Behavioral and Neurochemical Effects of Fencamfamine on Rats: A Chronobiologic Approach

Biological Rhythms in Clinical and Laboratory Medicine. Edited by Y. Touitou and E. Haus. Berlin, Heidelberg, New York Springer-Verlag, 1992, 730 pp. (347 figures and 54 tables), $210.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

A Chronobiologic Approach to Ethanol and Acidified Aspirin Injury of the Gastric Mucosa in the Rat

Several models of erosive peptic disease have used drug-induced lesions to examine protective mechanisms of the gastric mucosa. Physiological processes such as acid secretion, motility, or epithelial cell turnover have circadian rhythms which may modulate the susceptibility of the gastric mucosa to injury. In this review are described recent studies which demonstrated that susceptibility to gastric mucosal injury by acidified aspirin and absolute ethanol varied with the phases of the light-dark cycle. Acidified aspirin caused significantly more gastric mucosal lesions when administered early in the light phase compared to administration early in the dark phase. The differences in susceptibility were not altered by pretreatment conditions such as immobilization or length of the fasting period. Absolute ethanol also caused significantly greater gastric mucosal injury when administered in the light than in the dark phase, but this difference was only evident in rats immobilized during the pretreatment fasting period. Further studies are needed to correlate circadian susceptibility to drug-induced gastric mucosal injury with physiological defense mechanisms. Careful attention to circadian timekeeping may allow us to refine therapy to optimize physiological defense mechanisms in the stomach.     

A Chronobiologic Approach to Ethanol and Acidified Aspirin Injury of the Gastric Mucosa in the Rat

Several models of erosive peptic disease have used drug-induced lesions to examine protective mechanisms of the gastric mucosa. Physiological processes such as acid secretion, motility, or epithelial cell turnover have circadian rhythms which may modulate the susceptibility of the gastric mucosa to injury. In this review are described recent studies which demonstrated that susceptibility to gastric mucosal injury by acidified aspirin and absolute ethanol varied with the phases of the light-dark cycle. Acidified aspirin caused significantly more gastric mucosal lesions when administered early in the light phase compared to administration early in the dark phase. The differences in susceptibility were not altered by pretreatment conditions such as immobilization or length of the fasting period. Absolute ethanol also caused significantly greater gastric mucosal injury when administered in the light than in the dark phase, but this difference was only evident in rats immobilized during the pretreatment fasting period. Further studies are needed to correlate circadian susceptibility to drug-induced gastric mucosal injury with physiological defense mechanisms. Careful attention to circadian timekeeping may allow us to refine therapy to optimize physiological defense mechanisms in the stomach.     

慢性应激抑郁状态对大鼠外周神经内分泌因子生物节律的影响

目的：探讨慢性不可预见性应激状态下大鼠外周神经内分泌因子昼夜节律的表达特点。方法：成年雄性SD大鼠60只,随机分为模型组和对照组（n=30）,采用束缚、摇晃、鼠笼倾斜、湿垫料、冷刺激、拥挤（整夜）、断食或断水、夹尾、昼/夜颠倒等慢性不可预知性温和刺激结合孤养方式,每天暴露于2种应激原中饲养21 d,建立抑郁症模型。测定应激前后大鼠糖水偏爱、旷场行为及高架十字迷宫行为学变化。连续24 h分6个时间点（ZT1、ZT5、ZT9、ZT13、ZT17、ZT21）处死动物取血,每个时间点处死5只大鼠。放免法测定6个时间点血清促肾上腺皮质激素（ACTH）含量,ELISA法测定6个相同时间点血浆皮质酮（CORT）、褪黑素（MT）、血管活性肠肽（VIP）含量,采用单一余弦法比较2组大鼠上述各指标的节律周期、振幅、峰值相位、中值的变化特点。结果：与对照组相比,模型大鼠体重增加值明显降低（P<0.01）,各项行为学评分均显著减少（P<0.01）。慢性应激至抑郁样行为充分表达后,血浆ACTH、CORT的相位完全相反,时相大幅度提前,含量波动幅度减小,昼夜分泌节律紊乱;MT的24 h分泌节律完全丧失且整体水平下降,表达量显著降低;VIP虽仍存在24 h节律,但振幅明显降低,峰相位也延迟6 h,且表达量显著提高。结论：慢性应激抑郁状态可导致大鼠外周神经内分泌激素的近日节律非同步于SCN,表现为昼夜节律性和激素分泌量的异常。     

