Intraperitoneal injection of ginkgolide B, a major active compound of Ginkgo biloba, dose-dependently increases the amount of wake and decreases non-rapid eye movement sleep in C57BL/6 mice.

The terpene lactones of Ginkgo biloba extract, namely ginkgolides (A, B, and C) and bilobalide, possess antioxidant, anti-inflammatory, and neuroprotective effects. They are widely prescribed for the treatment of cerebral dysfunctions and neurological impairments. In addition, they demonstrate antagonistic action at the gamma-aminobutyric acid type A and glycine receptors, which are members of the ligand-gated ion channel superfamily. In the present study, the effects of ginkgolides (A, B, and C) and bilobalide on sleep in C57BL/6 mice were investigated. Ginkgolide B was found to dose-dependently increase the amount of wake and decrease that of non-rapid eye movement sleep without changes in the electroencephalography power density of each sleep/wake stage, core body temperature and locomotor activity for the first 6 h after intraperitoneal injection. Of note, the amount of wake after injection of 5 mg/kg of ginkgolide B showed a significant increase (14.9 %) compared with that of vehicle (P = 0.005). In contrast, there were no significant differences in the amount of sleep, core body temperature, and locomotor activity in the mice injected with ginkgolide A and C. Bilobalide briefly induced a decrease in locomotor activity but did not exert significant effects on the amounts of sleep and wake. The modes of action of the wake-enhancing effects of ginkgolide B are unknown. However, it may act through the antagonism of gamma-aminobutyric acid type A and glycine receptors because it is established that these inhibitory amino acids mediate sleep and sleep-related physiology. It is of interest to further evaluate the stimulant and awaking actions of ginkgolide B on the central nervous system in clinical and basic research studies.

Disruption of sleep, sleep-wake activity rhythm, and nocturnal melatonin production in breast cancer patients undergoing adjuvant chemotherapy: prospective cohort study.

OBJECTIVE: This prospective cohort study captured the patterns of sleep, sleep-wake activity rhythm, and first-morning urinary melatonin in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Breast cancer patients undergoing adjuvant chemotherapy wore wrist actigraph for 168 h and collected first-morning void urine samples before treatment, during the first, and at the last cycle of chemotherapy. We converted actigraphy data into sleep duration, sleep efficiency, nighttime total wake time, percent rhythm, F-statistic, amplitude, mesor, and acrophase. We then assessed urinary 6-sulfatoxymelatonin (aMT6s) levels. RESULTS: This cohort contained 180 participants. Compared with the baseline, sleep efficiency during the first and last cycle decreased by 10.16% [95% confidence interval (95% CI): 5.85%, 14.47%] and 5.01% (95% CI: 0.50%, 9.53%), respectively. Similarly, percent rhythm decreased by 27.20% (95% CI: 19.95%, 34.45%) during the first cycle and 21.20% (95% CI: 13.52, 28.89) during the last cycle. Taking the baseline as the reference, aMT6s levels during the first and last cycle decreased by 11.27% (95% CI: 0.37%, 22.16%) and 14.74% (95% CI: 2.34, 27.11), respectively. CONCLUSION: The first administration of adjuvant chemotherapy is associated with sleep disturbance and sleep-wake activity rhythm disruption among breast cancer patients, while the disturbance and disruption during the last cycle are less severe; nevertheless, repeated administration of chemotherapy results in progressive impairment of nocturnal melatonin production.

Chronic Consumption of Fructose Induces Behavioral Alterations by Increasing Orexin and Dopamine Levels in the Rat Brain.

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep⁻wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep⁻wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep⁻wake cycle.

Valerian/Cascade mixture promotes sleep by increasing non-rapid eye movement (NREM) in rodent model.

