Concentration-related metabolic rate and behavioral thermoregulatory adaptations to serial administrations of nitrous oxide in rats

BACKGROUND: Initial administration of ≥60% nitrous oxide (N(2)O) to rats evokes hypothermia, but after repeated administrations the gas instead evokes hyperthermia. This sign reversal is driven mainly by increased heat production. To determine whether rats will behaviorally oppose or assist the development of hyperthermia, we previously performed thermal gradient testing. Inhalation of N(2)O at ≥60% causes rats to select cooler ambient temperatures both during initial administrations and during subsequent administrations in which the hyperthermic state exists. Thus, an available behavioral response opposes (but does not completely prevent) the acquired hyperthermia that develops over repeated high-concentration N(2)O administrations. However, recreational and clinical uses of N(2)O span a wide range of concentrations. Therefore, we sought to determine the thermoregulatory adaptations to chronic N(2)O administration over a wide range of concentrations. METHODS: This study had two phases. In the first phase we adapted rats to twelve 3-h N(2)O administrations at either 0%, 15%, 30%, 45%, 60% or 75% N(2)O (n = 12 per group); outcomes were core temperature (via telemetry) and heat production (via respirometry). In the second phase, we used a thermal gradient (range 8°C—38°C) to assess each adapted group’s thermal preference, core temperature and locomotion on a single occasion during N(2)O inhalation at the assigned concentration. RESULTS: In phase 1, repeated N(2)O administrations led to dose related hyperthermic and hypermetabolic states during inhalation of ≥45% N(2)O compared to controls (≥ 30% N(2)O compared to baseline). In phase 2, rats in these groups selected cooler ambient temperatures during N(2)O inhalation but still developed some hyperthermia. However, a concentration-related increase of locomotion was evident in the gradient, and theoretical calculations and regression analyses both suggest that locomotion contributed to the residual hyperthermia. CONCLUSIONS: Acquired N(2)O hyperthermia in rats is remarkably robust, and occurs even despite the availability of ambient temperatures that might fully counter the hyperthermia. Increased locomotion in the gradient may contribute to hyperthermia. Our data are consistent with an allostatic dis-coordination of autonomic and behavioral thermoregulatory mechanisms during drug administration. Our results have implications for research on N(2)O abuse as well as research on the role of allostasis in drug addiction.