Effects of Li+, Rb+ and tetraethylammoniumchloride on the locomotor activity rhythm of Musca domestica

Abstract

The effect of Li⁺, Rb⁺ and tetraethylammoniumchloride (TEA) on the locomotor activity rhythm of Musca domestica was studied. Li⁺ as well as TEA lengthen the free run period t. This effect was more pronounced in animals with shorter period lengths. The effect of Rb? depends on the previous period length. In flies which had a short period, Rb⁺ lengthened, and in those with a long period Rb⁺ shortened t. Replacing the Li⁺ solution with water reverted the period lengthening partly. In the case of Rb? and TEA the rhythm became obscured after replacing the solutions with water. The involvement of K⁺ ions and transport ATPases in the expression of circadian rhythms is discussed.     

Effect of Chronic Caloric Restriction on the Synchronization of Various Physiological Measures in Old Female Fischer 344 Rats

-A variety of physiological and behavioral parameters which relate to metabolism were continuously monitored in 18 month old female Fischer 344 rats which were maintained on either ad libitum or reduced calorie diets. Caloric restriction (CR) stimulated average motor activity per day, the duration of each feeding episode, food consumed per episode, and water consumed per gram lean body mass (LBM). However, CR limited total food consumption, feeding time, number of feeding episodes per day, total eating and drinking time, and the daily ratio of food consumed to water consumed, CR also decreased average body temperature per day, O₂ consumption, CO₂, production, and respiratory quotient. A variety of parameters concerning water consumption were not affected. CR rats ate their food immediately when food was presented during the light span, while ad libitum fed animals ate numerous small meals throughout the entire dark span. An anticipatory response to restricted feeding was also noted. Total motor activity, metabolism, and body temperature increased just prior to scheduled feeding and reached maximum values shortly after feeding, suggesting that these parameters were highly synchronized to feeding. Females and males were found to respond to caloric restriction in a similar fashion. Dramatic changes in respiratory quotient and body temperature suggest rapid shifts between metabolic pathways (glycolysis to giuconeogenesis) to obtain optimal efficiency. Lower body temperature and metabolism may provide protection against DNA damage, thereby increasing the survival potential of restricted rats. These responses may provide insight into the mechanisms by which caloric restriction acts to extend life span.     

The full moon as a synchronizer of circa-monthly biological rhythms: Chronobiologic perspectives based on multidisciplinary naturalistic research

Biological rhythmicity is presumed to be an advantageous genetic adaptation of fitness and survival value resulting from evolution of life forms in an environment that varies predictably-in-time during the 24 h, month, and year. The 24 h light/dark cycle is the prime synchronizer of circadian periodicities, and its modulation over the course of the year, in terms of daytime photoperiod length, is a prime synchronizer of circannual periodicities. Circadian and circannual rhythms have been the major research focus of most scientists. Circa-monthly rhythms triggered or synchronized by the 29.5 day lunar cycle of nighttime light intensity, or specifically the light of the full moon, although explored in waterborne and certain other species, have received far less study, perhaps because of associations with ancient mythology and/or an attitude naturalistic studies are of lesser merit than ones that entail molecular mechanisms. In this editorial, we cite our recent discovery through multidisciplinary naturalistic investigation of a highly integrated circadian, circa-monthly, and circannual time structure, synchronized by the natural ambient nyctohemeral, lunar, and annual light cycles, of the Peruvian apple cactus (C. peruvianus) flowering and reproductive processes that occur in close temporal coordination with like rhythms of the honey bee as its pollinator. This finding led us to explore the preservation of this integrated biological time structure, synchronized and/or triggered by environmental light cues and cycles, in the reproduction of other species, including Homo sapiens, and how the artificial light environment of today in which humans reside may be negatively affecting human reproduction efficiency.     