The aim of this study was to investigate the beneficial effect of Valerian/Cascade mixture on sleeping in mammal models. In pentobarbital-induced sleep model, Valerian, Cascade, and Valerian/Cascade mixture significantly reduced the latency time for sleeping, and total sleeping time effectively increased in these sample groups compared with the control. Valerian/Cascade mixture increased sleep duration by 37%. The mixture significantly increased the non-rapid eye movement (NREM) sleep time by 53% compared with the control, while REM sleeping time was decreased by 33% with Valerian/Cascade mixture, in Electroencephalography (EEG) analysis, resulting in the increase of total sleep time and the decrease of awakening. This sleep-promoting effect was obvious in caffeine-induced awakening model; Valerian, Cascade, and the mixture significantly enhanced NREM and total sleep time, which were reduced by caffeine. Caffeine-induced increase of awakening was effectively deceased to the normal level by these three samples. In particular, delta wave responsible for deep sleep in NREM was greatly increased by the mixture in both normal and caffeine-induced awake models. This sleep-promoting effect of Valerian/Cascade mixture was shown to be due to the upregulation of gamma-aminobutyric acid A receptor (GABAAR). Valerian/Cascade mixture showed 91% binding capacity to GABAA-BZD receptor. Two compounds, Valerenic acid and Xanthohumol, were shown to significantly contribute to the binding activity of Valerian/Cascade mixture on the GABA receptor.

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study.

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status.

Effects of Ketamine on Basal Gamma Band Oscillation and Sensory Gating in Prefrontal Cortex of Awake Rats.

Gamma band oscillation (GBO) and sensory gating (SG) are associated with many cognitive functions. Ketamine induces deficits of GBO and SG in the prefrontal cortex (PFC). However, the time-courses of the effects of different doses of ketamine on GBO power and SG are poorly understood. Studies have indicated that GBO power and SG have a common substrate for their generation and abnormalities. In this study, we found that (1) ketamine administration increased GBO power in the PFC in rats differently in the low- and high-dose groups; (2) auditory SG was significantly lower than baseline in the 30 mg/kg and 60 mg/kg groups, but not in the 15 mg/kg and 120 mg/kg groups; and (3) changes in SG and basal GBO power were significantly correlated in awake rats. These results indicate a relationship between mechanisms underlying auditory SG and GBO power.

Sleep spindles and slow waves in schizophrenia and related disorders: main findings, challenges and future perspectives.

Sleep abnormalities have recently gained renewed attention in patients diagnosed with schizophrenia. Disrupted thalamocortical brain oscillations hold promise as putative biomarkers or endophenotypes of the disorder. Despite an increase in studies related to sleep spindle and slow-wave activity, findings remain in part contradictory. Although sleep spindle deficits have been confirmed in several groups of patients with chronic, medicated schizophrenia, data on the early stages of the disorder and in unmedicated subjects are still insufficient. Findings on slow-wave abnormalities are largely inconclusive, possibly due to the different criteria employed to define the phenomenon and to the influence of atypical antipsychotics. In this review, we aim to address the methodological and practical issues that may have limited the consistency of findings across research groups and different patient populations. Given the neurobiological relevance of these oscillations, which reflect the integrity of thalamocortical and cortico-cortical function, research in this domain should be encouraged. To promote widespread consensus over the scientific and clinical implications of these sleep-related phenomena, we advocate uniform and sound methodological approaches. These should encompass electroencephalographic recording and analysis techniques but also selection criteria and characterization of clinical populations.

Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials.

Caffeine is the most widely consumed psychoactive substance in the world. It is readily available in coffee and other foods and beverages, and is used to mitigate sleepiness, enhance performance, and treat apnea in premature infants. This review systematically explores evidence from epidemiological studies and randomized controlled trials as to whether coffee and caffeine have deleterious effects on sleep. Caffeine typically prolonged sleep latency, reduced total sleep time and sleep efficiency, and worsened perceived sleep quality. Slow-wave sleep and electroencephalographic (EEG) slow-wave activity were typically reduced, whereas stage-1, wakefulness, and arousals were increased. Dose- and timing-response relationships were established. The sleep of older adults may be more sensitive to caffeine compared to younger adults. Pronounced individual differences are also present in young people, and genetic studies isolated functional polymorphisms of genes implicated in adenosine neurotransmission and metabolism contributing to individual sensitivity to sleep disruption by caffeine. Most studies were conducted in male adults of Western countries, which limits the generalizability of the findings. Given the importance of good sleep for general health and functioning, longitudinal investigations aimed at establishing possible causal relationships among coffee- and caffeine-induced changes in sleep quality and health development are warranted.

Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice.

