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Day or Night Administration of Ketamine and Pentobarbital Differentially Affect Circadian Rhythms of Pineal Melatonin Secretion and Locomotor Activity in Rats
Abstract
Surgery with general anesthesia disturbs circadian rhythms, which may lead to postoperative sleep disorders and delirium in patients. However, it is unclear how circadian rhythms are affected by different anesthetics administered at different times during the rest-activity cycle. We hypothesized that pentobarbital (an agonist at the γ-aminobutyric acid A receptors) and ketamine (an antagonist at the N-methyl-d-aspartate receptors) would have differential effects on circadian rhythms, and these effects would also be influenced by the time of their administration (the active versus resting phase).
Rats were divided into 4 groups according to the anesthetic administered (pentobarbital or ketamine) and the timing of intraperitoneal administration (active/night phase or resting/day phase). Using online pineal microdialysis, we analyzed pineal melatonin secretion and locomotor activity rhythms in rats under a light/dark (12/12-hour) cycle for 5 days after anesthesia and microdialysis catheter implantation. The data were analyzed for rhythmicity by cosinor analysis.
Ketamine administered during the resting phase produced 65- and 153-minute phase advances, respectively, in melatonin secretion and locomotor activity rhythms on the first day after anesthesia. In contrast, ketamine administered during the active phase produced 43- and 235-minute phase delays. Pentobarbital had no effect on the phase of either melatonin secretion or locomotor activity, irrespective of the timing of administration. When administered during the active phase, both anesthetics decreased the amplitude of melatonin secretion on the day after anesthesia; when administered during the resting phase, however, neither anesthetic affected the amplitude. The amplitude of locomotor activity decreased in all animals for 3 days after anesthesia.
Ketamine has opposite phase-shifting effects on circadian rhythms according to the time of administration, whereas pentobarbital has no effect. Furthermore, both anesthetics decrease the postoperative amplitude of pineal melatonin secretion if administered during the active, but not the resting, phase of the 24-hour rest-activity cycle.
... To date, four studies have examined the effect of anaesthesia (sevoflurane, ketamine, pentobarbital and isoflurane) during the normal active phase of an animal on subsequent activity levels. All four described disrupted rest/ activity rhythms as a result of anaesthesia, with three showing a decrease in locomotor activity during the following active phase [8,13,15] and one showing an increase in activity during the subsequent rest phase [17]. ...
... The effects of anaesthesia administered during the rest phase of an animal is less clear. No change in activity level was observed in studies in which ether, ketamine or pentobarbital was administered during the rest period [13,18], however, total activity was reduced following sevoflurane treatment [8,15]. This may be due to differing effects of these drugs on the sleep homeostat. ...
... In the majority of studies administration of anaesthesia (pentobarbital, sevoflurane or isoflurane) during the animal's inactive period had no effect on the phase of locomotor activity rhythms [7,8,10,12,13] or resulted in relatively small phase delays (of between 15 and 25 min) [7,11,15] which, if acute, are unlikely to be of physiological relevance. The notable exceptions are ketamine, which induced a phase delay of 3.9 h when administered at the mid-point of the inactive period in rats [13], and propofol, which induced a phase delay of approximately 1 h when administered during the latter half of the inactive period in mice [19,20]. ...
Key points:
1) GA has strong effects on the main neurotransmitter systems linked with circadian control (Gamma aminobutyric acid/N-methyl-D-aspartate (GABA/NMDA)) and may act by interfering with light-entrainment of the clock. 2) Expression of the core clock gene per2 is inhibited by GA (possibly via a NMDA/glycogen synthase kinase 3β (GSK3β) pathway). 3) GA's effect on circadian rhythms appears greatest when administered during animals' active phases 4) GA may have different effects when administered under free-running and entrained conditions. 5) Anaesthesia may mimic the mechanism involved in adaptation of the clock to changes in daylength. There is agreement that GA can strongly affect the circadian clock. How anaesthesia-induced changes in the molecular clock lead to changes in behaviour remains unclear. The answer, and what it may mean for patients post-operatively, will rely on systematic studies at molecular, behavioural, and clinical levels using standardised protocols.
... 1,2 Numerous research using locomotor activities have been performed to explore the changes of gross motor activities by experimental drugs. 3 In addition, using the strong association between locomotor activity and sleep-wake state, there were studies to investigate sleep-wake states. 4 Furthermore, locomotor activities can be analyzed in a perspective of circadian rest-activity rhythm. ...
... Using Cosinor Analysis in Mice as 5 minutes, 15,16 10 minutes, 17,18 or 15 minutes. 5 Meanwhile, raw data may be processed in various methods, such as data summation, 3,19 data average, [20][21][22] or data moving average. 23 Although cosinor analysis is performed in various ways in each study, it is necessary to provide sufficient rationality for these specific methods. ...
Objective:
Data processing in analysis of circadian rhythm was performed in various ways. However, there was a lack of evidence for the optimal analysis of circadian rest-activity rhythm. Therefore, we aimed to perform mathematical simulations of data processing to investigate proper evidence for the optimal analysis of circadian rest-activity rhythm.
Methods:
Locomotor activities of 20 ICR male mice were measured by infrared motion detectors. The data of locomotor activities was processed using data summation, data average, and data moving average methods for cosinor analysis. Circadian indices were estimated according to time block, respectively. Also, statistical F and p-values were calculated by zero-amplitude test.
Results:
The data moving average result showed well-fitted cosine curves independent of data processing time. Meanwhile, the amplitude, MESOR, and acrophase were properly estimated within 800 seconds in data summation and data average methods.
Conclusion:
These findings suggest that data moving average would be an optimal method for data processing in a cosinor analysis and data average within 800-second data processing time might be adaptable. The results of this study can be helpful to analyze circadian restactivity rhythms and integrate the results of the studies using different data processing methods.
... Any agonism effects at the κ-opioid receptor would be prevented by autocrine, paracrine and pineal melatonin, which decreases kappa-κ-receptor levels, as shown in the hippocampus [111]. This suggest a circadian interaction with ketamine effects, especially via pineal melatonin, which is supported by preclinical data, where the effects of ketamine are modulated by the timing of its administration [160]. Such data may also indicate that the adjunctive use of melatonin would better optimize ketamine's acute and chronic antidepressant effects. ...
... The immune system is subject to circadian regulation by the night-time release of pineal melatonin, which generally dampens immune reactivity, at least in part via the upregulation of mitochondrial oxidative phosphorylation [80]. Ketamine interacts with the circadian melatonin rhythm in preclinical models, with daytime vs night-time ketamine administration leading to significant pineal melatonin phase advances and delays, respectively [160], whilst ketamine at night also increases pineal melatonin production [157]. A pilot study of MDD patients indicates that the presence and duration of an antidepressant response to ketamine may be significantly modulated by circadian factors [169]. ...
Background: There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of treatment that is targeted to pathophysiology. Recent data indicates a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD. Methods: Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial function, form the basis of this review article. Results: The endogenous opioidergic system is intimately linked to wider MDD pathophysiology, including alterations in the gut microbiome, gut permeability, circadian rhythm, amygdala-prefrontal cortex interactions, and mitochondrial function. A decrease in the μ-/κ-opioid receptor ratio is an important mediator of the changes in mood in MDD, with effects not only in neurons, but also in glia and immune cells. Conclusion: The endogenous opioidergic system is intimately interwoven with with MDD pathophysiology and provides a relevant target for novel treatment development, as well as providing a focus for the integration of wider MDD pathophysiology.
... (1) Type of anesthetics. As NMDA and GABA receptors have a critical role in regulating circadian clock and most anesthetics are NMDA receptor antagonists and/or GABA agonists, anesthetics may interfere with the internal clock [16,17]. (2) Ketamine, nitrous oxide, and xenon, which are NMDA receptor antagonists, reduce the excitatory activity of glutamate causing unconsciousness. ...
... Magnitude and direction of the shifts depend on the different types of anesthetics. Mihara et al. [17] found ketamine-induced anesthesia resulted in a large phase advance when administered during active period and a large phase delay when administered during rest period. ...
Purpose of review:
The alteration of circadian rhythms in the postoperative period has been demonstrated to influence the outcomes. With this narrative review we would revise how anesthesia, surgery and intensive care can interfere with the circadian clock, how this could impact on the postsurgical period and how to limit the disruption of the internal clock.
Recent findings:
Anesthesia affects the clock in relation to the day-time administration and the type of anesthetics, N-methyl-D-aspartate receptor antagonists or gamma-aminobutyric acid receptors agonists. Surgery causes stress and trauma with consequent alteration in the circadian release of cortisol, cytokines and melatonin. ICU represents a further challenge for the patient internal clock because of sedation, immobility, mechanical ventilation and alarms noise.
Summary:
The synergic effect of anesthesia, surgery and postoperative intensive care on circadian rhythms require a careful approach to the patient considering a role for therapies and interventions aimed to re-establish the normal circadian rhythms. Over time, approach like the Awakening and Breathing Coordination, Delirium Monitoring and Management, Early Mobility and Family engagement and empowerment bundle can implement the clinical practice.
... In this respect, marked differences related to the time of drugs administration were found. For instance, general anaesthesia during the active phase highly altered daily activity rhythms (Mihara et al. 2012, Anzai et al. 2013. Both honeybees and rats treated with isoflurane or ketamine, two general anaesthetics commonly used, showed a phase-shifts in the locomotor activity if the treatments were applied during the daytime (Cheeseman et al. 2012, Ludin et al. 2016. ...
... Both honeybees and rats treated with isoflurane or ketamine, two general anaesthetics commonly used, showed a phase-shifts in the locomotor activity if the treatments were applied during the daytime (Cheeseman et al. 2012, Ludin et al. 2016. Conversely, administration of anaesthesia during the resting period appeared to have minor effects on activity rhythms (Prudian et al. 1997, Mihara et al. 2012. It is worth noting that different anaesthetic drugs and different durations of the anaesthetic treatment may induce diverse species-specific reactions. ...
Although the proliferation of the wild boar in Europe makes capturing and handling necessary for both management and
research, the behavioural responses of this species to capture are still unknown. We evaluated how capture affects wild boar
behaviour during the first 30 days after the release, focusing on the animals’ total activity, mobility and activity rhythms and
their variation in response to different drug mixtures used for sedation. Low levels of activity and mobility characterized
the first 10 post-capture days. After this period, a gradual restoring of stable levels occurred. Wild boar captured by using
different drug mixtures exhibited slightly different patterns of activity depression. We also showed capture to produce a
partial effect on wild boar behavioural rhythmicity. Our findings highlight the case study variability of the capture effect
and offer useful insights into several conservation and management implications.
... In the recovery period, hallucinations can occur [10]. Ketamine disturbs the circadian rhythm [14] and has antidepressant-like properties [15], although longterm administration of ketamine can result in sex-dependent effects on anxiety-related behavior [16]. For anesthesia, ketamine is combined with an α2-adrenergic agonist such as xylazine, which provides sedation, mild to moderate analgesia, and muscle relaxation [9,10]. ...
... This was also observed in pigtailed macaques with appetite suppression after ketamine sedation [29]. Ketamine disturbs the circadian rhythm and, therefore, may result in a reduced food intake [14,72]. Moreover, an increase in stress levels, as indicated by elevated FCM levels in male mice after single KX anesthesia, can explain appetite suppression [29]. ...
Within the scope of the 3Rs of Russel and Burch, the number of laboratory animals can be reduced by repeated use of an animal. This strategy only becomes relevant, if the total amount of pain, distress or harm the individual animal experiences does not exceed the severity of a single manipulation. For example, when using imaging techniques, an animal can be examined several times during a study, but it has to be anesthetized each time imaging is performed. The severity of anesthesia is thought to be mild according to the Directive 2010/63/EU. However, the Directive does not differentiate between single and repeated anesthesia, although repeated anesthesia may have a greater impact on well-being. Hence, we compared the impact of single and repeated anesthesia (six times at an interval of three to four days) by injection of ketamine and xylazine (KX) on the well-being of adult female and male C57BL/6JRj mice. After anesthesia, well-being of mice was assessed according to a protocol for systematic assessment of well-being including nesting, the Mouse Grimace Scale (MGS), a test for trait anxiety, home cage activity, and the rotarod test for motor activity, food intake, and body weight, as well as corticosterone (metabolite) analysis. Repeated anesthesia increased the MGS in mice of both sexes and caused short-term effects on well-being of female mice in the immediate post-anesthetic period, indicated by longer lasting effects on trait anxiety-related behavior. However, corticosterone metabolite concentrations suggested that mice habituated to the stress induced by repeated KX administration. Hence, the mildly negative effects on well-being of repeated KX anesthesia do not seem to accumulate over time using the respective regimen. However, further observations for severity classification are warranted in order to more specifically determine the duration of mild distress and trait anxiety.
... This is due to the critical role played by N-methyl-D-aspartate (NMDA) and γ-Aminobutyric acid (GABA) receptors in regulating the circadian clock. Furthermore, it is noteworthy that most anesthetics function as either NMDA receptor antagonists and/or GABA receptor agonists [20,21]. Auvil-Novak et al. [22] observed that, in humans, the highest and lowest demands for morphine or hydromorphone occurred in the early morning and overnight, respectively. ...
Background: Pain intensity has been reported to fluctuate throughout the day in various clinical situations. This study aimed to evaluate the relationship between postoperative pain and circadian rhythm after pediatric acute appendicitis surgery.Methods: Two hundred patients, aged 6–18 years, undergoing acute appendicitis surgery were included in this prospective observational study. The patients were divided into four groups according to the time they underwent surgery: the night group, 01:01–07:00; morning group, 07:01–13:00; afternoon group, 13:01–19:00; and evening group, 19:01–01:00. Intraoperative and postoperative vital signs, postoperative 24-h Wong–Baker Faces Pain Rating Scale (FACEs) scores, and the amount of analgesic required were recorded.Results: A total of 186 patients were analyzed in the study. There was no statistically significant difference in the demographic characteristics of the patient groups. Additionally, no differences were observed in intraoperative and postoperative vital signs among the four groups. However, patients in the night group had significantly higher FACEs values than those in the other groups at each time point (1st, 3rd, 6th, and 12th h) up to 12 h (P = 0.007, P = 0.023, P = 0.048, and P = 0.003, respectively). The amount of analgesic required in the night group was statistically higher than in the other groups until 12 h (P = 0.002, P < 0.001, P = 0.002, and P = 0.004, respectively).Conclusion: A relationship was found between acute appendicitis operations performed at night (01:01 to 07:00) under general anesthesia and circadian rhythm in children. We believe that considering circadian time in the relief of postoperative pain would be beneficial.
