Nitrous Oxide-Induced Hypothermia in the Rat

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

“…It should be noted, however, that individual rats in the present study did exhibit acute tolerance (discussed below). In our previous studies, which used a polycarbonate exposure chamber, the mean T c profiles during N 2 O administration were indicative of significant acute tolerance development (30,54). Two factors may have worked against the expression of acute tolerance in the present study: 1) the water-cooled metalwalled surround of the direct calorimeter used in the present study likely imposed a greater environmental heat sink than polycarbonate does; and 2) urination resulted in some wetting of the dorsal surface of the rats, which may have worked against heat-conserving physiological responses.…”

“…An additional, desirable attribute is mediation by central regulatory mechanisms, reflecting the concept that drug use activates neuronal regulatory systems in ways that contribute to acute tolerance, chronic tolerance, withdrawal, drug dependence, and the potential for relapse in abstinent individuals (25,35,48,49,51,55,63). Core body temperature (T c ) epitomizes each of these attributes and has a long (59) and extensive history as an outcome variable in studies focused on major themes of drug addiction, including mechanisms of drug tolerance (6,14,24,27,36,38,39,54,64), mechanisms of drug dependence (62), and, more recently, the genetic basis of initial ethanol sensitivity (8,9,12,46). …”

“…This model of tolerance and its putative relationship to withdrawal and dependence can be illustrated in terms of the potent hypothermic effect of ethanol (17,36) or nitrous oxide (N 2 O) (30,52,54), an abusable inhalant with euphorigenic, anxiolytic, and analgesic properties (16). During an initial steady-state administration of either drug, substantial hypothermia first develops, but subsequently T c often returns toward baseline or control values, indicative of acute tolerance development (17,30,54). Acute tolerance to drug-induced hypothermia is proposed to reflect the reflexive, unconditioned activation of heat-producing/heatconserving effector responses by negative feedback emanating from the hypothermic state (15,27,55).…”

“…Acute tolerance to drug-induced hypothermia is proposed to reflect the reflexive, unconditioned activation of heat-producing/heatconserving effector responses by negative feedback emanating from the hypothermic state (15,27,55). With sufficient repeated administrations, the initial drug dose evokes limited hypothermia (36,54), indicative of chronic tolerance development. One explanation for this phenomenon is that the animal comes to associate the drug-induced hypothermic state with antecedent environmental and/or interoceptive drug onset cues and now promptly responds to these cues by preemptively activating anti-hypothermic responses (associative tolerance is reviewed in Refs.…”

“…Because T c is determined by the integrated difference between metabolic heat production (HP) and heat loss (HL), we have developed a rodent model to study these underlying determinants during steady-state administrations of a temperaturealtering drug of abuse. This experimental paradigm simultaneously records HP via indirect calorimetry, HL via direct gradient layer calorimetry, and T c via biotelemetry during exposures to N 2 O, a drug of abuse with a dose-related hypothermic effect (52) and one uniquely suited to protocols requiring prolonged steady-state administrations and freedom from active metabolites (30,54,68). This paper describes our experimental paradigm, reveals in detail the thermal basis of N 2 O hypothermia, and sets the stage for future applications to the study of tolerance development and the drug-dependent state.…”