Persistence of a hyperthermic sign-reversal during nitrous oxide inhalation despite cue-exposure treatment with and without a drug-onset cue

We asked whether chronic tolerance and the hyperthermic sign-reversal induced by repeated 60% N2O exposures could be extinguished using a cue-exposure paradigm. Rats received 18 N2O administrations in a total calorimetry system that simultaneously measures core temperature (Tc), metabolic heat production (HP), and body heat loss (HL). Each exposure entailed a 2-h baseline period followed by a 1.5-h N2O exposure. The 18 drug exposures induced a robust intra-administration hyperthermia in which the initial hypothermic effect of N2O inverted to a significant hyperthermic sign-reversal during N2O inhalation due primarily to an acquired robust increase in HP. The rats were then randomized to one of three extinction procedures (n=8/procedure) over a 20-d interval: 1) a N2O-abstinent home-cage group (HC) that received only the usual animal care; 2) a cue-exposure group (CEXP) in which the animals were placed in the calorimeter 8 times but received no N2O; and 3) a drug-onset-cue group (DOC) in which animals received a brief N2O exposure in the calorimeter that mimicked the first 3 min of an actual 60% N2O trial. Following the extinction sessions, all rats received a 60% N2O test trial and Tc, HP and HL were assessed. The hyperthermic sign-reversal remained fully intact during the test trial, with no significant differences observed among groups in any post-baseline change in any thermal outcome. These data suggest that cue exposure may not be an efficacious strategy to reduce sign-reversals that develop with chronic drug use.