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1.  Direct Animal Calorimetry, the Underused Gold Standard for Quantifying the Fire of Life* 
Direct animal calorimetry, the gold standard method for quantifying animal heat production (HP), has been largely supplanted by respirometric indirect calorimetry owing to the relative ease and ready commercial availability of the latter technique. Direct calorimetry, however, can accurately quantify HP and thus metabolic rate (MR) in both metabolically normal and abnormal states, whereas respirometric indirect calorimetry relies on important assumptions that apparently have never been tested in animals with genetic or pharmacologically-induced alterations that dysregulate metabolic fuel partitioning and storage so as to promote obesity and/or diabetes. Contemporary obesity and diabetes research relies heavily on metabolically abnormal animals. Recent data implicating individual and group variation in the gut microbiome in obesity and diabetes raise important questions about transforming aerobic gas exchange into HP because 99% of gut bacteria are anaerobic and they outnumber eukaryotic cells in the body by ~10-fold. Recent credible work in non-standard laboratory animals documents substantial errors in respirometry-based estimates of HP. Accordingly, it seems obvious that new research employing simultaneous direct and indirect calorimetry (total calorimetry) will be essential to validate respirometric MR phenotyping in existing and future pharmacological and genetic models of obesity and diabetes. We also detail the use of total calorimetry with simultaneous core temperature assessment as a model for studying homeostatic control in a variety of experimental situations, including acute and chronic drug administration. Finally, we offer some tips on performing direct calorimetry, both singly and in combination with indirect calorimetry and core temperature assessment.
PMCID: PMC3920988  PMID: 20427023
metabolic rate; energy expenditure; animal heat production; homeostasis; obesity; diabetes; drug tolerance
2.  Robust thermoregulatory overcompensation, rather than tolerance, develops with serial administrations of 70% nitrous oxide to rats 
Journal of thermal biology  2012;37(1):30-40.
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 (Tc), 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 Tc (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.
PMCID: PMC3255088  PMID: 22247586
Allostasis; Homeostasis; Drug tolerance; Addiction; Thermoregulation; Calorimetry; Sign-reversal; Associative tolerance; Homotopic conditioned reflex; Homoreflex; Drug-Onset-Cue
3.  Nitrous Oxide Causes a Regulated Hypothermia: Rats Select a Cooler Ambient Temperature While Becoming Hypothermic 
Physiology & behavior  2010;103(1):79-85.
An initial administration of 60% nitrous oxide (N2O) evokes hypothermia in rats and if the administration continues for more than 1 – 2 hours, acute tolerance typically develops such that the initial reduction in core temperature (Tc) reverses and Tc recovers toward control values. Calorimeter studies at normal ambient temperature indicate that hypothermia results from a transient reduction in heat production (HP) combined with an elevation in heat loss. Acute tolerance develops primarily due to progressive increases in HP. Our aim was to determine whether rats provided a choice of ambient temperatures would behaviorally facilitate or oppose N2O -induced hypothermia. A gas-tight thermally-graded alleyway (range, 6.7 – 37.0°C) enabled male Long-Evans rats (n=12) to select a preferred ambient temperature during a 5-hour steady-state administration of 60% N2O and a separate paired control gas exposure (order counterbalanced). Tc was measured telemetrically from a sensor surgically implanted into the peritoneal cavity > 7 days before testing. Internal LED lighting maintained the accustomed day:night cycle (light cycle 0700 – 1900 h) during sessions lasting 45.5 hours. Rats entered the temperature gradient at 1100 h, and the 5-h N2O or control gas period did not start until 23 hours later to provide a long habituation / training period. Food and water were provided ad libitum at the center of the alleyway. The maximum decrease of mean Tc during N2O administration occurred at 0.9 h and was −2.05 ± 0.25°C; this differed significantly (p<0.0001) from the corresponding Tc change at 0.9 h during control gas administration (0.01 ± 0.14°C). The maximum decrease of mean selected ambient temperature during N2O administration occurred at 0.7 h and was −13.58 ± 1.61°C; this differed significantly (p < 0.0001) from the corresponding mean change in selected ambient temperature at 0.7 h during control gas administration (0.30 ± 1.49°C). N2O appears to induce a regulated hypothermia because the selection of a cool ambient temperature facilitates the reduction in Tc. The recovery of Tc during N2O administration (i.e., acute tolerance development) could have been facilitated by selection of ambient temperatures that were warmer than those chosen during control administrations, but interestingly, this did not occur.
