Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of an acute dose of ethanol were tested twice during the course of genetic selection for their hypothermic response to other alcohols and sedative hypnotics. The drugs administered were ethanol, propanol, n-butanol, t-butanol, pentanol, diazepam, phenobarbital, pentobarbital, methyprylon and ethchlorvynol, all of which have sedative effects on the central nervous system, and hydralazine, a peripheral vasodilator. All drugs decreased body temperature of both HOT and COLD mice. In mice selected for seven to nine generations, COLD mice were more sensitive than HOT mice to all sedative drugs. The longer-chain alcohols were more potent than ethanol in inducing hypothermia, but the magnitude of the response difference between HOT and COLD mice appeared to be smaller. The difference between HOT and COLD mice in hypothermic sensitivity to an acute dose of ethanol was greater after 11-15 generations of selection than after seven generations. Similarly, the differential effect of the other alcohols, phenobarbital, pentobarbital, and methyprylon, on HOT and COLD mice increased with more generations of selection but to a lesser extent than ethanol. These data demonstrate that selecting for sensitivity to acute ethanol hypothermia has produced mice that are also differentially sensitive to other sedative hypnotic agents. They also support the hypothesis that the drugs used in the present study share a common mechanism of action for inducing hypothermia, which may be regulated by a common set of genes. Although there was no difference after seven selected generations between COLD and HOT mice in response to hydralazine, the drug was more potent in COLD than HOT mice after 12 selected generations. The hydralazine results suggest that some of the increased divergence in sensitivity may now be due to alterations in vascular mechanisms.
|Number of pages
|Journal of Pharmacology and Experimental Therapeutics
|Published - 1991
ASJC Scopus subject areas
- Molecular Medicine