
• To investigate the genetic underpinnings of the observed interaction and its effect on ethanol metabolism and sensitivity.

Main Methods:

• A heterogeneous stock of mice was used for a short-term selective breeding study.
• Selection was based on the difference in sleep time between animals treated with ethanol and S-propranolol versus ethanol and saline.
• Four generations of breeding were conducted to establish distinct high and low response lines.

Main Results:

• Successful separation into high and low lines based on sleep time differences after combined ethanol and S-propranolol treatment.
• No significant differences in blood ethanol levels at awakening were observed between the high and low lines.
• The observed effect was not due to variations in S-propranolol metabolism or ethanol-alone sleep times.

Conclusions:

• The magnitude of the ethanol-S-propranolol interaction is controlled by specific alleles within the mouse stock.
• The response is likely mediated by differences in thermogenesis mechanisms regulated by beta-adrenergic receptors.
• Central nervous system sensitivity to ethanol was not a correlated response to this selection process.