PMCID: PMC3056887  PMID: 21184766
Thermoregulation; acute tolerance; intrasessional tolerance; behavioral thermoregulation; allostasis
4.  Homeostasis: Beyond Curt Richter1 
Appetite  2007;49(2):388-398.
Curt Richter introduced behavioral control into the concept of homeostasis, thereby opening entire fields of research. The prevailing dogma, and the techniques he used, conspired to lead Richter and others to interpret regulation in strict negative feedback terms. Although this point of view continues to be embraced by many contemporary biologists, we believe that prevailing sentiment favors a broader view in which organisms integrate anticipatory pre-emptive control over regulated variables whenever possible.
PMCID: PMC2696031  PMID: 17524521
homeostasis; allostasis; rheostasis; set point; negative feedback; control theory; cephalic responses; glucose regulation; thermal regulation; sodium appetite; calcium appetite
5.  Reactivity and Regulation in Children Prenatally Exposed to Cocaine 
Developmental psychology  2006;42(4):688-697.
Children prenatally exposed to cocaine may be at elevated risk for adjustment problems in early development because of greater reactivity and reduced regulation during challenging tasks. Few studies have examined whether cocaine-exposed children show such difficulties during the preschool years, a period marked by increased social and cognitive demands and by rapid changes in reactivity and regulation. The authors addressed this question by examining frustration reactivity and regulation of behavior during a problem-solving task in cocaine-exposed and -unexposed preschoolers. Participants were 174 4.5-year-olds (M age = 4.55 years, SD = 0.09). Frustration reactivity was measured as latency to show frustration and number of disruptive behaviors, whereas regulation was measured as latency to approach and attempt the problem-solving task and number of problem-solving behaviors. Results indicated that cocaine-exposed children took longer to attempt the problem-solving task but that cocaine-exposed boys showed the most difficulties: They were quicker to express frustration and were more disruptive. Effect sizes were relatively small, suggesting both resilience and vulnerabilities.
PMCID: PMC1861810  PMID: 16802901
reactivity; regulation; prenatal cocaine exposure
6.  Effect of Prenatal Alcohol and Cigarette Exposure on Two- and Six-Month-Old Infants' Adrenocortical Reactivity to Stress1 
Journal of pediatric psychology  1996;21(6):833-840.
Examined the effect of prenatal alcohol and cigarette exposure on infant adrenocortical reactivity to stress at 2 and 6 months of age. Cortisol response (pre- to poststressor increase) at 2 months was lower for the exposed than nonexposed infants, whereas cortisol response at 6 months did not differ between the exposed and nonexposed infants. The 2-month group difference in cortisol response reflected a higher prestressor cortisol level in the exposed infants.
PMCID: PMC1538973  PMID: 8990727
adrenocortical reactivity; alcohol; cigarettes; cortisol; inoculation; prenatal exposure
7.  The Relation of ANS and HPA Activation to Infant Anger and Sadness Response to Goal Blockage 
Developmental psychobiology  2006;48(5):397-405.
This study examined the relation of anger and sadness to heart rate and cortisol in 4-month-old infants’ (N = 56) response to a goal blockage. The blockage occurred during a contingency learning procedure where infants’ response no longer produced a learned interesting event. Anger and sadness were the major emotional expressions to the blockage. The two emotional expressions were differentially related to heart rate and cortisol. Anger was related to increased heart rate, but not cortisol, whereas sadness was related to increased cortisol, but not heart rate. Along with other work, the present results support the view that infant anger in response to goal blockage involves autonomic as opposed to adrenocortical activation as a consequence of an expectation of control over the event. In contrast, sadness in response to goal blockage involves adrenocortical as opposed to autonomic activation stemming from the absence of an expectation of control.
PMCID: PMC1482732  PMID: 16770761
8.  Individual Differences in Initial Sensitivity and Acute Tolerance Predict Patterns of Chronic Drug Tolerance to Nitrous-Oxide-Induced Hypothermia in Rats 
Psychopharmacology  2005;181(1):48-59.
Rationale: A preventive strategy for drug addiction would benefit from being able to identify vulnerable individuals. Understanding how an individual responds during an initial drug exposure may be useful for predicting how that individual will respond to repeated drug administrations.
Objectives: This study investigated whether individual differences in initial drug sensitivity and acute tolerance can predict how chronic tolerance develops.
