Walter Nelson

An evaluation of time-dependent changes in susceptibility of mice to pentobarbital injection

Abstract The circadian rhythm in sleep-response of mice to pentobarbital injection was studied at four different doses. Characteristics of the rhythm, determined by least squares cosine fitting, varied significantly among doses. Parallel-line bioassay of log-transformed data permitted expression of the susceptibility rhythm as a variation in relative potency. Concomitant study of circadian-rhythmic and age-related changes in sleep-response to pentobarbital injection indicated significant differences on both time scales, and the absence of interaction. At circadian phases of long and short sleep duration, brain and blood pentobarbital concentrations were determined at intervals after injection, up to and including the time of awakening. The waking concentrations in brain and blood were significantly higher at the circadian phase of short sleep duration, while time-dependent differences in the rate of barbiturate disappearance from these sites could not be demonstrated. The waking brain pentobarbital concentration at a given circadian phase also differed between 4-month and 9-month old mice. Factors possibly responsible for time-dependent changes in susceptibility to barbiturate injection are discussed.

Schedule-shifts, circadian rhythms and lifespan of freely-feeding and meal-fed mice ☆

Mice feeding ad lib were subjected to weekly 12-hr shifts of the daily light-dark (LD) schedule beginning at either 7, 20 or 52 weeks of age and continuing until death. Other mice were meal-fed and, from 7 weeks of age until death, experienced weekly 12-hr shifts of the LD schedule alone (with mealtime fixed) or of both the LD schedule and mealtime. Telemetered core temperature data indicated marked differences in response to the different shift conditions and suggested, in the case of meal-fed animals, involvement of a food-anticipatory rhythm. Shifting of the LD schedule had no statistically significant effect on the mean survival time of mice feeding ad lib, regardless of when shifting began. While meal-feeding in itself prolonged life, the added imposition of schedule-shifting had no statistically significant effect on mean survival time, regardless of whether the meal schedule reinforced or opposed shifts of the LD schedule. In the latter case, tenth-decile survival time may have been increased.

Plans for orbital study of rat biorhythms results of interest beyond the biosatellite program

Long term zero gravity effects on mammal physiologic rhythms characteristics, studying rats in biosatellite orbits

Time-qualified reference intervals — chronodesms

Methods are presented for qualifying clinical reference intervals, for individuals as well as peer groups, according to circadian and other rhythms, using chronobiologically-defined single samples or time series.

Circadian Timing of Single Daily “Meal” Affects Survival of Mice

Summary The survival of young BALB/c mice after abrupt restriction to a single 4-hr span of daily food accessibility can depend on the temporal placement of this feeding span in relation to the lighting regimen. Housing conditions are an important code-terminant of this response.

Bone growth in the rat mandible following every-day or alternate-day methylprednisolone treatment schedules

Abstract The effects of a short-acting corticosteroid, methylprednisolone sodium succinate (MPSS), on alveolar and cortical bone growth in rats were tested within a chronopharmacologic context. Different groups of rats were injected intraperitoneally at 1 of 6 circadian stages, 4 h apart, daily (ED) or on alternate days (AD). The doses of MPSS were progressively raised from 0.25 – 0.50 mg/kg ED-AD to 40–80 mg/kg ED-AD within 26 days, and the total duration of the study was 46 days. Controls received daily saline injections. Tetracycline was injected at 6–10 day intervals to provide biological time-markers for each change in the MPSS dose level. Mandibular growth in rats treated with MPSS (either ED or AD) was generally less than that in saline-treated controls, except perhaps when the injections occurred early in the daily light span. Low doses (first 6 days) injected 1–5 h after the onset of the environmental photofraction, stimulated cortical appositional bone growth, but at other circadian times the same dose level appeared to be inhibitory. In the case of mandible length and cortical bone growth, the response of control animals to saline injection also exhibited a statistically-significant circadian rhythm, with highest values during the early or middle light span. The presence of this rhythm suggests that saline injections per se were a disturbance, the effects of which were mediated by endogenous corticosterone production; it provides additional evidence for a circadian stage dependence of bone response to corticosteroid, whether of endogenous or exogenous origin. The circadian rhythm in growth response was consistently most pronounced in the rats treated with MPSS daily, as indicated by higher amplitudes and lower probability values for fitted 24-h cosines. The temporal optimization of steroid effects in the rat jaw may be more readily achieved with ED dose schedules than with AD schedules.