Effects of a seven-day continuous infusion of ropivacaine on circadian rhythms in the rat

The present study was conducted to evaluate the effect of a 7 d continuous infusion of ropivacaine on the 24 h rhythms of body temperature, heart rate, and locomotor activity. After an initial 7 d baseline, rats were randomly divided into two groups of 4 rats each to receive ropivacaine or saline via an osmotic pump for 7 consecutive days. The pumps were removed thereafter and observed during a 7 d recovery span. The studied circadian rhythms were measured by radiotelemetry throughout each of the 7 d periods. An additional group of 4 rats was studied under the same experimental conditions to assess the plasma levels of ropivacaine on days 3 and 8 following pump implantation. Our results indicate that ropivacaine does not induce loss of the circadian rhythms of body temperature, heart rate, or locomotor activity; a prominent period of 24 h was found for all variables in all animals, before, during, and after ropivacaine treatment. However, ropivacaine treatment did modify some characteristics of the rhythms; it increased the MESOR (24 h mean) of the heart rate and locomotor activity rhythms and advanced the acrophase (peak time) of the locomotor activity circadian rhythm. The present study indicates that the circadian rhythms of heart rate and locomotor activity are modified after continuous infusion of ropivacaine, which is of particular interest, given the potential cardiotoxicity of this local anesthetic agent.     

XIIIth INTERNATIONAL COURSE ON CHRONOPHARMACOLOGY Ruprecht-Karls-Universität Heidelberg Summer School 2012: 30 July – 4 August

Daily rhythmicity in the locomotor activity of laboratory animals has been studied in great detail for many decades, but the daily pattern of locomotor activity has not received as much attention in humans. We collected waist-worn accelerometer data from more than 2000 individuals from five countries differing in socioeconomic development and conducted a detailed analysis of human locomotor activity. Body mass index (BMI) was computed from height and weight. Individual activity records lasting 7 days were subjected to cosinor analysis to determine the parameters of the daily activity rhythm: mesor (mean level), amplitude (half the range of excursion), acrophase (time of the peak) and robustness (rhythm strength). The activity records of all individual participants exhibited statistically significant 24-h rhythmicity, with activity increasing noticeably a few hours after sunrise and dropping off around the time of sunset, with a peak at 1:42?pm on average. The acrophase of the daily rhythm was comparable in men and women in each country but varied by as much as 3?h from country to country. Quantification of the socioeconomic stages of the five countries yielded suggestive evidence that more developed countries have more obese residents, who are less active, and who are active later in the day than residents from less developed countries. These results provide a detailed characterization of the daily activity pattern of individual human beings and reveal similarities and differences among people from five countries differing in socioeconomic development.     

Effects of nutritional lithium deficiency on behavior in rats

To demonstrate whether nutritional lithium deficiency is associated with behavioral changes, male Sprague-Dawley rats were placed on a lithium-deficient diet (Li content <.01 ppm). A lithium-deprived group, receiving drinking water containing 31 μM NaCl, were compared to a control group receiving drinking water containing 31 μM LiCl. Growth and general appearance were the same in both groups. However, lithium-deficient animals demonstrated decreased aggression in social interactions with other rats and also in response to handling. The phase of wheel-running activity was delayed by 0.8 h and exhibited decreased amplitude (p<.05). Other behaviors, including acquisition and retention of a passive avoidance response, were unaffected by lithium deprivation. An erratum to this article is available at .     

Temporal Morphology and Cap Formation in Acetabularia-Ii. Effects of Morphactin and Auxin

Afin d'apporter des arguments supplémentaires à?hypothese selon laquelle les rhythms circadiens sont impliqués dans la morphogénèse, des expériences ont été réalisées de manière a mettre en évidence la relation éventuelle de dépendance entre le moment (dans le cycle de 24 heures) où commence le traitement et ? effet (1) de la morphactine, un inhibiteur compétitif de ?'auxine et (2) de ? auxine (IAA).

Les résultats ont montré que (1) ? effet inhibiteur de la morphactine varie considérablement selon le moment auquel le traitement a commencé, plusieurs semaines avant ? expression morphogénétique; (2) le maximum d'inhibition change avec le stade de développement et le degré d'inhibition diminue avec le temps; (3) ?'IAA accélerè la formation du chapeau lorsque le traitement a commencé pendant la phase de croissance rapide des algues; ? effet depend du moment (du cycle de 24 heures) auquel il a commencé son effet diminue au cours du temps; (4) lorsque le traitement a commencé avec des algues plus petites que les precédéntes, il exerce un effet transitoirement inhibiteur qui dépend du moment du cycle de 24 heures auquel il a commence; (5) les fragments anucléés aussi répondent différentiellement à un traitement à ? IAA commencé a différents moments du cycle de 24 heures; ? effet est plus net quand des mRNA ont été accumulés; (6) ? effet de ? IAA n'est pas cumulé a celui d'une perturbation du cycle L-D; celui de la morphactine n'est pas modifyé ou est légérement amélioré par une perturbation du cycle L-D.