Prostaglandin (PG)D2 is an endogenous sleep substance, and a series of animal studies reported that PGD2 or PGD2 receptor (DP1) agonists promote sleep, while DP1 antagonists promote wakefulness. This suggests the possibility of use of PG DP1 antagonists as wake-promoting compounds. We therefore evaluated the wake-promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 × 10(-4) M roughly corresponded to those of modafinil at 100 mg/kg (p.o.). The wake promoting effects of ONO-4127Na was observed both during light and dark periods, and much larger effects were seen during the light period when mice slept most of the time. ONO-4127Na, when perfused in the hypothalamic area, had no effects on sleep. We further demonstrated that wake-promoting effects of ONO-4127Na were abolished in DP1 KO mice, confirming that the wake-promoting effect of ONO-4127Na is mediated by blockade of the PG DP1 receptors located in the BF area. ONO-4127Na reduced DREM, an EEG/EMG assessment of behavioral cataplexy in narcoleptic mice, suggesting that ONO-4127Na is likely to have anticataplectic effects. DP1 antagonists may be a new class of compounds for the treatment of narcolepsy-cataplexy, and further studies are warranted.

Antinociceptive Activity of an Ethanol Extract of Justicia spicigera.

Preclinical Research The aim of the present study was to evaluate the antinociceptive and sedative activity of an ethanol extract of Justicia spicigera an evergreen used in Mexican traditional medicine for the relief of pain, wounds, fever and inflammation. At 200 mg/kg po, the maximum dose examined, the ethanol extract of J. spicigera (JSE) had analgesic activity in mice in the acetic acid writhing test, the second phase of the formalin test and the tail flick test that was similar in efficacy to the NSAID, naproxen (150 mg/kg po). JSE was inactive in the hot plate test and and the ketamine-induced sleeping time test; it had no sedative effects. These results show that the ethanol extract from the leaves of J. spicigera has antinociceptive effects in mice without inducing sedation. Drug Dev Res 77 : 180-186, 2016. © 2016 Wiley Periodicals, Inc.

Effects of valerian on subjective sedation, field sobriety testing and driving simulator performance.

INTRODUCTION: The availability of herbal medicines over-the-counter (OTC) has increased the use of natural products for self-treatment. Valerian has been used to effectively treat generalized anxiety disorder and insomnia. Studies suggest that valerenic acid may increase gamma-aminobutyric acid (GABA) modulation in the brain. Benzodiazepines have a similar mechanism of action and have been linked to an increased risk of hospitalizations due to traffic accidents. Despite the risk of somnolence, the safety of driving while under the influence of valerian remains unknown. PURPOSE: The purpose of the study was to determine the effects of a one-time valerian 1600mg dose on subjective sedation effects, standardized field sobriety testing (SFST) and driving simulator performance parameters. METHODS: The study design was a randomized, placebo-controlled, double-blind, cross-over trial. For each session, participants received either a dose of valerian or placebo. The outcome measures included a simple visual reaction test (SVRT), subjective sleepiness scales, SFST performance scores, and driving simulator performance parameters. RESULTS: There were no significant differences in the SVRT or sleepiness scales between placebo and valerian exposures, but the study may have been underpowered. SFST total and individual test failure rates were not significantly different between the two exposures. The driving simulator performance parameters were equivalent between the two exposure conditions. CONCLUSIONS: A one-time valerian 1600mg dose, often used to treat insomnia, does not appear to impair driving simulator performance after acute ingestion.

Ketamine and propofol have opposite effects on postanesthetic sleep architecture in rats: relevance to the endogenous sleep-wakefulness substances orexin and melanin-concentrating hormone.

