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Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors.

ABSTRACT: Initial administration of 60% nitrous oxide (N2O) to rats at an ambient temperature of 21°C decreases core temperature (Tc), primarily via increased heat loss (HL). Over repeated N2O administrations, rats first develop tolerance to this hypothermia and subsequently exhibit hyperthermia (a sign-reversal) due primarily to progressive increases in heat production (HP). When rats initially receive 60% N2O in a thermal gradient, they become hypothermic while selecting cooler ambient temperatures that facilitate HL. This study investigated whether rats repeatedly administered 60% N2O in a thermal gradient would use the gradient to behaviorally facilitate, or oppose, the development of chronic tolerance and a hyperthermic sign-reversal. Male Long-Evans rats (N=16) received twelve 3-h administrations of 60% N2O in a gas-tight, live-in thermal gradient. Hypothermia (Sessions 1-3), complete chronic tolerance (Sessions 4-6), and a subsequent transient hyperthermic sign-reversal (Sessions 7-12) sequentially developed. Despite the progressive recovery and eventual hyperthermic sign-reversal of Tc, rats consistently selected cooler ambient temperatures during all N2O administrations. A final 60% N2O administration in a total calorimeter indicated that the hyperthermic sign-reversal resulted primarily from increased HP. Thus, rats did not facilitate chronic tolerance development by moving to warmer locations in the gradient, and instead selected cooler ambient temperatures while simultaneously increasing autonomic HP. The inefficient concurrent activation of opposing effectors and the development of a sign-reversal are incompatible with homeostatic models of drug-adaptation and may be better interpreted using a model of drug-induced allostasis.

SUBMITTER: Ramsay DS

PROVIDER: S-EPMC4414259 | biostudies-literature | 2014 Oct-Dec

REPOSITORIES: biostudies-literature

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Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors.

Ramsay Douglas S DS Woods Stephen C SC Kaiyala Karl J KJ

Temperature (Austin, Tex.) 20141001 3

Initial administration of 60% nitrous oxide (N2O) to rats at an ambient temperature of 21°C decreases core temperature (Tc), primarily via increased heat loss (HL). Over repeated N2O administrations, rats first develop tolerance to this hypothermia and subsequently exhibit hyperthermia (a sign-reversal) due primarily to progressive increases in heat production (HP). When rats initially receive 60% N2O in a thermal gradient, they become hypothermic while selecting ...[more]

PMID: 25938127

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Project description:Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug's pharmacological effect, the individual's autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (T(c)), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N(2)O)-induced hypothermia would exhibit different patterns of tolerance development across N(2)O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N(2)O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: 1) twelve 90-min exposures to 70% N(2)O using a classical conditioning procedure, 2) twelve 90-min exposures to 70% N(2)O using a random control procedure for conditioning, or 3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T(c) (via telemetry) were simultaneously quantified during N(2)O and control gas administrations. Initially insensitive rats rapidly acquired (3(rd) administration) a significant allostatic hyperthermic phenotype during N(2)O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N(2)O inhalation in the 4(th) and 5(th) sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11(th) and 12th N(2)O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N(2)O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N(2)O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production.

Project description:Initial administration of ?60% nitrous oxide (N2O) 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 N2O 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 N2O administrations. However, recreational and clinical uses of N2O span a wide range of concentrations. Therefore, we sought to determine the thermoregulatory adaptations to chronic N2O administration over a wide range of concentrations.This study had two phases. In the first phase we adapted rats to twelve 3-h N2O administrations at either 0%, 15%, 30%, 45%, 60% or 75% N2O (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 N2O inhalation at the assigned concentration.In phase 1, repeated N2O administrations led to dose related hyperthermic and hypermetabolic states during inhalation of ?45% N2O compared to controls (? 30% N2O compared to baseline). In phase 2, rats in these groups selected cooler ambient temperatures during N2O 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.Acquired N2O 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 N2O abuse as well as research on the role of allostasis in drug addiction.

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Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors.

Publications

Repeated nitrous oxide exposure in rats causes a thermoregulatory sign-reversal with concurrent activation of opposing thermoregulatory effectors.

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