title: Systems-level adaptations explain chronic tolerance development to nitrous oxide hypothermia in young and mature rats.
abstract: BACKGROUND
  Nitrous oxide (N(2)O) 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 N(2)O administrations. Simultaneous measurements of HP, HL, and T (core) during chronic N(2)O 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.
  
  
  OBJECTIVE
  The objective of the study was to measure HL and HP across repeated steady-state administrations of 60% N(2)O in young and mature rats.
  
  
  METHODS
  Synchronous measurements of HP (indirect calorimetry), HL (direct calorimetry), and T (core) (telemetry) were obtained during 60% N(2)O 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).
  
  
  RESULTS
  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, N(2)O consistently increased HL, but progressive increases of intrasessional HP over repeated administrations prevented hypothermia and subsequently promoted hyperthermia in adolescent rats.
  
  
  CONCLUSIONS
  Adolescent rats hyper-adapt to N(2)O hypothermia. Increases of intrasessional HP across N(2)O administrations explained both tolerance to N(2)O 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.
authors.affiliation: Department of Dental Public Health Sciences, University of Washington, Box 357475, Seattle, WA 98195-7475, USA. kkaiyala@u.washington.edu
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Kaiyala
authors.forename: Shehzad
authors.initials: S
authors.lastname: Butt
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Ramsay
mesh_terms: D000280:Administration, Inhalation; D052636:Allostasis / Q000187:drug effects; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects*; D002151:Calorimetry; D002153:Calorimetry, Indirect; D004361:Drug Tolerance; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D009609:Nitrous Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D019966:Substance-Related Disorders / Q000503:physiopathology; D013686:Telemetry; D022722:Thermogenesis / Q000187:drug effects; D013997:Time Factors
chemical_list: D009609:Nitrous Oxide