... Melatonin secretion is controlled by the SCN, which regulates the day/night cycle. The administration of anaesthesia regardless of surgery may affect the circadian rhythm of melatonin [18] . Another hormone affected by anaesthesia is the cortisol. ...
... Melatonin is a central circadian regulator, primarily produced by the pineal gland, and a normal melatonin rhythm is partly instrumental in the regulation of the sleepwake cycle. 9 The circadian rhythm of melatonin secretion is disturbed after surgery, 10,11 and this disturbance is thought to contribute to postoperative sleep disturbance. 12 Therefore, melatonin administration may modify the circadian rhythm and improve postoperative sleep disturbance. ...
PurposePostoperative sleep disturbances are common. Although several studies have examined the effect of melatonin on postoperative sleep disturbances, the results have not reached any definitive conclusion. We sought to conduct a systematic review to compare the effects of melatonin and melatonin agonists on postoperative sleep quality with those of placebo or no treatment in adult patients who underwent surgery under general or regional anesthesia.Methods
We searched MEDLINE, Cochrane Central Register of Controlled Trials, Embase, Web of Science, ClinicalTrials.gov, and the UMIN Clinical Trials Registry up to 18 April 2022. Randomized clinical trials examining the effects of melatonin or melatonin agonists in patients undergoing general or regional anesthesia with sedation for any surgery were eligible for inclusion. The primary outcome was sleep quality measured using a visual analog scale (VAS). The secondary outcomes were postoperative sleep duration, sleepiness, pain, opioid consumption, quality of recovery, and adverse events. A random-effects model was used to combine the results. We assessed study quality with the Cochrane Risk of Bias Tool version 2. We applied a trial sequential analysis to assess the precision of the combined results.ResultsEight studies (516 participants) were analyzed for sleep quality. Of those, four studies used only a short duration of melatonin, either on the night before and the day of surgery or only on the day of surgery. A random-effects meta-analysis showed that melatonin did not improve sleep quality measured by VAS compared with placebo (mean difference, -0.75 mm; 95% confidence interval, -4.86 to 3.35), with low heterogeneity (I2, 5%). Trial sequential analysis revealed that the accrued information size (n = 516) reached the estimated required information size (n = 295). We downgraded the certainty of the evidence because of the high risk of bias. The effect on postoperative adverse events was comparable between the melatonin and control groups.Conclusion
Our results indicate that melatonin supplementation does not improve postoperative sleep quality measured with the VAS compared with placebo in adult patients (GRADE: moderate).Study registrationPROSPERO (CRD42020180167); registered 27 October 2022.
... Although the exact mixture of anaesthetics we used has not yet been tested for its hypothetical effects on the circadian clock, it is known that other general anaesthetics with similar effects (e.g. isoflurane, ether, halothane, or ketamine administered in combination with benzodiazepines) differentially affect circadian rhythms in rodents (Bellet et al., 2011;Chong et al., 2021;Ludin et al., 2021;Mihara et al., 2012;Prudian et al., 1997;Rebuelto et al., 2004). Moreover, our observations show that even minimal changes in the slow-wave activity amplitude may affect the level of neuronal activity, and that, in turn, could influence the amplitude of the responses. ...
The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non‐photic (e.g. metabolic and arousal) cues. Both receive information about environmental light from photoreceptors, exhibit infra‐slow oscillations (ISO) in vivo, and connect to the master circadian clock. Although current evidence demonstrates that the IGL/VLG communicate metabolic information and are crucial for entrainment of circadian rhythms to time‐restricted feeding, their sensitivity to food intake‐related peptides has not been investigated yet. We examined the effect of metabolically relevant peptides on the spontaneous activity of IGL/VLG neurons. Using ex vivo and in vivo electrophysiological recordings as well as in situ hybridisation, we tested potential sensitivity of the IGL/VLG to anorexigenic and orexigenic peptides, such as cholecystokinin, glucagon‐like peptide 1, oxyntomodulin, peptide YY, orexin A and ghrelin. We explored neuronal responses to these drugs during day and night, and in standard vs. high‐fat diet conditions. We found that IGL/VLG neurons responded to all the substances tested, except peptide YY. Moreover, more neurons responded to anorexigenic drugs at night, while a high‐fat diet affected the IGL/VLG sensitivity to orexigenic peptides. Interestingly, ISO neurons responded to light and orexin A, but did not respond to the other food intake‐related peptides. In contrast, non‐ISO cells were activated by metabolic peptides, with only some being responsive to light. Our results show for the first time that peptides involved in the body's energy homeostasis stimulate the thalamus and suggest functional separation of the IGL/VLG cells. image
Key points
The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) of the rodent thalamus process various signals and participate in circadian entrainment.
In both structures, cells exhibiting infra‐slow oscillatory activity as well as non‐rhythmically firing neurons being observed.
Here, we reveal that only one of these two groups of cells responds to anorexigenic (cholecystokinin, glucagon‐like peptide 1 and oxyntomodulin) and orexigenic (ghrelin and orexin A) peptides. Neuronal responses vary depending on the time of day (day vs. night) and on the diet (standard vs. high‐fat diet).
Additionally, we visualised receptors to the tested peptides in the IGL/VLG using in situ hybridisation.
Our results suggest that two electrophysiologically different subpopulations of IGL/VLG neurons are involved in two separate functions: one related to the body's energy homeostasis and one associated with the subcortical visual system.
... The activation of GABAA receptors by the agonist muscimol has been reported to directly affect pacemaker cells within the SCN and produce large phase delays in rats [83]. Moreover, NMDA receptors are expressed in the SCN [84], and its antagonist ketamine can induce phase changes in the secretion of melatonin and locomotor activity rhythms in a time-dependent manner [85]. ...
Postoperative delirium (POD) is a complication characterized by disturbances in attention, awareness, and cognitive function that occur shortly after surgery or emergence from anesthesia. Since it occurs prevalently in neurosurgical patients and poses great threats to the well-being of patients, much emphasis is placed on POD in neurosurgical units. However, there are intricate theories about its pathogenesis and limited pharmacological interventions for POD. In this study, we review the recent insights into its pathogenesis, mainly based on studies within five years, and the five dominant pathological theories that account for the development of POD, with the intention of furthering our understanding and boosting its clinical management.
... There was no significant difference in the postoperative night pain between the two groups of patients, which was related to adequate postoperative analgesia, and it also ruled out the effect of pain on postoperative sleep. Animal experiments have shown that the MT secreted by the pineal gland and its rhythm of activity have opposite phase changes when ketamine anesthesia is given at different time points (rest period and exercise period) [19]. Despite only the morning and afternoon operations are compared in this study, but the results still indicate that the MT secretion is inhibited more significantly and the night sleep function is worse on the first night after surgery in the afternoon surgery group. ...
Objective:
This study aimed to investigate the effects of morning and afternoon surgeries on the early postoperative sleep function in patients undergoing general anesthesia.
Methods:
Fifty nine patients, aged 18-60 years, American society of anaesthesiologists (ASA) grade I or II, Body mass index of 18.5-28 kg/m2, undergoing laparoscopic myomectomy under total intravenous anesthesia, were included in the study. These patients were divided into two groups according to the start time of anesthesia: morning surgery group (group A, 8:00-12:00) and afternoon surgery group (group P, 14:00-18:00). The sleep conditions of the two groups of patients were evaluated by the Athens Insomnia Scale (AIS) one day before and one day after the operation. A total score of > 6 was regarded as postoperative sleep disturbance. The incidences of sleep disturbance one day after the operation in two groups were compared. The bispectral Index assessed the patient's total sleep duration, sleep efficiency, and overall quality of sleep from 21:00 to 6:00 on the first night after surgery. Plasma concentrations of melatonin and cortisol at 6:00 am 1 day before surgery, 1 day after surgery were measured by ELISA, and rapid random blood glucose was measured.
Results:
The total AIS score, overall quality of sleep, total sleep duration, and final awakening earlier than desired scores of the two groups of patients on the first night after surgery were significantly increased compared with preoperative scores (P < 0.01). In group P, the sleep induction and the physical and mental functioning during the day scores increased significantly after surgery compared with preoperative scores (P < 0.05). The postoperative AIS scores in group P increased significantly compared with those in group A (P < 0.01). The incidence of postoperative sleep disturbances (70.0%) in group P was significantly higher than that in group A (37.9%) (P < 0.05). Compared with group A, the total sleep duration under BIS monitoring in group P was significantly shorter, the sleep efficiency and the overall quality of sleep was significantly reduced (P < 0.01). Compared with those in group A, the level of melatonin on 1 d after surgery in group P was significantly decreased, and the level of cortisol in group P was significantly increased. There were no significant differences between the two groups in the levels of postoperative blood glucose and pain.
Conclusion:
Both morning and afternoon surgeries have significant impacts on the sleep function in patients undergoing general anesthesia, while afternoon surgery has a more serious impact on sleep function.
Trial registration:
ClinicalTrials, NCT04103528. Registered 24 September 2019-Retrospectively registered, http://www.
Clinicaltrials:
gov/ NCT04103528.
... We previously showed that sevoflurane caused suppression of Per2 expression and subsequent phase shifts in isolated rat SCN tissue cultures (Anzai et al. 2013), suggesting that the robustness of behavioral rhythms observed in this study may be due to correction of the expression cycle of clock genes in the SCN by signals from other brain regions and sensory inputs (Herzog et al. 2017) after perturbation by anesthesia. In addition, considering reports of behavioral rhythm phase shifts in other anesthesia-based studies (Dispersyn et al. 2009;Mihara et al. 2012;Imai et al. 2020) and phase shifts in mice induced by sevoflurane in our previous studies (Ohe et al. 2011;Kadota et al. 2012), the effects of general anesthesia on clock genes may vary with anesthetic duration, concentration, and interspecies differences. ...
The suprachiasmatic nucleus (SCN) of the hypothalamus is a nucleus that regulates circadian rhythms through the cyclic expression of clock genes. It has been suggested that circadian-rhythm-related, adverse postoperative events, including sleep disturbances and delirium, are partly caused by anesthesia-induced disruption of clock-gene expression. We examined the effects of multiple general anesthetics on the expression cycle of Period2 (Per2), one of the clock genes that regulate circadian rhythms in the SCN, and on the behavioral rhythms of animals. Rats were treated with sevoflurane, propofol, and dexmedetomidine for 4 h. The expression of Per2 in SCN was analyzed using in situ hybridization, and the behavioral rhythm before and after anesthesia was analyzed. Per2 expression in the SCN decreased significantly immediately after anesthesia in all groups compared with corresponding control groups. However, Per2 returned to normal levels within 24 h, and there was no phase change in the gene expression cycle or behavioral rhythm. This study suggests that acute suppression of Per2 expression may be a general phenomenon induced by general anesthesia, but that the molecular mechanism of the body clock is resilient to disturbances to some extent.
... Alteration of the circadian rhythm can also have an influence on animal weight after anesthesia. Ketamine disturbs the circadian rhythm, which may result in reduced food intake 36 . Additionally, post-surgical pain and stress following procedures undertaken during the light phase can suppress feeding and drinking because they occur mainly during the dark phase 15 . ...
Mouse inoculation test (MIT) is a technique widely used for rabies diagnosis and must be liable to refinement due to animal welfare. The present study aims to compare five different anesthetic associations to stablish a protocol to improve the MIT procedure suitable for animal welfare and safe for a routine of viral isolation in newly weaned mice (3 weeks of age). 80 Swiss-Webster mice (Mus musculus) - 40 females and 40 males, 3-week-old, weight ranging from 11 to 14 grams – were used to conduct all procedures. Five anesthetic associations were tested: KX (Ketamine 100 mg/kg and Xylazine 10 mg/kg), KXA (Ketamine 80 mg/kg, Xylazine 5 mg/kg, and Acepromazine 1 mg/kg), KXT (Ketamine 80 mg/kg, Xylazine 5 mg/kg, and Tramadol 5 mg/kg), KXAT (Ketamine 100 mg/kg, Xylazine 10 mg/kg, Acepromazine 2 mg/kg and Tramadol 5 mg/kg) and ATI (Acepromazine 1 mg/kg
+ Tramadol 5 mg/kg + Isoflurane 5% - 0.5 L/min for induction and 2.5% - 0.5L/min for maintenance). Injectable anesthesia was administered intraperitoneally. We monitored the respiratory rate and body temperature. Response to anesthesia was evaluated according to the induction, surgical anesthesia, and recovery periods. The KXAT and ATI protocols induced surgical anesthesia, with the ATI protocol being the most appropriate and safe to perform the MIT procedure with 100% efficiency, absence of mortality, and rapid recovery of respiratory
rate and temperature in the period after the procedure.
... In fact, there is experimental evidence that ketamine can influence circadian oscillations in different systems. For instance, ketamine caused a phase advance in the rhythms of rats' locomotor activity when administered in the resting phase, whereas when administered during the active phase, a phase delay was caused [38]. In addition, at the molecular level, ketamine induces a phase shift in Bmal1 and Dbp expression. ...
The choroid plexuses (CPs), located in the brain ventricles, form an interface between the blood and the cerebrospinal fluid named the blood-cerebrospinal barrier, which, by the presence of tight junctions, detoxification enzymes, and membrane transporters, limits the traffic of molecules into the central nervous system. It has already been shown that sex hormones regulate several CP functions, including the oscillations of its clock genes. However, it is less explored how the circadian rhythm regulates CP functions. This study aimed to evaluate the impact of sex hormones and circadian rhythms on the function of CP membrane transporters. The 24 h transcription profiles of the membrane transporters rAbca1, rAbcb1, rAbcc1, rAbcc4, rAbcg2, rAbcg4, and rOat3 were characterized in the CPs of intact male, intact female, sham-operated female, and gonadectomized rats. We found that rAbcc1 is expressed in a circadian way in the CPs of intact male rats, rAbcg2 in the CPs of intact female rats, and both rAbcc4 and rOat3 mRNA levels were expressed in a circadian way in the CPs of intact male and female rats. Next, using an in vitro model of the human blood–cerebrospinal fluid barrier, we also found that methotrexate (MTX) is transported in a circadian way across this barrier. The circadian pattern of Abcc4 found in the human CP epithelial papilloma cells might be partially responsible for MTX circadian transport across the basal membrane of CP epithelial cells.