Methods: During an initial 3-h administration of 60% nitrous oxide (N2O), male Long-Evans rats were screened for N2O’s hypothermic effect into subsets based on being initially insensitive (II), sensitive with acute tolerance (AT), or sensitive with no intrasessional recovery (NR). Animals in each individual difference category were randomly assigned to receive six 90-min exposures of either 60% N2O or placebo gas. Core temperature was measured telemetrically.
Results: Rats that exhibited a comparable degree of hypothermia during an initial N2O exposure, but differed in acute tolerance development, developed different patterns of chronic tolerance. Specifically, the NR group did not become fully tolerant over repeated N2O exposures while the AT group developed an initial hyperthermia followed by a return of core temperature to control levels indicative of full tolerance development. By the second N2O exposure, the II group breathing N2O became hyperthermic relative to the placebo control group and this hyperthermia persisted throughout the multiple N2O exposures.
Conclusions: Individual differences in initial drug sensitivity and acute tolerance development predict different patterns of chronic tolerance. The hypothesis is suggested that individual differences in opponent adaptive responses may mediate this relationship.
PMCID: PMC1470882  PMID: 15778887
Inhalant; addictive vulnerability; addiction; drug dependence; intrasessional tolerance; allostasis; homeostasis; regulation
9.  Infant Emotional and Cortisol Responses to Goal Blockage 
Child development  2005;76(2):518-530.
This study examined the relation of infant emotional responses of anger and sadness to cortisol response in 2 goal blockage situations. One goal blockage with 4-month-old infants (N = 56) involved a contingency learning procedure where infants’ learned response was no longer effective in reinstating an event. The other goal blockage with 6-month-old infants (N = 84) involved the still face procedure where infants’ reactions to their mothers’ lack of responsivity were not effective in reestablishing interaction. For both blockages, sadness was related to cortisol response, though anger was not—the greater the sadness, the higher the cortisol response. This differential relation is consistent with other evidence indicating the more positive role of anger as opposed to sadness in overcoming an obstacle.
PMCID: PMC1463181  PMID: 15784097
10.  Nitrous oxide analgesia in humans: Acute and chronic tolerance 
Pain  2005;114(1-2):19-28.
Electrical tooth stimulation was used to investigate whether humans develop tolerance to nitrous oxide (N2O) analgesia within a single administration as well as over repeated administrations. In a double-blind cross-over experiment, 77 subjects received a 40-minute administration of 38% N2O at one session and placebo gas at the other. The sessions were separated by 1 week and the order of gas administration was counterbalanced. Acute analgesic tolerance developed for pain threshold but not for detection threshold. There was no evidence of a hyperalgesic rebound effect following cessation of the N2O administration. In a second double-blind experiment, 64 subjects received both 30-min of placebo gas and 30-min of 35% N2O, separated by a 35-min gas wash-out period, during each of 5 sessions. Sensory thresholds were assessed prior to drug or placebo administration (baseline) and between 7-12 min and 25-30 min of gas administration. A control group of 16 subjects received only placebo gas at these 5 sessions. During a sixth session, the experimental procedures were similar to the previous sessions except that the control group received N2O for the first time and the experimental group was sub-divided to test for conditioned drug effects. For both detection and pain threshold measures, acute tolerance developed during the initial N2O exposure and chronic tolerance developed over repeated administrations. Although chronic tolerance developed, a test for Pavlovian drug conditioning found no evidence of conditioned effects on sensory thresholds. In conclusion, acute and chronic tolerance develop to N2O’s analgesic effects in humans.
PMCID: PMC1416628  PMID: 15733627
Pavlovian drug conditioning; pain; individual differences; electrical tooth stimulation; rebound; pain threshold
11.  Effects of Lidocaine with Epinephrine on Fear Related Arousal Among Dental Phobics 
Anesthesia Progress  1986;33(5):225-229.
The effects of 2% lidocaine containing 72 μg epinephrine on fear related arousal were tested using a cross-over design on dental patients fearful of injections and other dental procedures. Heart rate and body movement in the dental operatory were monitored, and subjects' self-reported upset in the Epinephrine condition than in the No-Epinephrine condition (F = 4.8, p = .04), but the clinical significance was negligible. No interaction between initial fear levels and the drug condition could be established. Results suggest that pre-existing dental fear levels may produce greater self-report, behavioral or physiological arousal in the dental operatory than exogenous epinephrine.
PMCID: PMC2177493  PMID: 3465257

Results 1-11 (11)