BACKGROUND: Anesthesia and surgery disturb sleep. Disturbed sleep adversely affects postoperative complications involving the cardiovascular system, diabetes, and infection. General anesthetics share neuronal mechanisms involving endogenous sleep-wakefulness-related substances, such as orexin (OX) and melanin-concentrating hormone (MCH). We evaluated changes in sleep architecture and the concentration of OX and MCH during the peri-anesthetic period. METHODS: To examine sleep architecture, male Sprague-Dawley rats weighing 350-450 g received ketamine 100 mg/kg (n = 9) or propofol 80 mg/kg (n = 6) by intraperitoneal injection. Electroencephalography was recorded from 2 days pre- to 5 days postanesthesia. To quantify levels of OX and MCH, 144 similar rats received the same doses of ketamine (n = 80) or propofol (n = 64). Brain concentrations of these substances were determined at 0, 20, 60, and 120 min after anesthetic administration. RESULTS: Ketamine decreased OX content in the hypothalamus during the anesthesia period. OX content was restored to pre-anesthesia levels in the hypothalamus and pons. Both anesthetics increased brain MCH content in the postanesthetic period, with the degree of increase being greater with propofol. Ketamine enhanced wakefulness and inhibited non-rapid eye movement sleep (NREMS) immediately after anesthesia. Conversely, propofol inhibited wakefulness and enhanced NREMS in that period. Ketamine inhibited wakefulness and enhanced NREMS during the dark phase on the first postanesthesia day. CONCLUSIONS: Anesthetics affect various endogenous sleep-wakefulness-related substances; however, the modulation pattern may depend on the type of anesthetic. The process of postanesthetic sleep disturbance was agent specific. Our results provide fundamental evidence to treat anesthetic-related sleep disturbance.

Beneficial effect of Danggui-Shaoyao-San, a traditional Chinese medicine, on drowsiness induced by chronic restraint stress.

Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, has a long history of treating dysmenorrhea in China. Recent studies showed that DSS had its therapeutic efficacy on depression. In the present study, the effects of aqueous extract of DSS were examined to investigate the pharmacological basis for its therapeutic efficacy on chronic restraint stress (CRS)-induced sleep disorder. Mice were treated with DSS by gavage administration at doses of 0.625g/kg, 1.25g/kg and 2.5g/kg for 10 days. Sleep time and sleep latency were measured 24h after the CRS procedures using the sodium pentobarbital-induced sleep test. Open field test was used to evaluate the mice locomotion and anxiety/depression levels. Body weight and food intake were determined as well. The results showed that DSS dose-dependently prolonged latency and decreased sleep time of CRS mice, reversed CRS-induced decrease of mean velocity, the percentage of center distance and time in central area, as well as decreased body weight and food intake. In conclusion, our results suggest that DSS has exerted measurable therapeutic effects in hypersomnia induced by chronic restraint stress.

Assessment of buccal aerosolized midazolam for pediatric conscious sedation.

AIM: To assess the acceptance and efficacy of aerosolized midazolam through buccal mucosa for conscious sedation. METHODS: Thirty-five children aged 2-6 years with Grade I and II Frankl behavior rating scale were selected for various dental procedures under local anesthesia. Initially behavior-shaping procedures were used and Houpt behavior scoring was recorded. Thereafter, midazolam was administered using a spray through buccal mucosa and scores for acceptance of drug and behavior after sedation were recorded. The data were compiled and a Wilcoxon signed ranks test was used to assess the difference in behavior before and after the sedation. RESULTS: Eighty-three percent of the patients accepted the drug without any complaint. A statistically significant improvement was seen in the Houpt scores before and after drug administration (P < 0.001). CONCLUSIONS: Buccal aerosolized midazolam can be used successfully for pediatric conscious sedation.

N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside induces sedative and hypnotic effects via GAD enzyme activation in mice.

BACKGROUND AND PURPOSE: N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an analog of N(6)-(4-hydroxybenzyl) adenine riboside (NHBA), which was originally isolated from Gastrodia elata Blume. Our laboratory has previously demonstrated that B2 can produce strong sedative and hypnotic effects, but the mechanism remains to be determined. There is evidence that gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the brain, plays a major role in sleep regulation, and participates in the sedative and hypnotic effects of B2. Therefore, we studied the interactions between B2 and several GABAergic neurochemical parameters based on the sedative and hypnotic effects of B2. EXPERIMENTAL APPROACH: The GABA and glutamic acid (Glu) in the mouse brain were derivatized with o-phthalaldehyde (OPA) and measured by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The GAD and GABA-T enzyme activities were determined by measuring GABA and NADH production, respectively. The sleep structure analyses were performed by EEG studies in mice. KEY RESULTS: B2 increased the GABA levels and GAD enzyme activity in the mouse hypothalamus and cortex. The EEG results confirmed that B2 significantly shortened the sleep latency and increased the amount of NREM sleep. The GAD enzyme inhibitor semicarbazide (SCZ) blocked the sedative and hypnotic effects of B2. CONCLUSIONS AND IMPLICATIONS: These findings suggest that the GAD enzyme plays a significant role in the sedative and hypnotic effects of B2. Therefore B2 may be a promising candidate for further clinical studies and the appropriate use of GAD agonist may be a promising approach for sleep disorders.

