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SLEEP AND TEMPERATURE REGULATION

Assessment of heat production, heat loss, and core temperature during nitrous oxide exposure: a new paradigm for studying drug effects and opponent responses

Departments of ¹Dental Public Health Sciences, ²Orthodontics, and ³Pediatric Dentistry, University of Washington, Seattle, Washington

Submitted 21 June 2004 ; accepted in final form 23 November 2004

Studies using core temperature (T_c) have contributed greatly to theoretical explanations of drug tolerance and its relationship to key features of addiction, including dependence, withdrawal, and relapse. Many theoretical accounts of tolerance propose that a given drug-induced psychobiological disturbance elicits opponent responses that contribute to tolerance development. This proposal and its theoretical extensions (e.g., conditioning as a mechanism of chronic tolerance) have been inferred from dependent variables, such as T_c, which represent the summation of multiple underlying determinants. Direct measurements of determinants could increase the understanding of opponent processes in tolerance, dependence, and withdrawal. The proximal determinants of T_c are metabolic heat production (HP) and heat loss (HL). We developed a novel system for simultaneously quantifying HP (indirect calorimetry), HL (direct gradient layer calorimetry), and T_c (telemetry) during steady-state administrations of nitrous oxide (N₂O), an inhalant with abuse potential that has been previously used to study acute and chronic tolerance development to its hypothermia-inducing property. Rats were administered 60% N₂O (n = 18) or placebo gas (n = 16) for 5 h after a 2-h placebo baseline exposure. On average, N₂O rapidly but transiently lowered HP and increased HL, each by 16% (P < 0.001). On average, rats reestablished and maintained thermal equilibrium (HP = HL) at a hypothermic T_c (–1.6°C). However, some rats entered positive heat balance (HP > HL) after becoming hypothermic such that acute tolerance developed, i.e., T_c rose despite continued drug administration. This work is the first to directly quantify the thermal determinants of T_c during administration of a drug of abuse and establishes a new paradigm for studying opponent processes involved in acute and chronic hypothermic tolerance development.

addiction; drug tolerance; acute tolerance; drug dependence; gradient layer calorimetry; indirect calorimetry