Role of environmental cues as Pavlovian-conditioned stimuli in enhancement of tolerance to ethanol effects: 1. Lethal effects in mice and rats.

Twice daily for 4 days, Swiss Webster or BALB/c mice were injected with 3.5 g/kg ethanol (20% w/v, IP) immediately after moving their home cages from the colony room to the experimental room. On day 5, half the mice were moved to the same room and the other half to a novel room with different lighting, acoustic, and olfactory stimuli. All mice were injected with ethanol overdoses ranging from 4.5-10.0 g/kg. LD50 for ethanol increased following ethanol preexposure as compared to control ethanol-naive mice tested in the same experimental room. However, LD50 was lower in both Swiss Webster and BALB/c mice tested in a novel environment than in the familiar environment. Novelty increased sensitivity to the effect of low and moderate but not the highest lethal doses of ethanol. This effect of novelty occurred only in ethanol-experienced, but not ethanol-naive mice. In the following experiments, using a balanced design, Swiss Webster mice and Wistar rats were exposed to ethanol and saline alternatively in two distinct experimental rooms. On the final day, we found that there was no difference between animals tested in the room previously associated with administration of ethanol and animals tested in a saline-associated room in terms of LD50 for ethanol. These results suggest that: a) Environmental stimuli do not play a role as Pavlovian conditioning stimuli in the development of tolerance to ethanol-induced lethality; and b) novelty acts as an unconditioned stimulus that increases ethanol's lethal effects by unspecific disruption of conditioned compensatory responses to internal conditioned stimuli, such as irritation of peritoneal cavity, smell, and taste of ethanol.