Thalamic δ-subunit containing GABAA receptors promote electrocortical signatures of deep non-REM sleep but do not mediate the effects of etomidate at the thalamus in vivo.

Extrasynaptic δ-subunits containing GABAA receptors (δGABAARs) are sensitive targets for several commonly used hypnotic agents and mediate tonic neuronal inhibition. δGABAARs are highly expressed within the thalamus and their activation promotes a switch from tonic to burst firing in vitro. Here we test two hypotheses in vivo. (1) Activation of thalamic δGABAARs will elicit electrocortical signatures consistent with widespread thalamocortical burst firing such as increased delta oscillations (1-4 Hz) and reciprocal changes in spindle-like oscillations (7-14 Hz). (2) These signatures will be recapitulated by the general anesthetic etomidate, if the electrocortical effects of etomidate at the thalamus are mediated by δGABAARs. Microperfusion of the δGABAAR-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 and 50 µM) into the ventrobasal complex produced significant effects on electrocortical activity in wild-type mice, but not in mice lacking δGABAARs (Gabrd(-/-)), i.e., the effects with THIP were dependent on δGABAARs. THIP (1) increased 1-4 Hz power in wakefulness and nonrapid-eye movement (NREM) sleep; (2) reduced spindle-like oscillations in NREM sleep; and (3) increased the speed of stable transitions into NREM sleep, indicating effects on state-space dynamics. In contrast, microperfusion of etomidate (10 and 30 µM) into the ventrobasal complex produced effects on electrocortical activity that were independent of δGABAARs, i.e., effects occurred in wild-type and Gabrd(-/-) mice. Etomidate (1) decreased 1-4 Hz power, increased 8-12 Hz, and/or 12-30 Hz power in all sleep-wake states; (2) increased spindle-like oscillations; and (3) increased REM sleep expression. These results indicate that thalamic δGABAARs promote electrocortical signatures of deep NREM sleep, but do not mediate the effects of etomidate at the thalamus in vivo.

WS0701: a novel sedative-hypnotic agent acting on the adenosine system.

To characterize the sedative and hypnotic profile of the novel adenosine derivative ((3S,4R,5R)-3,4-dihydroxy-5-(6-((4-hydroxy-3-methoxybenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-yl) methyl diaconate (WS0701), we performed a variety of behavioural tests and investigated the influence of WS0701 on various sleep stages. In mice, WS0701 significantly increased the number of entries and time spent in open arms in the elevated plus maze test, indicating an anxiolytic effect. WS0701 decreased locomotor activity counts and head dips in the hole-board test and enhanced sodium pentobarbital-induced hypnosis. However, WS0701 did not induce the loss of the righting reflex or amnesic effects in behavioural models. In rats, WS0701 exerted a sedative effect and markedly prolonged the time spent in non-rapid-eye-movement sleep, especially slow-wave sleep, but reduced the time spent in rapid-eye-movement sleep (REMS). Pretreatment with the selective adenosine A2a receptor antagonist SCH58261 attenuated the sedative and hypnotic effects of WS0701. WS0701 did not protect mice against picrotoxin-induced seizures, but inhibited adenosine deaminase activity and increased adenosine levels in the frontal cortex and hypothalamus of mice. In conclusion, WS0701 shows anxiolytic, sedative as well as sleep stage alterative effects, which may be related to the adenosine system.

Dietary heat-killed Lactobacillus brevis SBC8803 promotes voluntary wheel-running and affects sleep rhythms in mice.