... Small animals such as mice can cause hypothermia easily during and after anesthesia because of their high surface area to body weight ratio [9]. In the other studies, it has been reported that hypothermia during anesthesia produce bradycardia, disturbed circadian rhythm, increased infection, and delayed recovery from anesthesia [5,9,10,12,20,24,30,32,34]. To prevent from hypothermia, thermal support has been proposed during and after anesthesia [3,9,12,22,29,33]. ...
Hypothermia during anesthetic events is a common adverse effect of anesthesia in laboratory animals. In particular, small rodents such as mice is susceptible to hypothermia during anesthetic events. Therefore, the animals will need additional thermal support by external heating devices during and after anesthesia. In general, the time of recovery from anesthesia is typically longer in case of injectable anesthesia rather than inhalant anesthesia. However, the durations of thermal support have been almost limited to 1 hr from administration of anesthesia in general. Our study objectives are two-fold: 1) to compare the levels of hypothermia induced by injectable anesthesia with medetomidine-midazolam-butorphanol (MMB) and inhalant anesthesia with isoflurane (ISO); 2) to find the adequate durations of thermal support for preventing hypothermia induced by their anesthesia in mice. Adult male ICR mice were anesthetized during 40 min without and with the thermal support for 1 (both anesthetic groups), 2, 3, and 5 hr (in MMB group). Without thermal support, the decrease of body temperature in MMB group were more severe than that in ISO group. The durations of thermal support completely prevented hypothermia at 5 hr-support in MMB group and that at 1 hr-support in ISO group. However, the other short durations did not prevent hypothermia at 1, 2 and 3 hr-support in MMB group. These results suggest that the mice should be received thermal support over 5 hr after injection of MMB anesthesia to prevent hypothermia.
... Ketamine may also have agonistic effects at the κ-opioid receptor [158], although decreasing preprodynorphin mRNA, [159], which may be prevented by melatonin's inhibition of the κ-opioid receptor [111]. This may be parsimonious with the circadian regulation of ketamine effects [160], and may suggest that the adjunctive use of melatonin will modulate ketamine's acute and chronic antidepressant effects. Importantly, ketamine's antidepressant effects are not ubiquitous, with one study indicating that only 56/150 MDD patients experience acute and chronic antidepressant benefits [161], with metabolic syndrome significantly attenuating ketamine's antidepressant efficacy [161]. ...
Background
There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of treatment that is targeted to pathophysiology. Recent data indicates a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD.
Methods
Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial function, form the basis of this review article.
Results
The endogenous opioidergic system is intimately linked to wider MDD pathophysiology, including alterations in the gut microbiome, gut permeability, circadian rhythm, amygdala-prefrontal cortex interactions, and mitochondrial function. A decrease in the μ-/κ-opioid receptor ratio is an important mediator of the changes in mood in MDD, with effects not only in neurons, but also in glia and immune cells.
Conclusion
The endogenous opioidergic system is intimately interwoven with MDD pathophysiology and provides a relevant target for novel treatment development, as well as providing a focus for the integration of wider MDD pathophysiology.
... Light boxes are well established as a non-invasive treatment for correcting abnormal light/dark cycles with few side effects (Ancoli-Israel, Martin, Kripke, Marler, & Klauber, 2002;Eastman, Suh, Tomaka, & Crowley, 2015) and they have been effective in reducing symptom severity in other psychiatric disorders like Seasonal Affective Disorder (Glickman, Byrne, Pineda, Hauck, & Brainard, 2006). Additionally, the NMDA antagonist Ketamine has also been shown to reestablish circadian rhythm synchrony (Duncan et al., 2017;Mihara et al., 2012), and researchers have begun implementing it in the treatment of Major Depressive Disorder (Iadarola, Niciu, & Richards, 2015), suggesting that ketamine can treat depression by shifting circadian rhythms (Morgan, 2017). Few studies have implemented light boxes (Brinkhuijsen, Koenegracht, & Meesters, 2003;Hoflich, Kasper, & Moller, 1992) and Ketamine (Adams, Bloch, & Pittenger, 2017;Rodriguez et al., 2013) to treat OCD; however, those that have each reported significant reductions in symptom severity. ...
Background:
Treatments for Obsessive-Compulsive Disorder (OCD) have greatly improved over time. However, some patients do not respond to current interventions and many are left with residual symptoms even if they are 'responders'. There is increasing evidence that individuals with OCD frequently report delayed bedtimes and are at elevated risk for Delayed Sleep Phase Disorder (DSPD). Therefore, it is logical to ask whether interventions addressing disruptions in sleep timing and circadian rhythms would lead to reductions in OCD symptoms. A prior study from our group showed that behaviorally shifting sleep timing resulted in significant symptom reduction in a treatment resistant OCD patient.
Objectives:
Extending prior findings, this manuscript presents quantitative data from case studies which tested the use of a pharmacological intervention that targets melatonin receptors. Specifically, the case studies reviewed herein utilized the melatonin analog and melatonergic MT1 and MT2 receptor agonist, Agomelatine.
Methods:
A literature review revealed 10 cases which have used Agomelatine for OCD.
Results:
Seven of the cases were reported to have sleep and/or circadian disruptions prior to treatment. These cases OCD symptom reductions between 46%-90%. In contrast, three additional cases without pre-treatment sleep and/or circadian disruptions did not respond to the intervention.
Discussion:
There is growing evidence that disruptions in sleep and circadian rhythms may contribute to the maintenance of OCD. Further work is warranted.
... Furthermore, there is evidence of changes in the morphology of pinealocytes during periods of elevated geomagnetic activity (Bardasano et al. 1989). These findings are noteworthy as several studies have shown that melatonin can enhance GABAergic mediated currents and augment pentobarbitalinduced sleep in rats (Golombek et al. 1996;Marseglia et al. 2015;Mendelson 2002;Mihara et al. 2012;Rosenstein and Cardinali 1990;Wang et al. 2003). Taken together, these findings raise the possibility that during periods of increasing levels of geomagnetic activity, suppression in pineal melatonin might produce a disruptive effect on the sedative and hypnotic actions normally elicited by pentobarbital. ...
The influence of the geomagnetic environment on the human organism and other biological entities has been a topic of intense scientific investigation. A large and growing body of evidence has linked elevated geomagnetic activity with effects on an array of neurological, immunological, cardiovascular, and psychological outcomes. For example, elevations in the rates of epileptic seizures, suicides, aggressive behavior, sleep disturbances, and sudden unexpected death from cardiac pathologies have been reported to occur more frequently on days associated with increased geomagnetic activity. Additional evidence also suggests that geomagnetic conditions might have an impact on the biological actions of specific drugs classes that have important implications for pain management, sedation, and seizure control. The present study set out to determine if periods of enhanced geomagnetic activity could influence the induction of behavioral sedation by pentobarbital in rodents undergoing a routine surgical procedure. The surgical records of 250 subjects were retrospectively analyzed, and the occurrence of complete behavioral sedation (e.g., loss of righting reflex, lack of nociceptive response to tail pinch, absence of corneal and conjunctive reflexes) was noted. We found a significant correlation between periods of increased geomagnetic activity and the number of non-responsive surgical patients (i.e., patients still demonstrating behavioral responsiveness after treatment with pentobarbital). These findings provide evidence for the first time that the potential efficacy of some surgical anesthetic compounds might be reduced on days associated with increased geomagnetic activity. Potential mechanisms are presented, and the broad implications of these findings to phenomena such as surgical awareness are discussed.
... The present locomotor activity findings clearly propose that anesthetic ketamine depressed animals' motility in the motor activity test when injected 24 before testing. These motility results are in agreement with previous findings in which administration of anesthetic doses of ketamine (100-150 mg/kg) reduced rats' motor activity 24 h following treatment [26,27]. On the other hand, anesthetic ketamine (150 mg/kg) assessed at different time frames (24,48 and 72 h) after its administration did not alter mouse locomotor activity [28]. ...
There is scarce information regarding the effects of anesthetic doses of the non-competitive N-methyl-d-aspartate receptor antagonist ketamine on anxiety. The current study evaluated the acute effects of intraperitoneally (i.p.) administered anesthetic ketamine (100 mg/kg) i.p. on anxiety in rats. For this purpose, the light/dark and the open field tests were utilized. The effects of anesthetic ketamine on motility were also examined using a motility cage. In the light/dark test, anesthetic ketamine, administered 24 h before testing reduced the number of transitions between the light and dark compartments and the time spent in the light compartment in the rats compared with their control cohorts. In addition, ketamine was found to exert a depressive effect on rats’ motility. In the open field test, animals treated with anesthetic ketamine 24 h before testing spent essentially no time in the central area of the apparatus, decreased horizontal ambulatory activity, and preserved to a certain extent their exploratory behaviour compared to their control counterparts. The results suggest that, in spite of its hypokinetic effect, a single anesthetic ketamine administration apparently induces an anxiety-like state, while largely preserving exploratory behaviour in the rat. These effects were time-dependent they since they were extinguished when testing was carried out 48 h after anesthetic ketamine administration.
... Furthermore, pentobarbital-induced phase shifts were not due to increasing activity levels (Ebihara and Hayakawa 1990). In a study by Mihara et al. (2012), pentobarbital showed no phase effects on either melatonin secretion or locomotor activity in rats, regardless of the timing of administration. ...
The aim of study was to review the status of arterial pH, pO2 and pCO2 under general anesthesias in dependence on the light-dark (LD) cycle in spontaneously breathing rats. The experiments were performed using three- to four-month-old pentobarbital(P)-, ketamine/xylazine(K/X)- and zoletil(Z)-anesthetized female Wistar rats after a four-week adaptation to an LD cycle (12 h light:12 h dark). The animals were divided into three experimental groups according to the anesthetic agent used: P (light n=11; dark n=8); K/X (light n=13; dark n=11]); and Z (light n=18; dark n=26). pH and blood gases from arterial blood were analyzed. In P anesthesia, LD differences in pH, pO(2), and pCO(2) were eliminated. In K/X anesthesia, parameters showed significant LD differences. In Z anesthesia, LD differences were detected for pH and pO(2) only. Acidosis, hypoxia, and hypercapnia have been reported for all types of anesthesia during the light period. In the dark period, except for P anesthesia, the environment was more stable and values fluctuated within normal ranges. From a chronobiological perspective, P anesthesia was not the most appropriate type of anesthesia in these rat experiments. It eliminated LD differences, and also produced a more acidic environment and more pronounced hypercapnia than K/X and Z anesthesias.
... However, there is evidence to suggest that the central efects of melatonin include at least partial facilitation of GABAergic transmission by modulation of GABA receptors [87][88][89]. In a study by Mihara et al. [90], pentobarbital demonstrated no efect on melatonin secretion or on movement activity, regardless of the time of dosing. On the other hand, in rats under general propofol anesthesia, the plasma concentration of melatonin decreased over the irst 4 h after anesthesia induction and increased after 20 h. ...
... During the night hours, the lights were not on and all of the procedures were done in the dark with red light. It has been shown that red light does not alter the circadian rhythm of rats (11). ...
Objective:
The aim of this study is to investigate the effects of light and administration time of isoflurane on circadian gene expression in the brains and liver tissues of rats kept in light-dark cycle.
Methods:
Seventy two 15-days-old rats pups were divided into four groups. All animals were exposed to 1.5% concentration of isoflurane or to 6 L min(-1) O2 for six hours between Zeitgeber Time (ZT) 0-ZT06 (day-time administration) or ZT12-ZT18 (night-time administration). Rats were sacrificed after six hours of anaesthesia with four-hour time intervals. Total RNA was isolated from brains and liver tissues. Circadian gene expression was examined using quantitative real-time Reverse transcription polymerase chain reaction (RT-PCR).
Results:
BMAL1, CLOCK, PER2 and CRY2 gene expression levels were markedly suppressed after day-time anaesthesia in the both brain and liver, but night-time administration caused only temporary suppression of gene expression.
Conclusion:
The effect of isoflurane on the circadian clock is time-dependent, and administered isoflurane anaesthesia at night had minimal effect on clock gene expression. Additionally, when the treated animals were kept in a regular light-dark cycle, isoflurane-induced phase shift was not observed, possibly because of the light.
... Mihara et al., [23] has recently shown administration of ketamine have different effect on melatonin secretion and also on locomotor activity, depending on the time of the administration, whereas penobarbital has no effect. Their hypothesis was based on the most of the anesthetics target GABAA or NMDA receptors, which are found in suprachiasmatic nucleus of hypothalamus. ...
... During the night hours the lights were not on and all of the procedures were done in the dark with red light. It has been shown that red light does not alter the circadian rhythm of rats [7]. ...
The nocturnal peak of melatonin can be altered after anesthesia and surgery. We aimed to examine the melatonin levels during the day and night after anesthesia with three commonly used inhalational anesthetics. Forty-eight male Wistar albino rats were randomized into eight groups. Rats were administered anesthesia between 7:00 am and 1:00 pm (day groups) or 7:00 pm and 1:00 am (night groups) for 6 hours. At the end of the anesthesia, blood samples were collected for assessing melatonin levels. Mean values of melatonin levels after 6 hours of anesthesia during daytime were 43.17 ± 12.95 for control, 59.79 ± 27.83 for isoflurane, 50.75 ± 34.28 for sevoflurane and 212.20 ± 49.56 pg/mL for desflurane groups. The night groups’ mean melatonin levels were 136.12 ± 33.20 for control, 139.85 ± 56.29 for isoflurane, 117.48 ± 82.39 for sevoflurane and 128.70 ± 44.63 pg/mL for desflurane groups. Desflurane anesthesia between 7:00 am and 1:00 pm significantly increased melatonin levels (p < 0.001). Sevoflurane and desflurane anesthesia between 7:00 pm and 1:00 am decreased the melatonin levels but there were no significant differences (p = 0.904 and p > 0.99, respectively). Isoflurane anesthesia did not significantly change melatonin levels during day or night (p = 0.718 and p > 0.99, respectively). Our results demonstrate that during daytime desflurane anesthesia can alter melatonin levels. Altered melatonin rhythm following inhalational anesthesia can be related to sleep disorders observed after anesthesia.
