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.     

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.     

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.     

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

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

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.     

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.     

A complex rhythm problem: The possibility of a lunar modulation of plant function

Abstract

The analysis of long temporal series of gas exchange of seeds in moist atmosphere or of root lengths of seedlings reveals the existence of non‐random fluctuations. Several observations allow us to envisage the presence of rhythmicities with modulated periods.

The plant material was kept in darkness at stabilised temperature and humidity. The experiments were conducted on different plant species, in various conditions of temperature and humidity in different years. The gas exchange was measured with the Warburg apparatus; the roots on seedlings after 72 h of germination on Petri glasses. We compared the rhythmicities of the biological material with some periodicities of the geophysical environment. We chose as a reference the passages of the moon and of the sun at the meridian.

An analogy is observed between several of the observed rhythmicities and the circadian and low‐frequency rhythmicities of the geophysical environment. It seems as if submultiples of those natural periods would be generated. We consider the probable existence of modulated synchronisation and we propose an hypothesis for deriving the observed periodicities from three basic circadian rhythms: solar, lunar and "circadian”;.

A model is proposed and a theoretical curve elaborated which is in reasonal concordance with, the experimental curve. We point out that appropriate mathe‐. matical methods for modulated periods and amplitudes should be useful.     

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.     

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.     

Review: Microbial endocrinology: intersection of microbiology and neurobiology matters to swine health from infection to behavior

From birth to slaughter, pigs are in constant interaction with microorganisms. Exposure of the skin, gastrointestinal and respiratory tracts, and other systems allows microorganisms to affect the developmental trajectory and function of porcine physiology as well as impact behavior. These routes of communication are bi-directional, allowing the swine host to likewise influence microbial survival, function and community composition. Microbial endocrinology is the study of the bi-directional dialogue between host and microbe. Indeed, the landmark discovery of host neuroendocrine systems as hubs of host–microbe communication revealed neurochemicals act as an inter-kingdom evolutionary-based language between microorganism and host. Several such neurochemicals are stress catecholamines, which have been shown to drastically increase host susceptibility to infection and augment virulence of important swine pathogens, including Clostridium perfringens. Catecholamines, the production of which increase in response to stress, reach the epithelium of multiple tissues, including the gastrointestinal tract and lung, where they initiate diverse responses by members of the microbiome as well as transient microorganisms, including pathogens and opportunistic pathogens. Multiple laboratories have confirmed the evolutionary role of microbial endocrinology in infectious disease pathogenesis extending from animals to even plants. More recent investigations have now shown that microbial endocrinology also plays a role in animal behavior through the microbiota–gut–brain axis. As stress and disease are ever-present, intersecting concerns during each stage of swine production, novel strategies utilizing a microbial endocrinology-based approach will likely prove invaluable to the swine industry.     

Temporal Patterns of Reported Single-Vehicle Car and Truck Accidents in Texas, U.S.A. During 1980-1983

Reported single car and truck accidents due specifically to driver 'fatigue' for the 4-year span of 1980-1983 were analyzed for 24-hr, 7-d and 1-yr patterns. Three types of data were examined: (1) accidents in rural Texas, (2) accidents only in San Antonio, the fourth largest city in Texas and (3) accident ratio (number of accidents per time interval divided by traffic volume for the interval) in this city.

A statistically significant seasonal variation of relatively low amplitude with peaks in May and July was detected only for accidents in rural areas. High-amplitude periodicities of 7 d were evident in all the data sets, with a peak on the weekend. A very prominent 24-hr pattern was detected as well, with the acrophase determined by single cosinor around 0300. A slight secondary peak in accidents, around 1500, was evident in the data from the rural areas. This secondary peak represented a 12-hr rhythm in addition to the 24-hr. Overall, features of the temporal patterns in accidents over 24 hr and over the year in urban and rural areas differed only slightly. Accident ratios yielded results similar to accident frequencies. However, with regard to the rural data, the shape of the 24-hr temporal pattern varied with driver age; older drivers exhibited a flatter curve with a more pronounced afternoon rather than early morning (around 0300) peak.     

Behavioral and Morphological Studies of Fetal Neural Transplants into SCN-Lesioned Rats

We have studied the effects of fetal neuronal grafts on the temporal pattern of drinking behavior of suprachiasmatic nuclei (SCN)-lesioned adult rats. Additionally, in an independent set of animals, the immunohistochemical staining for vasopressin, vasoactive intestinal polypeptide, and neuropeptide Y and the retinal connections to the hypothalamus were studied. The behavioral experiments indicate that anterior hypothalamic transplants induced reorganization of the temporal pattern of drinking behavior when placed in the third ventricle of adult hosts bearing complete SCN lesions, but not when placed in a cavity in the occipital cortex. Such rhythmicity persists only when the animals were recorded under constant darkness but not under constant light, indicating that the restored rhythmicity was generated endogenously but that the oscillator was extremely sensitive to light. Fetal occipital cortex induced reorganization of the temporal pattern of previously arrhythmic hosts, but it disappeared when the animals were recorded under constant light or constant darkness. It is clear that this rhythmicity was exogenous. In contrast to the cortical transplants, the hypothalamic transplants showed a morphological organization similar to that found in the normal hypothalamus regardless of their placement in the host brain. From these observations it is concluded that development of neocortex is more affected by environmental factors than that of the hypothalamus. Both hypothalamic and cortical transplants induced sprouting of retinal fibers into the anterior hypothalamus and the grafted tissue. It is possible that such fibers could be the neuroanatomical substrate by which rhythmicity is induced by cortical tissue.