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

Abstract

We have previously demonstrated that there is an interaction between S-propranolol, a beta-adrenergic blocking agent, and ethanol on the hypnotic sensitivity of inbred short- and long-sleep mice (ISS and ILS). We found that the interaction was due to an additive hypothermic effect of ethanol and S-propranolol that markedly decreased the disappearance rate of ethanol. There was no discernible effect of S-propranolol on the hypnotic actions of ethanol as evidenced by the waking blood ethanol levels. Because ISS mice were more sensitive to this effect than were ILS mice, it seemed that there was a genetic effect to the response. Therefore, we carried out a short-term breeding project to determine whether the response could be selectively bred. We used the heterogeneous stock of mice from the Institute for Behavioral Genetics to carry out the selection study. The index for selection was the difference in sleep time between the same animal treated with propranolol and ethanol versus treatment with saline and ethanol at least 1 week apart. In four generations, we were able to achieve separation between mice with a large difference in sleep time (high line) from those with a smaller difference in sleep (low line) time. There was no difference between the average blood ethanol at awakening in the high line versus the low line. The effect was not due to a difference in rate of propranolol metabolism between the two lines. Sleep time with ethanol alone was not different between the high and low lines. The magnitude of the interaction between ethanol and S-propranolol is controlled by alleles with polymorphisms present in the HS stock of mice. The response is most likely due to a difference in the mechanisms of thermogenesis controlled by the beta-adrenergic receptors in muscle and fat. Because there were no sleep time differences between the high and low lines given ethanol alone, central nervous system sensitivity to ethanol is not a correlated response to the selection.