... The results clearly show differences among three types of anaesthetics and their effects on the circadian rhythmicity of myocardial electrophysiological parameters in an in vivo rat model, presented in our studies as 'light-dark differences'. Although studies from other groups (Ohno et al. 2009, Mihara et al. 2012) have reported moderate or, alternatively, no effects of pentobarbital on the circadian rhythm of locomotor activity and the secretion of specific hormones in mice and rats, the disruptive effect of pentobarbital on circadian oscillations in electrophysiological parameters of the rat heart was evident in our study. Results regarding the effect of ketamine/xylazine anaesthesia on myocardial electrophysiology in rats are supported by the work of Pelissier et al. (1998), who also described the disruptive effect of ketamine on circadian rhythms of locomotor activity, heart rate and body temperature. ...
The design and development of experimental, in vivo chronobiological animal models may help reveal some of the relationships between circadian rhythms and biological function, which can be very difficult to study in humans. To perform ethically acceptable cardiovascular research involving animals, the use of general anaesthesia is often necessary. However This article is protected by copyright. All rights reserved.
... Ketamine increases AD associated processes and its long-term use leads to cognitive deficits [369 -371]. Interestingly, ketamine may decrease melatonin levels when given at an anaesthetic dose [372] and can decrease macrophage phagocytosis [373]. This could suggest that ketamine is having an effect on levels of immune cell melatonin synthesis and release and requires investigation, especially as ketamine is being mooted as a treatment for depression [366,374]. ...
As reviewed in the previous chapter above, tryptophan utilization for serotonin synthesis increases the necessary precursor for the melatoninergic pathways. The changes and susceptibility factors associated with Alzheimer's disease (AD) regulate, and can be regulated by, the melatoninergic pathways. In this chapter we look at the role of the melatoninergic pathways in more detail in relation to changes and interventions relevant to AD. Many pharmaceutical and dietary factors, with efficacy in AD and/or AD models, regulate the melatoninergic pathways, either directly or indirectly. As such, much of the experimental data pertaining to regulators of the etiology, course and treatment of AD, such as zinc, selenium, acetylcholinesterase inhibitors and valproate, may be intimately intertwined with the melatoninergic pathways. In this chapter, we review the role of the melatoninergic pathways in AD, highlighting its previously little recognised involvement in a host of susceptibility factors and treatment approaches. More insight as to the relevant changes occurring in AD should allow treatments to better target relevant biochemical targets, thereby improving the management of this poorly conceptualized, and therefore poorly treated, disease.
... This could be due to the long sleeping time and recovery period, such that the rats ate and drank less. Another negative effect on food and water uptake could be the disturbing influence of ketamine on the circadian rhythm of the animal [36,37]. The seriousness of a BW loss of 8% depends on the initial body weight of the animal. ...
Background:
This study evaluated the influence of repeated anaesthesia using isoflurane (ISO, 2-3 Vol%), ketamine-xylazine (KX, 100 mg·kg(-1) + 5 mg·kg(-1), i.m.) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg·kg(-1) + 2.0 mg·kg(-1) + 0.005 mg·kg(-1), i.m.) on heart rate (HR), arterial blood pressure (BP), body temperature (BT), duration of anaesthetic intervals and body weight (BW) in Wistar rats. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), HR and BT during induction, maintenance and recovery of anaesthesia. Each anaesthesia was performed six times within three weeks. KX was not antagonized, but ISO delivery was terminated 40 minutes after induction and MMF was reversed with atipamezole-flumazenil-naloxone (AFN, 0.75 mg·kg(-1) + 0.2 mg·kg(-1) + 0.12 mg·kg(-1), s.c.).
Results:
With repeated anaesthesia, ISO showed a decrease of HR and BP. A significant decrease of PP could be observed with repeated anaesthesia using MMF. HR and BP were not affected by repeated KX anaesthesia, but we noted a reduction of sleeping time and BW. Neither MMF nor ISO showed significant differences in the duration of anaesthetic intervals and BW. With KX we observed tissue necrosis at the injection site and surgical tolerance was not achieved in 25% of the anaesthesias performed.
Conclusion:
HR, BP values, BT, duration of anaesthetic intervals and BW were affected differently by repeated anaesthesia performed with ISO, KX or MMF. ISO produced a reproducible anaesthesia, thereby being suitable for repeated use, but with a decrease of HR and BP throughout the six anaesthesias. The use of ISO in cases where these parameters should be unaffected is therefore not advised. The inability to produce a surgical tolerance, the reduction of sleeping time and BW, as well as the tissue necrosis are significant contraindications for a repeated use of KX. Only mild changes of BP were found with repeated MMF anaesthesia, so it seems suitable for serial use, unless the high BP and the low HR during the surgical plane of anaesthesia are undesirable for a special procedure.
... Therefore, experimental data concerning MMF anaesthesia are limited. This anaesthesia offers the advantage of a rapid and complete reversal by using an injection of atipamezole, flumazenil and naloxone (AFN) [20,[22][23][24][25]. Anaesthesia in rodents influences diurnal rhythm and often results in hypothermia and hypoglycemia because of their high metabolic rate and their large surface area to body weight ratio [3,20,[26][27][28]. Due to a fast resumption of food and water intake because of a very short recovery period when antagonized and, by our experience, its excellent survival rate, MMF seems to be advantageous over other anaesthesias in rodents. ...
Background
This study investigated effects on cardiovascular parameters during anaesthesia with isoflurane (ISO, 2¿3 Vol%), ketamine-xylazine (KX, 100 mg¿kg¿1¿+¿5 mg¿kg¿1) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg¿kg¿1¿+¿2.0 mg¿kg¿1¿+¿0.005 mg¿kg¿1) in rats throughout induction, maintenance and recovery from anaesthesia. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), heart rate (HR) and core body temperature (BT). The parameters were continuously measured before, during and after each type of anaesthesia. Forty minutes after induction, ISO delivery was terminated and MMF was antagonized with atipamezole-flumazenil-naloxone (AFN, 0.75 mg¿kg¿1¿+¿0.2 mg¿kg¿1¿+¿0.12 mg¿kg¿1) whereas KX was not antagonized.ResultsDifferences were observed between anaesthesias with KX (301 min) lasting much longer than MMF (45 min) and ISO (43 min). HR in ISO ( x¯ = 404¿±¿25 bpm) increased during the time of surgical tolerance whereas a HR decrease was observed in KX ( x¯ = 255¿±¿26 bpm) and MMF ( x¯ = 209¿±¿24 bpm). In ISO (MAP during time of surgical tolerance: x¯ = 89¿±¿12.3 mmHg) and KX (MAP during wake-up period: x¯ = 84¿±¿8.5 mmHg) mild hypotensive values were observed, whereas blood pressure (BP) in MMF (MAP during time of surgical tolerance: x¯ = 138¿±¿9.9 mmHg) increased. Despite keeping animals on a warming pad, a loss of BT of about 1°C was observed in all groups. Additionally, we observed a peaked increase of HR ( x¯ = 445¿±¿20 bpm) during the wake-up period with ISO and an increase of PP ( x¯ = 59¿±¿8.5 mmHg) in MMF during the time of surgical tolerance.Conclusion
The anaesthesias influenced very differently the cardiovascular parameters measured in Wistar rats. ISO caused mild hypotension and increased HR whereas MMF produced a marked hypertension and a significant decrease of HR. The slightest alterations of BP, HR and BT were observed using KX, but the long wake-up and recovery period suggest the need for prolonged monitoring.
... These results are of the same context shown in the present study that active-phase anesthesia dissociates circadian rhythm between neuronal and locomotor activity. Recently, we reported that melatonin secretion in rat surgical model was suppressed for 24 h after pentobarbital and ketamine anesthesia only when they applied in the active phase but not rest phase ( Mihara et al., 2012). In that study, locomotor activity was significantly suppressed both after active-and rest-phase anesthesia with both pentobarbital and ketamine anesthesia. ...
General anesthesia is occasionally associated with postoperative complications such as sleep disorder, drowsiness, or mood alterations. Hippocampal acetylcholine (ACh), the extracellular level of which increases during the dark (active) phase and decreases during the light (rest) phase in rats, is thought to be associated with locomotor activity and be crucial for learning and memory. Propofol, an intravenous anesthetic, is known to shift the circadian rhythms of physiological parameters including locomotor activity and body temperature in both rodents and humans, while the effects of volatile anesthetics on the circadian rhythm largely remain unclear. The present study examined the effects of isoflurane anesthesia on the diurnal changes in hippocampal ACh release and locomotor activity in rats. Rats were divided into 3 groups: a light-phase anesthesia group (LA group), a dark-phase anesthesia group (DA group), and a control group. They were exposed to a 12-hour light/12-hour dark environment and anesthetized with 1.4% isoflurane for 4 hours during the middle of the light phase (LA group) and dark phase (DA group). Simultaneous measurement of hippocampal ACh by microdialysis and locomotor activity were done for 60 hours under free-moving conditions. Hippocampal ACh release and locomotor activity showed a clear circadian rhythm. In the DA group, but not in the LA group, the diurnal variation in ACh release was significantly disturbed and a more than 2-hour phase-advance in locomotor activity was observed. There was a significant correlation between hippocampal ACh release and locomotor activity, and isoflurane anesthesia disrupted it even after anesthesia was discontinued. This study revealed that the levels and circadian rhythms of hippocampal ACh release and locomotor activity was more sensitive to isoflurane anesthesia when it was administered during the active phase. Our findings suggest that anesthesia exerts differential effects on the regulation of circadian rhythms depending on the circadian phase.
Objective:
The objective of this study was to compare the time to discharge between daytime and nighttime ketamine administration to children undergoing primary facial repair in the emergency department (ED).
Methods:
This retrospective, cross-sectional study was performed in a sample of children aged younger than 18 years and requiring sedation for primary facial repair in 2019. Children who received ketamine for reasons other than facial repair were excluded. All patients were initially injected with 4 mg/kg of ketamine intramuscularly and additionally injected if sedation failed. The time of injection and awakening were recorded in the electronic medical record system by nurses in charge, and the level of wakefulness was determined with a postanesthesia discharge scoring system administered by physicians.
Results:
A total of 562 cases of ketamine administration were divided into 2 groups: daytime and nighttime. We defined daytime and nighttime as 8 a.m. and 8 p.m./sunrise and sunset, respectively. They found that there were no significant differences between 2 groups in each standard (95% confidence interval, -4.55-4.55; P = 0.877 and 95% confidence interval, -6.41-2.41; P = 0.487, respectively).
Conclusions:
The findings of the study suggest that the time of ketamine injection has no relationship to duration of sedation for primary facial repair in children.
Obsessive-compulsive disorder (OCD) and related disorders such as hoarding disorder and their relationship to disorders or problems of sleep have not been fully elucidated. Many people with OCD have insomnia. Many also have a comorbid circadian rhythm disorder in the form of delayed sleep-wake phase disorder. This chapter reviews the standard diagnostic criteria for OCD and the evidence for various findings related to sleep and OCD. It touches on special populations such as children, pregnant women, and those with or impacted by COVID-19. The pathophysiology connecting OCD and sleep disorders is discussed as is treatment—both pharmacologic and non-pharmacologic.
Introduction
The circadian rhythm of melatonin secretion is disturbed after general anaesthesia, leading to postoperative sleep disturbance. Small studies investigating the preventive effect of melatonin administration on postoperative sleep disturbance have not reached any conclusions. Therefore, we will conduct a systematic review and meta-analysis to obtain conclusive results.
Methods and analysis
We prepared this protocol following the 2015 Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols guidelines. We will conduct a search for randomised controlled trials that evaluated the effect of melatonin and melatonin agonists on postoperative sleep quality in adult patients undergoing general anaesthesia or regional anaesthesia with sedation. We will exclude patients undergoing regional anaesthesia without sedation. Relevant studies will be searched in the following eight databases: MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science and four preregistration sites from inception to 1 January 2021. No language restrictions will be applied. Two authors will independently scan and select eligible studies and perform data extraction and assessment of the risk of bias. The Visual Analogue Scale scores for sleep quality will be combined as the mean difference with a 95% CI using a random-effect model; we will use I ² to assess heterogeneity. We will evaluate the quality of trials using the Cochrane methodology and assess the quality of evidence using the Grading of Recommendation Assessment, Development and Evaluation approach. If appropriate, trial sequential analysis will be performed.
Ethics and dissemination
No ethical approval is required for this meta-analysis, as it does not include individual patient data. We will disseminate the results of this meta-analysis in a peer-reviewed journal.
PROSPERO registration number
CRD42020180167.
Objective: It was aimed to investigate the effects of ketamine combination administered with xylazine used for general anesthesia in dogs on arterial blood pressure, heart rate, and body temperature.Materials and Methods: In the study, a total of 20 dogs, 14 females and 6 males, from various breeds and ages 1 to 5, which undergone elective ovariohysterectomy or castration according to body weights. 1 mg/kg xylazine (xylazine hydrochloride, 23.3mg/ml, Xylazinbio 2% Bioveta®, Czechia) and 10 mg/kg ketamine (ketamine hydrochloride, 100 mg/ml, Ketasol 10% Richter® Pharma Ag, Austria) combination within a single injection with 21G needle were applied intramuscularly. The food and water access were ceased 12 hours before drug administration. Systolic and diastolic blood pressures, pulse measurements, and body temperatures were measured 3 times before and 5 times during anesthesia (at the 15th, 30th, 45th, 60th and 120th minutes of anesthesia) by using the AM6100 veterinary bedside monitör. Muff was placed to cover 1/3 of the proximal leg and for the artery to be recognizable by the microprocessor. Pulse rates were measured with electrodes connected to the device. Body temperature was measured by a rectal thermometer which was a part of the device. Measurements were taken before anesthesia was considered as control measurements.Results: In systolic blood pressure, the recordings at 0, 15th, 30th mins have been found as statistically significant in relation to 45th, 60th, and 120th (p<0.05). In diastolic blood pressure, there were no significant differences recorded. The change between the preintervention and post-application has been found significant (p<0.001). Body temperature has shown a meaningful change in comparison to the starting point after the readings (p<0.001).Conclusion: Eventually, decreases in blood pressure, heartbeat, and body temperature were observed for the dogs that have been anesthetized with the combination of xylazine-ketamine.
