Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats.

Nitrous oxide (N₂O) can initially lower core temperature ( T _core), but hypothermic tolerance develops with chronic administration. Therefore, one or both of T _core’s controlling determinants, heat production (HP) and heat loss (HL), must adapt across repeated N₂O administrations. Simultaneous measurements of HP, HL, and T _core during chronic N₂O administrations will elucidate this adaptive process and constitute a rigorous model for studying the systems-level dynamics of tolerance in both mature and young animals. This approach is justified by the need to better understand the increased vulnerability to addiction associated with adolescent drug use. The objective of the study was to measure HL and HP across repeated steady-state administrations of 60% N₂O in young and mature rats. Synchronous measurements of HP (indirect calorimetry), HL (direct calorimetry), and T _core (telemetry) were obtained during 60% N₂O administrations in adolescent (28–45 days, n = 11) and mature rats (>90 days, n = 8). Rats received five 90-min drug exposures (every other day). Compared to mature rats, adolescents initially exhibited greater hypothermia, but acquired tolerance more rapidly and actually developed hyperthermia during the fifth administration. In both groups, N₂O consistently increased HL, but progressive increases of intrasessional HP over repeated administrations prevented hypothermia and subsequently promoted hyperthermia in adolescent rats. Adolescent rats hyper-adapt to N₂O hypothermia. Increases of intrasessional HP across N₂O administrations explained both tolerance to N₂O hypothermia and the unexpected hyperthermia observed in adolescents. These findings raise the possibility that the increased vulnerability to addiction associated with adolescent drug use involves a hyper-adaptive tolerance mechanism. [ABSTRACT FROM AUTHOR]