Interaction between S-propranolol and ethanol in mice selectively bred for ethanol sensitivity: the inbred short- and long-sleep mice.
BACKGROUND
We have studied the effect of a beta-adrenergic blocking agent, S-propranolol, on the response of mice to anesthetic doses of ethanol. We used the selectively bred short and long sleep (ISS and ILS) mice. These mice were selected for their differential sensitivity to anesthetic doses of ethanol and then inbred. The study was prompted by the finding that the effect of ethanol on the firing rate of cerebellar Purkinje cells is modulated by beta-adrenergic input. In addition, this firing rate depression by ethanol is highly correlated with the anesthetic potency of ethanol. We were attempting to find a behavioral correlate of this effect of beta-adrenergic agents in the ISS and ILS mice.


METHODS
We studied the effect of S-propranolol plus ethanol on the sleep time and blood ethanol at awakening in the inbred ILS and ISS mice. We administered anesthetic doses of ethanol with and without S-propranolol. We conducted studies of the rate of disappearance of ethanol in the presence of S-propranolol and carried out sleep time and metabolic studies with mice in an incubator held at 32 to 33 degrees C.


RESULTS
We found that S-propranolol caused a prolonged anesthetic time brought about by ethanol but only in ISS mice. There was no significant difference in the blood ethanol levels at awakening with or without S-propranolol, indicating that S-propranolol had no effect on the brain sensitivity. Subsequently, we showed that this was due to a profound hypothermia caused by a combination of S-propranolol and ethanol. This was greater in the ISS mice because a larger dose of ethanol was required for the anesthetic effect of ethanol. The effect on ethanol disappearance rate, temperature drop, and anesthesia time all were largely reversed by placing the animals in an incubator at 32 to 33 degrees C.


CONCLUSIONS
Profound hypothermia lowers the ethanol disappearance rate when both S-propranolol and ethanol are given. The effect of S-propranolol is likely due to the blockade of beta-adrenergic receptors that prevents thermogenic responses to the hypothermia brought about by ethanol. The results indicated that there might be a genetic effect controlling the hypothermic response to the combination of S-propranolol and ethanol. Further experiments to investigate this are reported in a subsequent article. We could find no evidence of a central nervous system effect of S-propranolol on the hypnotic actions of ethanol in these strains of mice.
Deitrich
Richard A
RA
Department of Pharmacology, University of Colorado Health Science Center, Denver, Colorado 80262, USA. Richard.Deitrich@uchsc.edu
Bludeau
Pequita
P
D000428:Alcohol Drinking / Q000097:blood / Q000235:genetics*; D000818:Animals; D004347:Drug Interactions / Q000235:genetics / Q000502:physiology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D007035:Hypothermia / Q000097:blood / Q000139:chemically induced / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011433:Propranolol / Q000097:blood / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity
D000431:Ethanol; D011433:Propranolol