The role of the serotonin 7 receptor (5-HT7 receptor) subtype in a number of domains has been widely recognized, but its role in the regulation of changes of the circadian rhythm after anesthesia is still unclear. We used intraperitoneal injection of 5-HT7 receptor agonist LP-211 or antagonist SB-269970 in mice to influence the level of 5-HT7 receptor protein in the SCN and to observe the role of this receptor on circadian rhythm changes after isoflurane anesthesia. Our results show the appropriate dose of SB-269970 significantly alleviated the circadian rhythm disorder induced by isoflurane anesthesia, while LP-211 significantly aggravated it after anesthesia, which is different from the phase shift that can be caused by the administration of LP-211 before anesthesia. These findings may indicate the 5-HT7 receptor plays a complex role in the regulation of circadian rhythm after anesthesia. Our findings may provide some positive significance for alleviating circadian rhythm disorder in patients after anesthesia and ultimately promoting rapid postoperative recovery.
General anaesthesia is a widely used tool to enable surgery in animal experimentation. There is now convincing evidence that general anaesthesia can cause profound and strongly time-dependant shifts in circadian rhythms of behaviour (sleep-wake cycles), physiology (core body temperature, blood pressure, heart rate and hormone release) and cognitive parameters (learning and memory) in a range of species. These effects have the potential to confound laboratory experiments, and may lead to misinterpretation of results. Here, we summarise these effects and advise caution to those conducting laboratory experiments in which anaesthesia forms part of the protocol.
Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) worsen quality of life in postoperative patients and, moreover, impose huge cost on hospitals. Previous clinical reports revealed that POD appears to be a risk for high mortality in the elderly and POCD appears to have long-lasting adverse effect on learning performance in children. Nevertheless nobody has proposed the effective way to cure them. We are still struggling in exploring mechanisms underlying POD and POCD because of the following reasons: (1) clinical definitions may be obscure, (2) underlying mechanisms are multifactorial, (3) less animal models comparable with patients are available. Under these difficulties, a considerable number of studies have contributed to identify key molecules and neural circuits essential for the establishment of these diseases and fortunately some of them appear to postulate reliable mechanisms. Integrating latest findings, here we discuss about these mechanisms underlying POD and POCD.
Animal research involves the collection of data from carefully designed experiments. The validity of the research and the conclusions drawn from the data are influenced by many factors. Some of these factors may confound experimental results and therefore must be carefully considered and, where possible, controlled. This chapter describes potential intrinsic and extrinsic research confounders described in the scientific literature that can influence experimental outcomes. In order to obtain reliable, meaningful results, an attempt should be made to control or standardize all known biological, environmental, and social factors when conducting experiments involving animals.
Administration of anaesthesia may influence specific aspects of in vivo animal experiments and is an especially important consideration for experiments conducted during the daytime. Although chronobiological studies investigating interactions between general anaesthesia and circadian rhythms are sparse, all suggest that general anaesthetic agents have a significant effect on circadian rhythms. To assess the suitability of pentobarbital anaesthesia in chronobiological studies, this study was performed using pentobarbital-anaesthetized (40 mg/kg, intraperitoneal) female Wistar rats after adaptation to a light–dark (LD) cycle (12 h:12 h). Heart rate, rectal temperature (RT), electrocardiographic parameters, autonomic nervous system activity, acid–base balance and plasma concentrations of Na+, K+, Ca2+ and Cl- were evaluated for their dependence on the LD cycle. LD differences were found in heart rate and RT, measured before the administration of the anaesthetic agent. Pentobarbital anaesthesia eliminated LD differences in all electrophysiological parameters, parameters of heart rate variability (except RR intervals) and parameters of acid–base balance and ion concentrations. LD differences with borderline statistical significance were found only for Na+ levels, with a higher level in the light period (i.e. nonactive) of the rat regimen day. During pentobarbital anaesthesia, parasympathetic tone predominates and sympathetic activity is depressed. Spontaneously breathing rats under pentobarbital anaesthesia are in an asphyxic state independent of the LD cycle in in vivo experiments. Results of this study suggest that pentobarbital anaesthesia is not suitable for chronobiological studies. However, it is suitable for cardiovascular research that is done regardless of the circadian rhythmicity, because it does not cause significant changes in heart activity.
Objective: Melatonin synthesis in the pineal gland shows a circadian rhythm and reaches its maximum level during the phase of darkness. Surgery and anaesthesia affect melatonin secretion and endocrine function. The aim of this study was to investigate the effects of isoflurane anaesthesia during night vs. day on plasma melatonin level in rats. Methods: Twenty-six 15-day-old male rats were included and divided into 4 groups by randomization. Isoflurane (1.5%) was administered between 07:00 pm and 01:00 am (night group) or 07:00 am and 01:00 pm (day group) in winter; 6 L min-1 of oxygen was administered to control groups during the same time periods. At the end of 6 hours the rats were sacrificed and blood samples were taken. Blood samples were centrifuged and plasma melatonin levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: When Group Gc-I (night-isoflurane) was compared with Group Gc-K (night-control), Group Gc-I with Group Gn-I (day-isoflurane), and Group Gc-K with Group Gn-K (day-control), no significant differences were found in plasma melatonin levels (p=0.132, p=0.180 and p=0.065, respectively). When Group Gn-I was compared with Group Gn-K, plasma melatonin levels were significantly increased in Group Gn-I (p=0.009). Conclusion: It was concluded that 1.5% isoflurane administered over 6 hours in 15 day old rats increases plasma melatonin levels significantly in the daytime but does not affect them at night.
To the Editor,Melatonin, an indole neurohormone, is the principalsecretory product of the pineal gland that is synthesizedfrom tryptophan and released directly into the bloodstreamin a circadian pattern governed by the light and dark cycle.It produces hypnotic effects by accelerating sleep initiationand improving sleep maintenance and efficiency. Unlikemost hypnotics, melatonin is not associated with significantchanges in sleep architecture, hangover effects, substancedependence, or the potential for substance abuse. In addi-tion, melatonin possesses the capacity to resynchronize thehuman circadian rhythm, and it may play a role in physi-ological adaptation to jet lag and shift work. Consideringits hypnotic and chronobiotic properties, melatonin mayalso serve a role in the perioperative setting when thepatient’s sleeping patterns are likely to be disturbed.Indeed, the literature reveals an altered pattern of melato-nin secretion after anesthesia and surgery.
General anesthesia is commonly associated with sleep disorders, fatigue, drowsiness, and mood alterations in patients. The authors examined whether general (propofol) anesthesia can impact the circadian temporal structure by disturbing circadian rest-activity and body temperature rhythms under normal light-dark conditions (light-dark 12:12 h) in rats.
A group of rats was anesthetized with propofol, and another was injected with 10% Intralipid, which was used as a control lipidic solution. The authors examined six groups of rats according to the Zeitgeber time of intraperitoneal administration (ZT6, ZT10, ZT16) and the substance injected (propofol or Intralipid).
On the day after anesthesia, propofol induced a significant 60- to 80-min phase advance of both rest-activity and body temperature rhythms. A significant 45- to 60-min phase advance of body temperature and a significant 20-min phase advance of rest-activity were still observed on the second day after anesthesia. The amplitudes of both rest-activity and body temperature rhythms were decreased on the first and second days after anesthesia. The 24-h mean rest-activity rhythm was decreased on the day after anesthesia, whereas the 24-h mean body temperature rhythm was not modified.
The results demonstrate the disturbing effects of propofol anesthesia on the circadian time structure in rats under normal light conditions.
first decades of genetic and molecular genetic analysis of clocks) and the fact that the Drosophila timeless gene, tim, was still in the process of arriving. This era was Life is a cyclical chemical process that is regulated in spent convincing ourselves that such genes really were four dimensions. We distinguish parts of the cycle: de- the key to understanding how clocks work. Flies and velopment describes the changes from single cell to fungi were PERFRQT systems for working out basic adult, and aging the changes from adult to death. Birth tools, paradigms, and approaches—gene products whose to death, a cycle, and there are cycles within cycles— expression levels themselves oscillate, the importance circannual rhythms, menstrual cycles, semilunar cycles, of negative feedback, criteria to begin to distinguish and daily 24 hr or circadian cycles. which oscillatory gene products might contribute to the Twice a year we get a reminder of the importance of action of an internal timer as distinct from being output our internal circadian biological clocks. Daylight sav- (reviewed in Dunlap, 1996), and a universal appreciation ings: in October we fall back just an hour, and yet we of the importance of genetics. If overall this left us with wake up an hour early on Monday anyway and think a less than PERFRQT understanding of timing in gen- meals are late—but only for a day, until our clocks are eral, at least many found optimism in the sense that we reset. The reminder is about the way we process envi- were, finally, asking the right questions. This naturally ronmental information and time, namely that we use segued into an interlude where light resetting was ex- external time cues (light and temperature changes that plained by two different mechanisms, through transcrip- track the day without) to set an internal clock that guides tional induction of oscillator components in Neurospora the day within. This internal clock is the lens through (Crosthwaite et al., 1995) or protein turnover in Drosoph- which we survey acute external factors; it takes the lead ila (reviewed in Young, 1998). But by mid 1997 the word in determining what we perceive as time. was PASWCCLK (the first clock components with known It used to be that research in chronobiology moved biochemical functions (transcriptional activators), the along at a gentlemanly pace. It was a field in that it first mammalian clock gene, and the first protein domain shared a common set of problems, a common vocabu- (PAS) conserved among clock molecules from different lary, and a series of common assumptions: only eukary- phyla) and then MPERMPER (mammalian orthologs and otes had real clocks and they probably evolved just paralogs of model system clock genes), and then in mid once, since the basic properties of the rhythms were 1998 the already ungainly CYCBMALJRKDBT (and a generally the same. Any cell in fungi, plants, or protists grand unifying theory for clocks within the animal/fungal could be a clock cell, but only neurons kept time in clade of the crown eukaryotes; e.g., Dunlap, 1998b), and organisms that had them. Input to the clock was readily for the close of 1998 (WHAT WORD?). So if you can be separable from how the clock itself worked. But within satisfied by intoning the four words in a dimly lit room, the past few years progress in understanding how then enjoy your evening; and if not, read on to find out clocks work in this assemblage of organisms has been who's who in the phylogeny of timers. increasing exponentially, coming to a crescendo during the final half of 1998 in an eruption of data that has Clocks in Cells largely disproven the assumptions and permanently It is now common to begin from a general assertion that, changed the face of the field. The dust is still settling,
Although there is substantial evidence that glutamate mimics the effects of light on the mammalian circadian clock in vitro, it has been reported that microinjection of glutamate into the suprachiasmatic nucleus of the hypothalamus (SCN) region in vivo does not result in a pattern of phase shifts that mimic those caused by light pulses. The present study was designed to test the hypothesis that microinjection of NMDA into the SCN would induce light-like phase shifts of the circadian clock through activation of the NMDA receptor. Hamsters housed in constant darkness received microinjections of NMDA through guide cannulas aimed at the SCN region at various times throughout the circadian cycle. Wheel running was monitored as a measure of circadian phase. Microinjection of NMDA resulted in circadian phase shifts, the size and direction of which were dependent on the time of injection. The resulting phase-response curve closely resembled that of light. The circadian response showed a clear dose-dependence at circadian time (CT) 13.5 but not at CT19. Both phase delays and advances induced by NMDA were blocked by coinjection of the NMDA antagonist 2-amino-5-phosphopentanoic acid but were slightly attenuated by the non-NMDA antagonist 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione disodium. The ability of NMDA to induce phase shifts was not altered by coinjection with tetrodotoxin. These data are consistent with the hypothesis that activation of NMDA receptors is a critical step in the transmission of photic information to the SCN.
The tiny suprachiasmatic nucleus (SCN) of the hypothalamus plays a central role in the daily programming of organismic functions by regulating day-to-day oscillations of the internal milieu and synchronizing them to the changing cycles of day and night and of body state. This biological clock drives the daily expression of vital homeostatic functions as diverse as feeding, drinking, body temperature, and neurohormone secretion. It adaptively organizes these body functions into near-24-hour oscillations termed circadian rhythms. The SCN imposes temporal order 1) through generating output signals that relay time-of-day information, and 2) through gating its own sensitivity to incoming signals that adjust clock timing. Each of these properties, derived from the timebase of the SCN's endogenous near-24-hour pacemaker, persists when the SCN is maintained in a hypothalamic brain slice in vitro. Single-unit recording experiments demonstrate a spontaneous peak in the electrical activity of the ensemble of SCN neurons near midday. By utilizing this time of peak as a "pulse" of the clock, we have characterized a series of time domains, or windows of sensitivity, in which the SCN restricts its own sensitivity to stimuli that are capable of adjusting clock phase. Pituitary adenylyl cyclase-activating peptide (PACAP) and cAMP comprise agents that reset clock phase during the day time domain; both PACAP and membrane-permeable cAMP analogs cause phase advances only when applied during the day. In direct contrast to PACAP and cAMP, acetylcholine and cGMP analogs phase advance the clock only when applied during the night. Sensitivity to light and glutamate arises concomitant with sensitivity to acetylcholine and cGMP. Light and glutamate cause phase delays in the early night, by acting through elevation of intracellular Ca2+, mediated by activation of a neuronal ryanodine receptor. In late night, light and glutamate utilize a cGMP-mediated mechanism to induce phase advances. Finally, crepuscular domains, or dusk and dawn, are characterized by sensitivity to phase resetting by the pineal hormone, melatonin, acting through protein kinase C. Our findings indicate that the gates to both daytime and nighttime phase resetting lie beyond the level of membrane receptors; they point to critical gating within the cell, downstream from second messengers. The changing patterns of sensitivities in vitro demonstrate that the circadian clock controls multiple molecular gates at the intracellular level, to assure that they are selectively opened in a permissive fashion only at specific points in the circadian cycle. Discerning the molecular mechanisms that generate these changes is fundamental to understanding the integrative and regulatory role of the SCN in hypothalamic control of organismic rhythms.
Different wavelengths of light were compared for melatonin suppression and phase shifting of the salivary melatonin rhythm. The wavelengths compared were 660 nm (red), 595 nm (amber), 525 nm (green), 497 nm (blue/green), and 470 nm (blue). They were administered with light-emitting diodes equated for irradiance of 130 muW/cm2. Fifteen volunteers participated in all five wavelength conditions and a no light control condition, with each condition conducted over two consecutive evenings. Half-hourly saliva sam ples were collected from 19:00 to 02:00 on night 1 and until 01:00 on night 2. Light was administered for the experimental conditions on the first night only from midnight to 02:00. Percentage melatonin suppression on night 1 and dim light melatonin onset (DLMO) for each night were calculated. The shorter wavelengths of 470, 497, and 525 nm showed the greatest melatonin suppression, 65% to 81%. The shorter wavelengths also showed the greatest DLMO delay on night 2, ranging from 27 to 36 min. The results were consistent with the involvement of a scotopic mechanism in the regulation of circadian phase.
