Tolerance to hypothermia induced by ethanol depends on specific drug effects

Two experiments were conducted to test the hypothesis that tolerance to the hypothermic effect of ethanol fails to develop if rats are denied the unconditional stimulus represented by hypothermia. In both experiments, rats were injected with either ethanol (1.9 or 2.5 g/kg) or saline and given microwave hyperthermia (MHT) to offset the hypothermic effect of the drug or sham-MHT. In one experiment, rats no longer demonstrated a hyperthermic response to a saline challenge after hypothermia was offset during 5 MHT treatment sessions. In a second experiment, rats prevented from becoming hypothermic did not develop tolerance to the hypothermic effect of ethanol due to MHT treatment, but did become tolerant to the ataxic effects of ethanol, which were unaffected by MHT. Results suggest that rats must experience the specific consequences of a drug to become tolerant to that effect.