Evidence that genetic differences in habituation and GABAergic mechanisms may be related to sensitivity to ethanol and development of ethanol tolerance in mice.

Habituation to a test environment following daily exposure for 5 days was examined in three genetically different strains of mice. C57 animals showed significant habituation to the new environment already on the second day. The habituation of NMRI mice was significant on the third day, whereas CBA mice showed no habituation at all during the experimental period. There was no difference between the animal strains in learning capacity in a passive avoidance test, but CBA mice displayed a significant increase in latency in their performance. When tested for sensitivity to the convulsant actions of GABAergic antagonists, picrotoxin produced seizures at lower doses in CBA as compared to NMRI and C57 mice, whereas there was no difference between the strains in the seizure activity produced by the specific GABA receptor antagonist bicuculline. When the animals were tested for sensitivity to ethanol in a horizontal wire test, ethanol (2 g/kg, IP) produced muscle relaxation in CBA mice whereas the performance of NMRI and C57 was not affected. A large dose of ethanol (4 g/kg, IP) produced a significantly longer sleeping time in CBA mice as compared to NMRI and C57 animals. Ethanol-produced hypothermia was, however, similar in all animals. Environment-dependent development of tolerance to ethanol following daily injections of ethanol for 4 days was examined. C57 mice showed the most rapid development of tolerance towards ethanol's hypnotic actions, whereas CBA mice showed no tolerance to this effect of ethanol. No difference between the strains to the development of tolerance to ethanol's hypothermic effects was observed. The present findings indicate that sensitivity to ethanol and ethanol tolerance are complex phenomena which cannot be adequately characterized by measuring only one single functional response to ethanol. The possibility that a genetically determined perturbation in the functions of the GABA receptor-coupled chloride channel, noted as variable sensitivity to picrotoxin, may be of importance for the observed disturbance in habituation to a new environment, for the different sensitivity to ethanol, and for the different rate of development of ethanol tolerance is discussed. [ABSTRACT FROM AUTHOR]