The pineal hormone, melatonin, is an important regulator of seasonal reproduction and circadian rhythms. Its effects are mediated via high-affinity melatonin receptors, located on cells of the pituitary pars tuberalis (PT) and suprachiasmatic nucleus (SCN), respectively. Two subtypes of mammalian melatonin receptors have been cloned and characterized, the MT1 (Mel(1a)) and the MT2 (Mel(1b)) melatonin receptor subtypes. Both subtypes are members of the seven-transmembrane G protein-coupled receptor family. By using recombinant melatonin receptors it has been shown that the MT1 melatonin receptor is coupled to different G proteins that mediate adenylyl cyclase inhibition and phospholipase C beta activation. The MT2 receptor is also coupled to inhibition of adenylyl cyclase and additionally it inhibits the soluble guanylyl cyclase pathway. In mice with a targeted deletion of the MT1 receptor, the acute inhibitory effects of melatonin on SCN multiunit activity are completely abolished, while the phase-shifting responses to melatonin (given in physiological concentrations) appear normal. Furthermore, melatonin inhibits the phosphorylation of the transcription factor cyclic AMP response element binding protein, induced by the pituitary adenylate cyclase-activating polypeptide in SCN cells predominantly via the MT1 receptor. However, a functional MT2 receptor in the rodent SCN is partially able to compensate for the absence of the MT1 receptor in MT1 receptor-deficient mice. These findings indicate redundant and non-redundant roles of the receptor subtypes in regulating SCN function. In the PT, a functional MT1 receptor is essential for the rhythmic synthesis of the clock gene product mPER1. Melatonin produces a long-lasting sensitization of adenylyl cyclase and thus amplifies cyclic AMP signaling when melatonin levels decline at dawn. This action of melatonin amplifies gene expression rhythms in the PT and provides a mechanism for reinforcing rhythmicity in peripheral tissues which themselves lack the capacity for self-sustained oscillation. Mice with targeted deletion of melatonin receptor subtypes provide an excellent model to understand cellular mechanisms through which melatonin modulates circadian and photoperiodic rhythmicity.
Effects of temperature and temperature changes on circadian clocks in cyanobacteria, unicellular algae, and plants, as well as fungi, arthropods, and vertebrates are reviewed. Periodic temperature with periods around 24 h even in the low range of 1-2 degrees C (strong Zeitgeber effect) can entrain all ectothermic (poikilothermic) organisms. This is also reflected by the phase shifts-recorded by phase response curves (PRCs)-that are elicited by step- or pulsewise changes in the temperature. The amount of phase shift (weak or strong type of PRC) depends on the amplitude of the temperature change and on its duration when applied as a pulse. Form and position of the PRC to temperature pulses are similar to those of the PRC to light pulses. A combined high/low temperature and light/dark cycle leads to a stabile phase and maximal amplitude of the circadian rhythm-when applied in phase (i.e., warm/light and cold/dark). When the two Zeitgeber cycles are phase-shifted against each other the phase of the circadian rhythm is determined by either Zeitgeber or by both, depending on the relative strength (amplitude) of both Zeitgeber signals and the sensitivity of the species/individual toward them. A phase jump of the circadian rhythm has been observed in several organisms at a certain phase relationship of the two Zeitgeber cycles. Ectothermic organisms show inter- and intraspecies plus seasonal variations in the temperature limits for the expression of the clock, either of the basic molecular mechanism, and/or the dependent variables. A step-down from higher temperatures or a step-up from lower temperatures to moderate temperatures often results in initiation of oscillations from phase positions that are about 180 degrees different. This may be explained by holding the clock at different phase positions (maximum or minimum of a clock component) or by significantly different levels of clock components at the higher or lower temperatures. Different permissive temperatures result in different circadian amplitudes, that usually show a species-specific optimum. In endothermic (homeothermic) organisms periodic temperature changes of about 24 h often cause entrainment, although with considerable individual differences, only if they are of rather high amplitudes (weak Zeitgeber effects). The same applies to the phase-shifting effects of temperature pulses. Isolated bird pineals and rat suprachiasmatic nuclei tissues on the other hand, respond to medium high temperature pulses and reveal PRCs similar to that of light signals. Therefore, one may speculate that the self-selected circadian rhythm of body temperature in reptiles or the endogenously controlled body temperature in homeotherms (some of which show temperature differences of more than 2 degrees C) may, in itself, serve as an internal entraining system. The so-called heterothermic mammals (undergoing low body temperature states in a daily or seasonal pattern) may be more sensitive to temperature changes. Effects of temperature elevation on the molecular clock mechanisms have been shown in Neurospora (induction of the frequency (FRQ) protein) and in Drosophila (degradation of the period (PER) and timeless (TIM) protein) and can explain observed phase shifts of rhythms in conidiation and locomotor activity, respectively. Temperature changes probably act directly on all processes of the clock mechanism some being more sensitive than the others. Temperature changes affect membrane properties, ion homeostasis, calcium influx, and other signal cascades (cAMP, cGMP, and the protein kinases A and C) (indirect effects) and may thus influence, in particular, protein phosphorylation processes of the clock mechanism. The temperature effects resemble to some degree those induced by light or by light-transducing neurons and their transmitters. In ectothermic vertebrates temperature changes significantly affect the melatonin rhythm, which in turn exerts entraining (phase shifting) functions.
Several common postdischarge symptoms, such as sleep disorders, headache, drowsiness or general malaise, evoke disturbances of circadian rhythms due to jet lag (ie crossing time zones) or shift work rotation. Considering that general anesthesia is associated with numerous effects on the central nervous system, we hypothesized that it may also act on the circadian timing system. We first determined the effects of the circadian timing on general anesthesia. We observed that identical doses of propofol showed marked circadian fluctuations in duration of effects, with a peak at the middle of the resting period (ie 7 h after lights on). Then, we examined the effects of general anesthesia on circadian timing, by analysing stable free-running circadian rhythms (ie in constant environmental conditions), an experimental approach used widely in circadian biology. Free-running rats were housed in constant darkness and temperature to assess possible phase-shifting effects of propofol anesthesia according to the time of the day. When administered around (+/-2 h) the daily rest/activity transition point, a 30-min propofol anesthesia induced a 1-h phase advance in the free-running rest-activity rhythm, while anesthesia had no significant resetting effect at other times of the day. Anesthesia-induced hypothermia was not correlated with the phase-shifting effects of propofol anesthesia. From our results, anesthesia itself can reset circadian timing, and acts as a synchronizing cue for the circadian clock.
We have recently reported dynamic circadian rhythms of serotonin (5-HT, 5-hydroxytryptamine) output in the pineal gland of rat, which precedes the onset of N-acetylserotonin (NAS) and melatonin secretion at night. The present study was aimed at investigating in detail the relationship between 5-HT onset (5HT-on) and melatonin onset (MT-on) in multiple strains of rats and comparing them with those of hamsters.
Animals were maintained in chambers equipped with light (250 lux at cage levels) and ventilation in a temperature-controlled room. Following surgical implantation of a microdialysis probe in the pineal gland, animals were individually housed for on-line pineal microdialysis and for automated HPLC analysis of 5-HT and melatonin. Animals were under a light-dark cycle of 12:12 h for the duration of the experiments.
All animals displayed dynamic 5-HT and melatonin rhythms at night. In all cases, 5HT-on (taken at 80% of the daily maximum levels) preceded MT-on (taken at 20% of the daily maximum levels). Within the same animals, 5HT-on as well as MT-on across multiple circadian cycles exhibited minimum variations under entrained conditions. Large inter-individual variations of both 5HT-on and MT-on were found in outbred rats and hamsters under entrained conditions. In comparison, inbred rats displayed very small individual variations of 5HT-on and MT-on. Importantly, we have uncovered a species-specific relationship of 5HT-on and MT-on. 5HT-on of rats, regardless of the strain, preceded MT-on of the same rats by 50 min. In contrast, 5HT-on of hamsters led MT-on by as much as 240 min. Thus, while a constant relationship of 5HT-on and MT-on exists for animals of the same species, the relative timings of 5HT-on and MT-on differ between animals of different species.
These results suggest that both 5-HT and melatonin could serve as reliable markers of the circadian clock because of their day-to-day precision of onset timings within the same animals or within individuals of the same strain or same species. The results also demonstrate that data for MT-on cannot be compared directly between different species, and that 5HT-on may be a more reliable circadian marker when data from animals of different species are compared.
Activation of gamma-aminobutyric acid (GABA) A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABA A receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABA A agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABA A receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.
Many physiological and behavioral phenomena are controlled by an internal, self-sustaining oscillator with a periodicity of approximately 24 hr. In mammals, the principal oscillator resides in the suprachiasmatic nucleus (SCN). A light pulse during the subjective night causes a phase shift of the circadian rhythm via direct glutamatergic retinal afferents to the SCN [1]. Along with the accepted theoretical models of the clock, it is suggested that behavioral resetting of mammals is completed within 2 hr [2]; however, the molecular mechanism has not been elucidated. Here, we show the real-time image of the transcription of the circadian-clock gene mPer1 in the cultured SCN by using the transgenic mice that carry a luciferase reporter gene under the control of the mPer1 promoter [3]. The real-time image demonstrates that the mPer1 promoter activity oscillates robustly in a circadian manner and that this promoter activity is reset rapidly (within 2–3 hr) when a phase shift occurs.
There is considerable interest in the neuronal pathways involved in the generation and entrainment of circadian rhythms. We have monitored the output of the pineal gland via the urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT.6S), following drug treatment to provide information on the transmitters mediating the effects of light. As a check on the specificity of the response [suprachiasmatic nucleus (SCN) versus direct pineal effects] we also monitored in separate experiments c-Fos induction in the SCN in response to the treatments. Administration of the excitatory amino acid (EAA) antagonist MK-801 (3 mg/kg) failed to inhibit either the acute or entraining effects of light on melatonin production and only partially (approximately 30%) prevented the induction of c-Fos in the SCN. These results suggested that EAA are either not important in mediating the effects of light in the rat or that pathways utilising transmitters other than EAA may be involved. When the non-specific serotonin agonist quipazine was administered at CT 18, it mimicked both the acute and phase delaying effects of light on melatonin secretion and induced c-Fos in the SCN with a regional distribution identical to that observed following light treatment. Characterisation of the receptor subtypes involved in this response implicated the 5HT2c receptor on the basis of the response to (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane HCl (DOI, 0.1-0.5 mg/kg) and the potent antagonism by ritanserin and ketanserin. DOI (0.5 mg/kg) also induced c-Fos in the SCN and the induction was prevented by ritanserin and ketanserin. Despite the potency of 5HT2c agonists in mimicking light effects on melatonin rhythmicity, at the time of preparation we have not been able to block the effects of 2-1x/1-min light pulses on the melatonin rhythm with either metergoline (15 mg/kg), ritanserin (3 mg/kg) or ketanserin (3 mg/kg). Similarly ritanserin (10 mg/kg) failed to block light-induced c-Fos induction in the SCN. We conclude that in the rat there may be two pathways mediating the effects of light on rhythmicity, one being the retino-hypothalamic tract (RHT) utilising excitatory amino acids and the other a retino-raphe-SCN pathway utilising 5HT2c receptors. These conclusions stand in stark contrast to the situation in the hamster where the RHT is paramount in the transmission of light to the SCN.
The suprachiasmatic nucleus (SCN) of the hypothalamus contains a neural oscillatory system which regulates many circadian rhythms in mammals. Immunohistochemical evidence indicates that a relatively high density of GABAergic neurons exist in the suprachiasmatic region. Since intraperitoneal injections of the benzodiazepine, triazolam, have been shown to induce phase shifts in the free-running circadian rhythm of locomotor activity in the golden hamster, the extent to which microinjections of muscimol, a specific agonist for gamma-aminobutyric acid (GABA), may cause phase-shifts in hamster activity rhythms was investigated. Stereotaxically implanted guide cannulae aimed at the region of the SCN were used to deliver repeated microinjections in individual animals. A phase-response curve (PRC) generated from microinjections of muscimol revealed that the magnitude and direction of permanent phase-shifts in the activity rhythm were associated with the time of administration. The PRC generated for muscimol was characterized by maximal phase-advances induced 6 h before activity onset and by maximal phase-delays which occurred 6 h after activity onset. The PRC for muscimol had a shape similar to a PRC previously generated for the short-acting benzodiazepine, triazolam. Single microinjections of different doses of muscimol given 6 h before activity onset induced phase-advances in a dose-dependent fashion. Histological analysis revealed that phase shifts induced by the administration of muscimol were associated with the proximity of the injection site to the SCN area. These data indicate that a GABAergic system may exist within the suprachiasmatic region as part of a central biological clock responsible for the regulation of the circadian rhythm of locomotor activity in the golden hamster.
Environmental light cycles are the dominant synchronizers of circadian rhythms in the field, and artificial light cycles and pulses are the major tools used in the laboratory to analyse properties of circadian systems. It is therefore surprising that few studies have analysed the physical parameters of light stimuli that affect circadian rhythms. There have previously been no spectral sensitivity measurements for phase shifting the circadian rhythms of mammals and only two preliminary reports on the wavelength dependence of this response exist. Using the magnitude of phase shift caused by a single 15-min pulse of monochromatic light given 6 h after activity onset, we have now characterized the spectral sensitivity of the photoreceptors responsible for phase shifting the locomotor rhythm of the hamster (Mesocricetus auratus). The sensitivity curve for this response has a maximum near 500 nm and is similar to the absorption spectrum for rhodopsin. Although the spectral sensitivity is consistent with a rhodopsin-based photopigment, two features of the photoreceptive system that mediates entrainment are unusual: the threshold of the response is high, especially for a predominantly rod retina like that of the hamster, and the reciprocal relationship between intensity and duration holds for extremely long durations (up to 45 min). These results suggest that the photoreceptive system mediating entrainment is markedly different from that involved in visual image formation.