Mots clefs–Acetabularia, rhymes circadiens, morphogénèse, auxine, morphactine.

In order to support the hypothesis that circadian rhythms are implicated in cap formation, experiments were undertaken on the possible time-dependency of the effects of (a) a competitive inhibitor of auxins, morphactin and (b) of auxin (IAA). It was found that: (i) the inhibitory effect of morphactin varies dramatically with the time at which the several weeks' treatment was first begun; (ii) the maximum inhibition varies with development and decreases with time; (iii) IAA accelerates cap formation when the algae are submitted to IAA during the exponential growth phase; the effect is time dependent and decreases with time; (iv) IAA first applied on smaller algae has a transient inhibitory effect which is time dependent; (v) anucleate fragments also respond differentially to an IAA treatment begun at several times in the 24-hr cycle, most clearly when newly formed mRNA have been accumulated and (vi) the effect of iAA is not cumulative with that of a LD shift; that of morphactin is not, or only slightly, improved by a LD shift.     

Temporal morphology and cap formation in Acetabularia--II. Effects of morphactin and auxin

In order to support the hypothesis that circadian rhythms are implicated in cap formation, experiments were undertaken on the possible time-dependency of the effects of (a) a competitive inhibitor of auxins, morphactin and (b) of auxin (IAA). It was found that: (i) the inhibitory effect of morphactin varies dramatically with the time at which the several weeks' treatment was first begun; (ii) the maximum inhibition varies with development and decreases with time; (iii) IAA accelerates cap formation when the algae are submitted to IAA during the exponential growth phase; the effect is time dependent and decreases with time; (iv) IAA first applied on smaller algae has a transient inhibitory effect which is time dependent; (v) anucleate fragments also respond differentially to an IAA treatment begun at several times in the 24-hr cycle, most clearly when newly formed mRNA have been accumulated and (vi) the effect of iAA is not cumulative with that of a LD shift; that of morphactin is not, or only slightly, improved by a LD shift.     

The statistical analysis of tidal rhythms: Tests of the relative effectiveness of five methods using model simulations and actual data

Endogenous rhythms in intertidal organisms are often very complex and imprecise. Thus, confusing results are sometimes obtained when applying various interpretive analytical techniques. In an attempt to resolve this problem, ten different models representing typical organismic tidal‐rhythm displays were created and examined with five different inferential statistical techniques. The exercise was designed to test the relative effectiveness of these techniques in detecting the presence of known cycles in the models, and estimating their period lengths. The same comparison was then repeated on sets of animal‐derived data.

All of the five methods had their merits, but, depending on the model being examined, the results from the various methods were not identical. Three of the techniques produce harmonics, making data that contain multiple periods especially difficult to decipher. Often both tidal and circadian periods are displayed by shore dwellers; all five methods were able to find these two periods. But when the difference in circa period length was close, only one technique (array analysis) could make a distinction. This technique was also the only one able to handle data in which the period was not constant. Interestingly, this simplest of methods is probably the best all‐round method of discovery. Many more subtle, but important, differences were also noted, and it is recommended that more than one method always be used to ensure accuracy.     

Behavioral characteristics and pharmacological manipulations of a nicotine-entrainable circadian oscillator

Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35–60?d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16–24?d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0?mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2?d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the μ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.     

Characteristics of Food-Entrained Orcadian Rhythms in Rats During Long-Term Exposure to Constant Light

Rats possess a system of circadian oscillators that permit entrainment of circadian activity rhythms independently to 24 hr cycles of light-dark and food access. The nature of interactions between food- and light-entrainable oscillators was examined by observing the generation and persistence of food-entrained circadian rhythms in rats whose light-entrainable rhythms were eliminated by long-term exposure to constant light. Most of these rats showed a delayed generation of food-entrained rhythms and only one of eight animals showed persistence of food associated rhythms during a 4-day food deprivation test. Rats whose light-entrainable rhythms are eliminated by suprachiasmatic nuclei ablation show, in contrast, normal generation and persistence of food-entrained rhythms. The results suggested a disruptive influence of constant light on non-photic entrainment, possibly due to coupling forces between damped light-entrainable oscillators and the food-entrainable oscillators.