Food restriction, circadian disorder and longevity of rats and mice

Evidence that food restriction alters circadian rhythms as it prolongs the healthful life of rats and mice is reviewed. Because rhythms in different variables are changed in different ways, the circadian organization that is characteristic of freely feeding animals is disrupted. In the case of daily food restriction (meal feeding), the extent of disruption depends on the timing of the meal in relation to the daily light-dark schedule. Recent studies indicate that the extension of life span by a given level of food restriction is similar regardless of mealtime, whether fixed or shifted at weekly intervals throughout life. Such results suggest that the effects of food restriction on circadian organization are not involved in the effect on survival. On the other hand, changes in any given rhythm (such as an increased amplitude and a decreased overall average of body temperature) could point to the mechanism by which longevity is increased.

THE EFFECT OF DIISOPROPYLPHOSPHORO-FLUORIDATE (DFP) ON MOUSE BRAIN PHOSPHORUS METABOLISM

THE pharmacological effects of diisopropylphosphorofluoridate (DFP)? are commonly attributed to its inhibition of nervous system cholinesterases. There are, however, a number of indications that other factors may be involved (MCNAMARA et a[., 1454). Following inhibition by 32P-labelled DFP, cholinesterase and other enzymes such as chymotrypsin are found on hydrolysis to yield ~2P]-phosph.oserine; this suggests that the reaction of DFP with serine residues prevents the catalytic action of these enzymes (SCHAFFER et a]., 1953, 1954). The possibility that serine may also play an important role in enzymes of phosphorus metabolism is indicated by the relatively rapid rate at which protein-bound phosphoserine of animal tissues becomes labelled following the injection of 32P-labelled orthophosphate (KENNEDY and SMITH, 1954). On the basis of these considerations it seemed plausible that DFP might interfere with phosphorus metabolism by tying up serine groups which may be necessary for the functioning of the enzymes involved. Thus, KENNEDY and KOSHLAND (1957) have observed that serine may be involved in the action of phosphoglucomutase, and that this enzyme could be inhibited by DFP. Such an effect of DFP on the phosphorus metabolism of the nervous system could conceivably be responsible for some of the pharmacological effects of this agent.

Effects of a synchronizer phase shift on circadian rhythms in response of mice to ethanol or ouabain.

The percentage of mice dying from a toxic dose of ethanol or ouabain was determined at 4-hour intervals during the first 3 days after inversion of an LD(12:12) lighting regimen. In comparison to unshifted control animals at similar stages of the synchronizer schedule, spans of relative advantage alternated with spans of relative disadvantage due to a gradual phase-shift of the circadian susceptibility rhythm. Overall mortality, determined for an integral number of day, was not obviously affected by the regimen-shift.

Dose-response evaluations of a circadian rhythmic change in susceptibility of mice to ouabain

Abstract Relations between dose of ouabain, administered to mice either intraperitoneally or subcutaneously, and mortality were examined at times of high and low response in the previously reported circadian rhythm in susceptibility to this drug, i.e., at about 08:00 and 20:00 for mice housed under standard conditions, including light from 06:00 to 18:00 and darkness from 18:00 and 06:00. Animals tested at about 08:00 on the regimen showed significantly higher susceptibility to ouabain, regardless of the route of administration. Parallelism of dose-response relations for the two times of administration suggests a similarity in the mechanism of drug action. Possible changes underlying the circadian rhythm in susceptibility of mice to ouabain are briefly discussed.