Blind male hamsters were maintained in running-wheel cages in a LD 12:12 light-dark cycle. After regular running patterns were established hypothermia was induced by ether anesthesia, wetting of the fur with ethanol, and cooling with ice. The hamsters were kept hypothermic for 3-24 h at colonic temperatures from 10 to 20 degrees C. Following hypothermia the animals were rewarmed and replaced in their home cages. Examination of the locomotor activity records showed phase shifts (delays) in activity onset that were correlated with the temperature and duration of the hypothermia but not with the circadian time at which the hypothermia was administered. The data were interpreted to mean that the circadian pacemaker was running at a reduced rate during the hypothermic bout. Calculation of the Q10 for the rate of the clock during hypothermia produced a range from 1.08 to 1.34 depending on the method of calculation. When compared with earlier data gathered from rats under similar conditions, the hamsters circadian pacemaker appears to be better temperature compensated.
Identification of the neurotransmitter receptor subtypes within the suprachiasmatic nuclei (SCN) will further understanding of the mechanism of the biological clock and may provide targets to manipulate circadian rhythms pharmacologically. We have focused on the ionotropic GABA and glutamate receptors because these appear to account for the majority of synaptic communication in the SCN. Of the 15 genes known to code for GABA receptor subunits in mammals we have examined the expression of 12 in the SCN, neglecting only the alpha 6, gamma 3, and rho 2 subunits. Among glutamate receptors, we have focused on the five known genes coding for the NMDA receptor subunits, and two subunits which help comprise the kainate-selective receptors. Expression was characterized by Northern analysis with RNA purified from a large number of mouse SCN and compared to expression in the remaining hypothalamus, cortex and cerebellum. This approach provided a uniform source of RNA to generate many replicate blots, each of which was probed repeatedly. The most abundant GABA receptor subunit mRNAs in the SCN were alpha 2, alpha 5, beta 1, beta 3, gamma 1 and gamma 2. The rho 1 (rho 1) subunit, which produces GABAC pharmacology, was expressed primarily in the retina in three different species and was not detectable in the mouse SCN despite a common embryological origin with the retina. For several GABA subunits we detected additional mRNA species not previously described. High expression of both genes coding for glutamic acid decarboxylase (GAD65 and GAD67) was also found in the SCN. Among the NMDA receptor subunits, NR1 was most highly expressed in the SCN followed in order of abundance by NR2B, NR2A, NR2C and NR2D. In addition, both GluR5 and GluR6 show clear expression in the SCN, with GluR5 being the most SCN specific. This approach provides a simple measure of receptor subtype expression, complements in situ hybridization studies, and may suggest novel isoforms of known subunits.
The present study describes the development of a new technique to measure melatonin contents in the pineal gland of freely moving rats, by means of on-line microdialysis. The transcerebral cannula was modified, and a sensitive assay of melatonin, using HPLC with fluorimetric detection, was set up. With this system it is possible to monitor the melatonin levels on-line in the pineal gland during day- and nighttime. The nightly increase in melatonin release was recorded. Tetrodotoxin had an inhibitory effect on nighttime levels, whereas even high concentrations did not alter the daytime level. From this we conclude that neuronal activity is necessary to synthesize melatonin and that during daytime no net neuronal activity is present. Melatonin levels could be greatly enhanced by systemic administration of the beta-agonist isoprenaline (ISO). Also, local infusion of ISO or 8-bromoadenosine 3',5'-cyclic monophosphate, an analogue of the second messenger cyclic AMP, resulted in increased melatonin levels, demonstrating the presence of beta-adrenergic receptors, coupled to a cyclic AMP-based second messenger system, on the pineal gland. Injection of phenylephrine had no effect on daytime levels. Only when administered during ISO-induced stimulation of melatonin release did it enhance this stimulated release. This proved the regulatory role of alpha 1-receptors on pinealocytes. The method presented is of special interest for investigating the innervation of the pineal gland and the biochemical processes that regulate the biosynthesis of melatonin. Also, for studies on the diurnal rhythms of melatonin release and factors that influence these rhythms in freely moving animals, this model will be of great value.
The present study describes the effects of implantation of microdialysis probes on temperature and activity rhythms of the rat, measured with a telemetry system. For comparison two widely used types of microdialysis probes were investigated, a transcerebral probe, inserted into the pineal gland and a set of two I-shaped concentric probes, implanted bilateral into the striatum. Starting from 5 days before the operation until 8 days after surgery, activity and temperature recordings were carried out continuously with the help of previously implanted transmitters. In separate experiments the effects of two different types of anaesthesia (chloralhydrate and Hypnorm) were determined. The results show that there is a pronounced effect of surgery on amplitude and rhythmicity of the temperature and activity patterns which is still detectable 6-7 days after operation. Few differences were noticed between the transverse probe and the I-shaped probes. Anaesthesia alone induced much smaller changes, most of which had disappeared within 2 or 3 days after the treatment. The duration of action of chloralhydrate is somewhat longer compared to Hypnorm. The conclusion is that when microdialysis is used in behavioural experiments, the effects of the surgical procedure should be taken into account. If these effects are serious, the use of previously implanted guide cannulae might be necessary.
Endogenous circadian rhythms govern most aspects of physiology and behaviour in mammals, including body temperature, autonomic and endocrine function, and sleep-wake cycles. Such rhythms are generated by the suprachiasmatic nucleus of the hypothalamus (SCN), but are synchronised to the environmental light-dark cycle by photic cues perceived by the retina and conveyed to the SCN via the retinohypothalamic tract (RHT). This review considers many lines of evidence from diverse experimental approaches indicating that the RHT employs glutamate (or a related excitatory amino acid) as a neurotransmitter. Ultrastructural studies demonstrate the presence of glutamate in presynaptic terminals within the SCN. In situ hybridisation and immunocytochemical studies reveal the presence of several NMDA (NMDAR1, NMDAR2C), non-NMDA (GluR1, GluR2, GluR4) and metabotropic (mGluR1) glutamate receptor subunits in the SCN. Messenger RNA encoding a glutamate transporter protein is also present. In behavioural tests, glutamate antagonists can block the effects of light in phase-shifting circadian rhythms. Such treatments also block the induction of c-fos within SCN cells by light, whereas a glutamate agonist (NMDA) induces c-fos expression. In hypothalamic slice preparations in vitro, electrical stimulation of the optic nerves induces release of glutamate and aspartate, and glutamate antagonists block field potentials in the SCN evoked by stimulation of the optic nerve. Circadian rhythms of electrical activity which persist in vitro are phase shifted by application of glutamate in a manner which mimics the phase shifting effects of light in vivo. This wide range of experimental findings provides strong support for the hypothesis that glutamate is the principal neurotransmitter within the RHT, and thus conveys photic cues to the circadian timing system in the SCN.
This article reviews the evidence that melatonin, a hormone produced by the pineal gland during the dark hours, plays a major role in the regulation of the sleep-wake cycle. In recent years, our laboratory has been involved in a large-scale project aimed at investigating the role of endogenous melatonin in sleep-wake regulation and the effects of nonpharmacological levels of melatonin on sleep. Based on our finding on the precise coupling between the endogenous nocturnal increase in melatonin secretion and the opening of the nocturnal sleep gate, we propose that the role of melatonin in the induction of sleep does not involve the active induction of sleep, but is rather mediated by an inhibition of a wakefulness-producing mechanism in the central nervous system. Our studies also suggest that exogenously administered melatonin may be beneficial in certain types of insomnia that are related to disturbances in the normal secretion of the hormone.
GABA (gamma-amino-butyric acid) is the predominant neurotransmitter in the mammalian suprachiasmatic nucleus (SCN), with a central role in circadian time-keeping. We therefore undertook an ultrastructural analysis of the GABA-containing innervation in the SCN of mice and rats using immunoperoxidase and immunogold procedures. GABA-immunoreactive (GABA-ir) neurons were identified by use of anti-GABA and anti-GAD (glutamic acid decarboxylase) antisera. The relationship between GABA-ir elements and the most prominent peptidergic neurons in the SCN, containing vasopressin-neurophysin (VP-NP) or vasoactive intestinal polypeptide (VIP), was also studied. Within any given field in the SCN, approximately 40-70% of the neuronal profiles were GABA-ir. In GABA-ir somata, immunogold particles were prominent over mitochondria, sparse over cytoplasm, and scattered as aggregates over nucleoplasm. In axonal boutons, gold particles were concentrated over electron-lucent synaptic vesicles (diameter 40-60 nm) and mitochondria, and in some instances over dense-cored vesicles (DCVs, diameter 90-110 nm). GABA-ir boutons formed either symmetric or asymmetric synaptic contacts with somata, dendritic shafts and spines, and occasionally with other terminals (axo-axonic). Homologous or autaptic connections (GABA on GABA, or GAD on GAD) were common. Although GABA appeared to predominate in most neuronal profiles, colocalisation of GABA within neurons that were predominantly neuropeptide-containing was also evident. About 66% of the VIP-containing boutons and 32% of the vasopressinergic boutons contained GABA. The dense and complex GABAergic network that pervades the SCN is therefore comprised of multiple neuronal phenotypes containing GABA, including a wide variety of axonal boutons that impinge on heterologous and homologous postsynaptic sites.
Sleep disturbance is common postoperatively. We examined whether melatonin concentrations were related to this disturbance in seven postoperative patients. Nocturnal concentrations of melatonin were significantly (p=0.005) lower on the first than on the second or third nights after surgery. This finding raises the possibility that melatonin suppression and associated sleep disturbance might be prevented by melatonin replacement.
This study was designed to determine whether respiratory stimuli can influence the mammalian circadian timing system. Three-hour pulses of hypoxia (inspired O(2) concentration = 8%) or hypercapnia (inspired CO(2) concentration = 11%) were presented for 7 days at mid-subjective day (circadian time 6-9) under constant darkness. Hypoxic and hypercapnic pulses caused cumulative phase delays of 46. 4 +/- 6.9 and 25.9 +/- 12.3 min, respectively. Distance run per day was significantly reduced on hypoxic and hypercapnic pulse days, compared with nonpulsed days. Phase shifts were correlated with the reduction in daily running activity (multiple r(2) = 0.521, P = 0.036), metabolic depression (multiple r(2) = 0.772, P < 0.001), and reduction in body temperature (multiple r(2) = 0.539, P = 0.027), but not lung ventilation (multiple r(2) = 0.306, P = 0.414) during pulses. We conclude that hypoxia and hypercapnia can influence the phase and quantity of activity in free-running hamsters.
Because the rapid induction of Period (Per) genes is associated with the photic entrainment of the biological clock, we examined whether N-methyl-D-aspartate (NMDA) receptors were involved in the photic induction of Per genes in the hamster suprachiasmatic nucleus (SCN). In situ hybridization observation revealed that light during the early subjective night [circadian time (CT) 13.5] or the late subjective night (CT20) caused an induction of Per1 and Per2 but not Per3 mRNA in the SCN. Photic induction of Per mRNA at CT13.5 was observed especially in the ventrolateral SCN, whereas that at CT20 was more widespread from the ventrolateral to the dorsal SCN. A noncompetitive NMDA receptor antagonist, +MK801, dose-dependently (0. 1-5.0 mg/kg) suppressed only the ventrolateral part of Per1 and Per2 mRNA induction by light at CT13.5 or CT20 in the SCN. The suppressive effects of +MK801 on Per mRNA strongly correlated with the attenuating action of this compound on phase shifts by light at both CT13.5 and CT20. A competitive NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), also exhibited inhibitory actions on light (CT20)-induced Per1 and Per2 mRNA expression in the ventrolateral SCN. Furthermore, local injection of NMDA into the SCN resulted in the induction of Per1 and Per2 mRNA in the SCN. Among NMDA receptors, NR2B and NR2C mRNA were expressed in the ventrolateral and dorsal SCN, respectively. These results suggest that the activation of NMDA receptor is a critical step for photic induction of Per1 and Per2 transcripts in the SCN, which are linked to a photic behavioral entrainment.
The purpose of this study was to clarify the changes in psycho-physiological functions after anaesthesia with propofol (PF). The subjects were seven healthy male volunteers and the duration of the anaesthesia was 1 h (14:00-15:00 h). The plasma concentration of PF immediately decreased after the anaesthesia. The subjective sleepiness and VAS (visual liner analogue scale) scores (i.e. effort to do something) increased significantly at 20 min after the anaesthesia. However, these changes were improved at 80 min after the anaesthesia. The sleep latency at the nocturnal sleep 8 h after the anaesthesia was prolonged significantly, but the other parameters including the distributions of stage 3 + 4 and the rapid eye movement 'REM' stage were not changed.
A variety of photic and nonphotic stimuli can phase-shift the mammalian circadian pacemaker. It has been suggested that the phase-response curves (PRCs) characterizing these diverse stimuli may comprise two major PRC families, one typified by the photic PRC describing the response to brief light pulses, and the other typified by the nonphotic PRC describing the response to stimuli evoking behavioral arousal and/or locomotor activity. Additionally, the mammalian circadian pacemaker can be phase-shifted by dark pulses presented on a constant-light (LL) background. While dark pulse-induced phase shifting was interpreted originally as a mirror-image photic effect, other observations suggest that the dark pulse PRC may instead belong to the family of nonphotic, activity-dependent PRCs. In a recent study, we reexamined the phase-shifting effects of dark pulses in the Syrian hamster, and concluded that the dark pulse PRC reflects both nonphotic and photic mirror-image mechanisms. In the current report, we reanalyze previously published hamster PRC data using polynomial curve-fitting procedures. The results of these analyses reveal that (a) the photic and nonphotic PRCs have identical shape but opposite phasing, and (b) the dark pulse PRC can be modeled by simple summation of nonphotic and photic mirror-image PRCs. This model predicts accurately the shape of the dark pulse PRC, particularly the extension of the phase-advance region into the subjective night.
Many physiological and behavioral phenomena are controlled by an internal, self-sustaining oscillator with a periodicity of approximately 24 hr. In mammals, the principal oscillator resides in the suprachiasmatic nucleus (SCN). A light pulse during the subjective night causes a phase shift of the circadian rhythm via direct glutamatergic retinal afferents to the SCN [1]. Along with the accepted theoretical models of the clock, it is suggested that behavioral resetting of mammals is completed within 2 hr [2]; however, the molecular mechanism has not been elucidated. Here, we show the real-time image of the transcription of the circadian-clock gene mPer1 in the cultured SCN by using the transgenic mice that carry a luciferase reporter gene under the control of the mPer1 promoter [3]. The real-time image demonstrates that the mPer1 promoter activity oscillates robustly in a circadian manner and that this promoter activity is reset rapidly (within 2-3 hr) when a phase shift occurs.