AIMS: We previously reported that heat-killed Lactobacillus brevis SBC8803 enhances appetite via changes in autonomic neurotransmission. Here we assessed whether a diet supplemented with heat-killed SBC8803 affects circadian locomotor rhythmicity and sleep architecture. MAIN METHODS AND KEY FINDINGS: Daily total activity gradually increased in mice over 4 weeks and supplementation with heat-killed SBC8803 significantly intensified the increase, which reached saturation at 25 days. Electroencephalography revealed that SBC8803 supplementation significantly reduced the total amount of time spent in non-rapid eye movement (NREM) sleep and increased the amount of time spent being awake during the latter half of the nighttime, but tended to increase the total amount of time spent in NREM sleep during the daytime. Dietary supplementation with SBC8803 can extend the duration of activity during the nighttime and of sleep during the daytime. Daily voluntary wheel-running and sleep rhythmicity become intensified when heat-killed SBC8803 is added to the diet. SIGNIFICANCE: Dietary heat-killed SBC8803 can modulate circadian locomotion and sleep rhythms, which might benefit individuals with circadian rhythms that have been disrupted by stress or ageing.

"Clozapine makes me quite drowsy, so when I wake up in the morning those first cups of coffee are really handy": an exploratory qualitative study of excessive caffeine consumption among individuals with schizophrenia.

BACKGROUND: Research has shown that individuals with schizophrenia use caffeine at higher rates than the general population; however, no qualitative research has been undertaken investigating problematic caffeine use and its effects on this population. This article explores the role of caffeine consumption in the lives of people with schizophrenia through a narrative analysis of the attitudes and beliefs associated with this practice, and how these, in turn, influence caffeine consumption. METHODS: A qualitative study was undertaken with individuals who had previously scored in either a 'moderate' or 'high' risk category for caffeine use on the Alcohol, Smoking and Substance Involvement Screening Tool (ASSIST). In-depth interviews were undertaken with 20 individuals, and transcripts were analysed thematically to identify prominent perspectives. RESULTS: Consistent with previous literature, participants' caffeine consumption was driven largely by its stimulating properties; however, participants also identified 'cravings' as an important motivating factor. Participants' behaviours related to caffeine consumption seemed to be tempered by their previous experiences of consumption; if participants had experienced positive effects such as alertness or relaxation in the past, their use was maintained at a similar level or increased. Conversely, participants who anticipated negative consequences often altered their patterns of caffeine consumption; for example, by substituting caffeinated drinks that minimised or ceased their experience of negative side effects for those that directly caused such impacts. Overall, participants largely identified caffeine consumption as a highly meaningful activity, which provided structure to their day and facilitated opportunities for social interaction. CONCLUSIONS: The inconsistencies between individuals' beliefs about their health and the actual risk of harm associated with health-related behaviours present significant and ongoing challenges for the implementation of relevant and effective strategies for health promotion among individuals diagnosed with mental illness. As a starting point, it would be worthwhile for services engaging with people diagnosed with mental illness, and in particular schizophrenia, to consider implementing caffeine-related health literacy strategies to educate consumers about the risk of excessive caffeine consumption and the interactions between caffeine and antipsychotic medications.

Acute enhancement of non-rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride.

Cadmium (Cd) is a heavy metal widely used or effused by industries. Serious environmental Cd pollution has been reported over the past two centuries, whereas the mechanisms underlying Cd-mediated diseases are not fully understood. Interestingly, an increase in reactive oxygen species (ROS) after Cd exposure has been shown. Our group has demonstrated that sleep is triggered via accumulation of ROS during neuronal activities, and we thus hypothesize the involvement of Cd poisoning in sleep-wake irregularities. In the present study, we analyzed the effects of Cd intake (1-100 ppm CdCl2 in drinking water) on rats by monitoring sleep encephalograms and locomotor activities. The results demonstrated that 100 ppm CdCl2 administration for 28 h was sufficient to increase non-rapid-eye-movement (non-REM) sleep and reduce locomotor activities during the night (the rat active phase). In contrast, free-running locomotor rhythms under constant dim red light and their re-entrainment to 12:12-h light/dark cycles were intact under chronic (1 month) 100 ppm CdCl2 administrations, suggesting a limited influence on circadian clock movements at this dosage. The relative amount of oxidized glutathione increased in the brain after the 28-h 100 ppm CdCl2 administrations similar to the levels in cultured astrocytes receiving H2O2 or CdCl2 in culture medium. Therefore, we propose Cd-induced sleep as a consequence of oxidative stress. As oxidized glutathione is an endogenous sleep substance, we suggest that Cd rapidly induces sleepiness and influences activity performance by occupying intrinsic sleep-inducing mechanisms. In conclusion, we propose increased non-REM sleep during the active phase as an index of acute Cd exposure.