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Nitrous oxide (N2O) is a gaseous drug with abuse potential. Despite its common clinical use, little is known about whether N2O administration activates the HPA axis and/or the sympathetic adrenomedullary system. The goal of this study was to determine whether 60% N2O alters plasma concentrations of corticosterone (CORT), epinephrine (EPI), and norepinephrine (NE) in male Long-Evans rats. A gas-tight swivel assembly in the lid of a gas administration chamber allowed the remote collection of blood samples from an indwelling jugular vein catheter at four time-points: baseline and at 30, 60, and 120 min during a two-hour administration of 60% N2O. Relative to baseline, plasma CORT (n = 9) was significantly elevated at all three time-points during N2O inhalation (mixed model analysis, p = .001) and plasma EPI and NE levels were each significantly elevated (n = 8, p ≤ .001) at the 30 min assessment. EPI then declined and did not differ from baseline at the 60 and 120 min assessments (p > .05) whereas NE remained elevated (120 min, p = .001). Administration of 60% N2O increases circulating CORT, EPI, and NE, supporting N2O as a physiological stressor. An N2O-induced increase in CORT is consistent with the observation that addictive drugs typically activate the HPA axis causing increased plasma levels of glucocorticoids. Allostatic models of drug addiction typically involve stress systems and the possible role of stress hormones in N2O-induced allostatic dysregulation is discussed. [ABSTRACT FROM AUTHOR]

Contrary to dogma, much physiological regulation utilizes learning from past experience to make responses that preemptively and effectively neutralize anticipated regulatory challenges. Understanding physiological regulation therefore requires expanding explanatory models beyond homeostasis and allostasis to emphasize the prominence of conditioning. [ABSTRACT FROM AUTHOR]

Initial administration of ≥60% nitrous oxide (N 2 O) to rats promotes hypothermia primarily by increasing whole-body heat loss. We hypothesized that the drug promotes heat loss via the tail and might initially inhibit thermogenesis via brown adipose tissue (BAT), major organs of thermoregulation in rodents. Following repeated administrations, N 2 O inhalation evokes hyperthermia underlain by increased whole-body heat production. We hypothesized that elevated BAT thermogenesis plays a role in this thermoregulatory sign reversal. Using dual probe telemetric temperature implants and infrared (IR) thermography, we assessed the effects of nine repeated 60% N 2 O administrations compared to control (con) administrations on core temperature, BAT temperature, lumbar back temperature and tail temperature. Telemetric core temperature, telemetric BAT temperature, and IR BAT temperature were reduced significantly during initial 60% N 2 O inhalation (p≤0.001 compared to con). IR thermography revealed that acute N 2 O administration unexpectedly reduced tail temperature (p=0.0001) and also inhibited IR lumbar temperature (p<0.0001). In the 9th session, N 2 O inhalation significantly increased telemetric core temperature (p=0.007) indicative of a hyperthermic sign reversal, yet compared to control administrations, telemetric BAT temperature (p=0.86), IR BAT temperature (p=0.85) and tail temperature (p=0.47) did not differ significantly. Thus, an initial administration of 60% N 2 O at 21 °C may promote hypothermia via reduced BAT thermogenesis accompanied by tail vasoconstriction as a compensatory mechanism to limit body heat loss. Following repeated N 2 O administrations rats exhibit a hyperthermic core temperature but a normalized BAT temperature, suggesting induction of a hyperthermia-promoting thermogenic adaptation of unknown origin. [ABSTRACT FROM AUTHOR]

Homeostasis, the dominant explanatory framework for physiological regulation, has undergone significant revision in recent years, with contemporary models differing significantly from the original formulation. Allostasis, an alternative view of physiological regulation, goes beyond its homeostatic roots, offering novel insights relevant to our understanding and treatment of several chronic health conditions. Despite growing enthusiasm for allostasis, the concept remains diffuse, due in part to ambiguity as to how the term is understood and used, impeding meaningful translational and clinical research on allostasis. Here, we provide a more focused understanding of homeostasis and allostasis by explaining how both play a role in physiological regulation, and a critical analysis of regulation suggests how homeostasis and allostasis can be distinguished. Rather than focusing on changes in the value of a regulated variable (e.g., body temperature, body adiposity, or reward), research investigating the activity and relationship among the multiple regulatory loops that influence the value of these regulated variables may be the key to distinguishing homeostasis and allostasis. The mechanisms underlying physiological regulation and dysregulation are likely to have important implications for health and disease. [ABSTRACT FROM AUTHOR]

Studies using core temperature (Tc) have contributed greatly to theoretical explanations of drug tolerance and its relation- ship 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 Tc, 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 Tc 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 Tc (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 Tc (-1.6°C). However, some rats entered positive heat balance (HP > HL) after becoming hypothermic such that acute tolerance developed, i.e., Tc rose despite continued drug administration. This work is the first to directly quantify the thermal determinants of Tc during administration of a drug of abuse and establishes a new paradigm for studying opponent processes involved in acute and chronic hypothermic tolerance development. [ABSTRACT FROM AUTHOR]

Abstract: 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 (N2O)-induced hypothermia would exhibit different patterns of tolerance development across N2O 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% N2O-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% N2O using a classical conditioning procedure, (2) twelve 90-min exposures to 70% N2O 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 N2O and control gas administrations. Initially insensitive rats rapidly acquired (3rd administration) a significant allostatic hyperthermic phenotype during N2O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N2O inhalation in the 4th and 5th sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11th and 12th N2O 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 N2O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N2O 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. [Copyright &y& Elsevier]