Melatonin, a hormone produced in the pineal gland, is involved in circadian rhythms and the sleep-wake cycle. Postoperative delirium is encountered frequently in elderly patients after major surgery; whether changes in the pattern of melatonin secretion are associated is unclear.
Plasma samples were obtained every 2 hours from 19 patients without delirium and 10 with delirium after major abdominal surgery. Postoperative delirium was determined using the Confusion Assessment Method in the Practice Guideline of the American Psychiatric Association.
All patients without delirium showed nearly identical preoperative and postoperative melatonin secretion for 24 hours, although peak values were significantly lower in patients more than 80 years old (7.2 +/- 2.3 pg/mL) than in patients younger than 80 years (24.4 +/- 4.1 pg/mL, P = 0.022). Patients with delirium showed two different abnormal postoperative patterns: in 5 patients without complications, melatonin levels were lower than preoperative values (11.0 +/- 5.8 versus 6.5 +/- 4.2 pg/mL, P = 0.079); and in 5 patients with complications, melatonin levels were markedly increased (21.1 +/- 4.5 versus 58.8 +/- 12.4 pg/mL, P = 0.043).
Abnormal melatonin secretion may be involved in postoperative sleep disturbances, which triggered delirium in elderly patients.
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Postoperative delirium is a common problem associated with increased morbidity and mortality, prolonged hospital stay, additional tests and consultations and therefore, increased cost (1,2). The reported incidence of delirium or confusion after surgery ranges from 8% to 78% (2,3-5), depending on methods and population studied. The elderly seem to be at significantly increased risk for this complication. Sleep-wake cycle disruption has been associated with delirium and behavioral changes (5) and sleep deprivation can even result in psychosis (6). Environmental changes (i.e., hospital stay), medications, and general anesthesia can affect the sleep-wake cycle (3,4). Plasma melatonin levels, which play an important role in the regulation of the sleep-wake cycle, are decreased after surgery (18) and in hospitalized patients (7,11). We report the successful use of melatonin in treating severe postoperative delirium unresponsive to antipsychotics or benzodiazepines in one patient. In another patient with a history of postoperative delirium, melatonin was used to prevent another episode of delirium after repeat lower extremity surgery.
Implications:
Postoperative delirium or confusion after surgery is a common problem associated with complications and death. Delirium has been linked to sleep-wake cycle disruption. Melatonin levels, which play an important role in regulating the sleep-wake cycle, are decreased after surgery. Two cases are presented where melatonin was used to treat and prevent postoperative delirium.
Operations are typically associated with sleep and other circadian rhythm disturbances. The present study was set up to evaluate the influence of spinal and general anaesthesia associated with knee surgery on the circadian rhythm of melatonin, which has sleep inducing properties. Previously this context has been studied only in some invasive operations and it might be that general anaesthesia induces more disturbances on circadian rhythm of melatonin than operations done with patients awake.
The circadian secretion pattern of melatonin was monitored during the pre- and postoperative evenings, nights and mornings to clarify possible anaesthesia/surgery-induced changes in the nocturnal secretion of melatonin and in the phase of the melatonin rhythm. The study included 20 patients scheduled for minor orthopaedic operations. The patients were randomised to receive either spinal or general anaesthesia. Melatonin was measured from evening and morning saliva samples radioimmunologically. The nocturnal urine before and after surgery was radioimmunologically examined for 6-hydroxymelatonin sulphate.
Melatonin secretion evaluated from the saliva samples was significantly diminished during the first postoperative evening as compared with that during the preoperative evening (P<0.001). There was also a significant decline of 26% (P<0.05) in postoperative 6-hydroxymelatonin sulphate excretion. There was no significant difference in melatonin secretion between the spinal and general anaesthesia groups.
Our findings suggest that anaesthesia in conjunction with surgery acutely disturbed the normal circadian rhythm of melatonin by delaying the onset of nocturnal melatonin secretion.
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Melatonin, a neurohormone, plays an important role in adjusting the "biological clock" in humans. We sought to describe perioperative patterns of melatonin secretion in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass (CPB). After IRB approval and written informed consent, 12 male patients scheduled for elective coronary artery bypass grafting under hypothermic CPB were enrolled in the study. During anesthesia, patients' eyes were carefully covered to prevent light effects. Blood samples were taken at specific time points during surgery, every 3 h in the immediate postoperative period, and for 24 h from 6:00 PM of Postoperative Day 2 until 6:00 PM of Postoperative Day 3. Plasma melatonin and cortisol concentrations were measured by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. During surgery, plasma melatonin concentrations were below the minimum sensitivity concentration, yet small concentrations, without circadian variation, were detected during the immediate postoperative period. During Postoperative Days 2 and 3, circadian secretion patterns of melatonin were present in 10 patients and showed an inverse correlation with light intensity (r = 0.480; P < 0.01). Plasma cortisol concentrations in the immediate postoperative period were significantly larger than those before the induction of anesthesia (P < 0.01). Only three patients regained circadian secretion of cortisol. We concluded that melatonin and cortisol secretion was disrupted during cardiac surgery with CPB and in the immediate postoperative period. However, circadian rhythms of melatonin were present in most patients from Postoperative Day 2. Only 30% of the patients regained circadian rhythm of cortisol secretion.
Implications:
Melatonin is a hormone that plays an important role in adjusting the biological clock in humans and that regulates secretion of various other hormones. We studied melatonin secretion in patients undergoing cardiac surgery with cardiopulmonary bypass. Melatonin secretion was disturbed during and immediately after surgery but had recovered a circadian rhythm 24 h later, raising the question of whether melatonin should be supplemented before cardiac surgery.
Circadian rhythms impact many physiological functions that may affect drug pharmacological response. Ketamine is a dissociative agent commonly used for surgical anesthesia in rats. The aim of the present study was to analyze the central nervous system (CNS) depression and lethality of ketamine injected intraperitoneally at different times during the 24 h. The study was conducted in October 2001, spring in the Southern hemisphere. Female prepuberal Sprague-Dawley rats synchronized to a 12h light: 12h dark cycle (light, 07:00h-19:00h) were studied. Ketamine (40 mg/kg) was administered to one of six different clock-time treatment groups (n = 6-7 rats each). Duration of latency period, ataxia, loss of righting reflex (LRR), post-LRR ataxia, and total pharmacological response were determined by visual assessment. To investigate acute toxicity, ketamine lethal dose 50 (148.0 mg/kg) was also administered as a single injection to six different treatment-time groups of rats. Significant temporal differences and circadian rhythms were detected in drug-induced post-LRR ataxia and total pharmacological response duration. The longest pharmacological response occurred in rats injected during the light (rest) phase and the shortest response in the dark (activity) phase. No circadian rhythm was detected in acute toxicity. The study findings indicate that the duration of CNS depression of ketamine in rats exhibits circadian rhythmic variation.
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The purpose of this study was to investigate the effect of general anesthesia and surgery on melatonin production, and to assess the relationship between melatonin secretion and cortisol levels. Twenty (9 males and 11 females) consecutive otherwise healthy patients aged 27 to 52 years were included in this study. The patients underwent laparoscopic cholecystectomy or laparoscopic hernioplasty. All patients had general anesthesia with the same anesthetic drugs. Serum cortisol levels were measured at several time periods. Urine collections for melatonin were performed from 18:00 to 7:00 the day prior to surgery, on the operation day, and on the first postoperative day. Baseline melatonin metabolites were measured the night prior to surgery, and the level was found to be 1979 +/- 1.76 ng. The value decreased to 1802 +/- 1.82 ng (NS) on the night of surgery, and it became a significantly higher, reaching 2981 +/- 1.55 ng the night after surgery (p = .003). The baseline daytime cortisol level was significantly lower than the baseline night cortisol level (6.87 +/- 1.51 microg/dl, 14.89 +/- 1.66 micrograms/dl, respectively, p < 0.0001). Surgery induced a significant increase in both day and night cortisol levels. Daytime cortisol levels increased from 6.89 +/- 1.51 microg/dl to 16.90 +/- 1.27microg/dl (p < 0.0001), whereas right levels increased from 14.89 +/- 1.66 microg/dl to 29.20 +/- 1.24 microg/ dl (p <0.0001). The morning after surgery, cortisol levels decreased to 10.16 +/- 1.40 microg/dl, lower than the value obtained on the day of surgery (p < 0.0001). As was true of melatonin, cortisol levels did not reach the pre operative level (p < 0.005). The finding of the current study is that melatonin and cortisol levels show an inverse correlation after surgery.
General anesthetics are essential to modern medicine, and yet a detailed understanding of their mechanisms of action is lacking. General anesthetics were once believed to be "drugs without receptors" but this view has been largely abandoned. During the past decade significant progress in our understanding of the mechanisms of general anesthetic action at the molecular, cellular and neural systems levels has been made. Different molecular targets in various regions of the nervous system are involved in the multiple components of anesthetic action, and these targets can vary between specific anesthetics. Neurotransmitter-gated ion channels, particularly receptors for GABA and glutamate, are modulated by most anesthetics, at both synaptic and extrasynaptic sites, and additional ion channels and receptors are also being recognized as important targets for general anesthetics. In this article, these developments, which have important implications for the development of more-selective anesthetics, are reviewed in the context of recent advances in ion channel structure and function.
Circadian rhythms of animals are reset by exposure to light as well as dark; however, although the parameters of photic entrainment are well characterized, the phase-shifting actions of dark pulses are poorly understood. Here, we determined the tonic and phasic effects of short (0.25 h), moderate (3 h), and long (6-9 h) duration dark pulses on the wheel-running rhythms of hamsters in constant light. Moderate- and long-duration dark pulses phase dependently reset behavioral rhythms, and the magnitude of these phase shifts increased as a function of the duration of the dark pulse. In contrast, the 0.25-h dark pulses failed to evoke consistent effects at any circadian phase tested. Interestingly, moderate- and long-dark pulses elevated locomotor activity (wheel-running) on the day of treatment. This induced wheel-running was highly correlated with phase shift magnitude when the pulse was given during the subjective day. This, together with the finding that animals pulsed during the subjective day are behaviorally active throughout the pulse, suggests that both locomotor activity and behavioral activation play an important role in the phase-resetting actions of dark pulses. We also found that the robustness of the wheel-running rhythm was weakened, and the amount of wheel-running decreased on the days after exposure to dark pulses; these effects were dependent on pulse duration. In summary, similarly to light, the resetting actions of dark pulses are dependent on both circadian phase and stimulus duration. However, dark pulses appear more complex stimuli, with both photic and nonphotic resetting properties.
Chronobiology, which focuses on the biological rhythms that occur in the organization of living organisms, has been studied for several decades. Chronopharmacology, however, has received little attention until recently. We examined the hypnotic duration of intraperitoneally administered ketamine, pentobarbital, propofol, midazolam, and ethanol, to test whether they have obvious dosing-time dependent effects. Male C57BL/6 mice, which showed clear circadian rhythms of water-intake under a strict 12-h lighting cycle, were used. All tested drugs had significantly longer episodes of loss of righting reflex when administered at 22:00 (early active phase) than at 10:00 (early inactive phase). This dosing-time dependent hypnotic duration did not depend on the contents and activities of cytochrome P450 enzymes in the liver. These findings might be of clinical benefit in deciding the administration time and doses of anesthetics.
GABA is the main neurotransmitter of the hypothalamic suprachiasmatic nucleus (SCN) and plays a key role in the function of this master circadian pacemaker. Despite the evidence that disturbances of biological rhythms are common during aging, little is known about the GABAergic network in the SCN of the aging brain. We here provide a brief overview of the GABAergic structures and the role of GABA in the SCN. We also review some age-related changes of the GABAergic system occurring in the brain outside the SCN. Finally, we present preliminary data on the GABAergic system within the SCN comparing young and aging mice. In particular, our study on age-related changes in the SCN focused on the daily expression of the alpha3 subunit of the GABA(A) receptor and on the density of GABAergic axon terminals. Interestingly, our preliminary findings point to alterations of the GABAergic network in the biological clock during senescence.
Melatonin signals time of day and time of year in mammals by virtue of its pattern of secretion, which defines 'biological night.' It is supremely important for research on the physiology and pathology of the human biological clock. Light suppresses melatonin secretion at night using pathways involved in circadian photoreception. The melatonin rhythm (as evidenced by its profile in plasma, saliva, or its major metabolite, 6-sulphatoxymelatonin [aMT6s] in urine) is the best peripheral index of the timing of the human circadian pacemaker. Light suppression and phase-shifting of the melatonin 24 h profile enables the characterization of human circadian photoreception, and circulating concentrations of the hormone are used to investigate the general properties of the human circadian system in health and disease. Suppression of melatonin by light at night has been invoked as a possible influence on major disease risk as there is increasing evidence for its oncostatic effects. Exogenous melatonin acts as a 'chronobiotic.' Acutely, it increases sleep propensity during 'biological day.' These properties have led to successful treatments for serveal circadian rhythm disorders. Endogenous melatonin acts to reinforce the functioning of the human circadian system, probably in many ways. The future holds much promise for melatonin as a research tool and as a therapy for various conditions.
The mammalian circadian clock can be entrained by photic and nonphotic environmental time cues. gamma-aminobutyric acid (GABA) is a nonphotic stimulus that induces phase advances in the circadian clock during the middle of the subjective day. Several nonphotic stimuli suppress Period 1- and Period 2 mRNA expression in the suprachiasmatic nucleus (SCN); however, the effect of GABA on Period mRNA is unknown. In the present study we demonstrate that microinjection of the GABA(A) receptor agonist muscimol into the SCN region suppresses the expression of Period 1 mRNA in the hamster. A significant suppression of Period 2 mRNA following microinjection of muscimol was not observed in free-running conditions. However, Period 2 mRNA was significantly reduced following muscimol treatment when animals were maintained under a light cycle and transferred to constant darkness 42 h prior to treatment. An additional study investigated the maximum behavioural phase advance inducible by GABA(A) receptor activation.Together, these data indicate that, like other nonphotic stimuli, GABA suppresses Period 1- and Period 2 mRNA in the SCN.