Bottom-Up versus Top-Down Induction of Sleep by Zolpidem Acting on Histaminergic and Neocortex Neurons

Zolpidem, a GABAA receptor-positive modulator, is the gold-standard drug for treating insomnia. Zolpidem prolongs IPSCs to decrease sleep latency and increase sleep time, effects that depend on α2 and/or α3 subunit-containing receptors. Compared with natural NREM sleep, zolpidem also decreases the EEG power, an effect that depends on α1 subunit-containing receptors, and which may make zolpidem-induced sleep less optimal. In this paper, we investigate whether zolpidem needs to potentiate only particular GABAergic pathways to induce sleep without reducing EEG power. Mice with a knock-in F77I mutation in the GABAA receptor γ2 subunit gene are zolpidem-insensitive. Using these mice, GABAA receptors in the frontal motor neocortex and hypothalamic (tuberomammillary nucleus) histaminergic-neurons of γ2I77 mice were made selectively sensitive to zolpidem by genetically swapping the γ2I77 subunits with γ2F77 subunits. When histamine neurons were made selectively zolpidem-sensitive, systemic administration of zolpidem shortened sleep latency and increased sleep time. But in contrast to the effect of zolpidem on wild-type mice, the power in the EEG spectra of NREM sleep was not decreased, suggesting that these EEG power-reducing effects of zolpidem do not depend on reduced histamine release. Selective potentiation of GABAA receptors in the frontal cortex by systemic zolpidem administration also reduced sleep latency, but less so than for histamine neurons. These results could help with the design of new sedatives that induce a more natural sleep

Desynchronization of pathological low-frequency brain activity by the hypnotic drug zolpidem.

Reports of the beneficial effects of the hypnotic imidazopyridine, zolpidem, described in persistent vegetative state^1, 2^ have been replicated recently in brain-injured and cognitively impaired patients^3-7^. Previous single photon emission computed tomography (SPECT) studies have suggested that sub-sedative doses of zolpidem increased regional cerebral perfusion in affected areas^5, 8^, implying enhanced neuronal metabolic activity; which has led to speculation that zolpidem 'reawakens' functionally dormant cortex. However, a neuronal mechanism by which this hypnotic drug affords benefits to brain injured patients has yet to be demonstrated. Here, we report the action of sub-sedative doses of zolpidem on neuronal network oscillatory activity in human brain, measured using pharmaco-magnetoencephalography (pharmaco-MEG). Study participant JP suffered a stroke in 1996, causing major damage to the left hemisphere that impaired aspects of both motor and cognitive function. Pharmaco-MEG analyses revealed robust and persistent pathological theta (4-10Hz) and beta (15-30Hz) oscillations within the lesion penumbra and surrounding cortex. Administration of zolpidem (5mg) reduced the power of pathological theta and beta oscillations in all regions of the lesioned hemisphere. This desynchronizing effect correlated well with zolpidem uptake (occurring approximately 40 minutes after acute administration) and was coincident with marked improvements in cognitive and motor function. Control experiments revealed no effect of placebo, while a structurally unrelated hypnotic, zopiclone, administered at a comparable dose (3.5mg) elicited widespread increases in cortical oscillatory power in the beta (15-30Hz) band without functional improvement. These results suggest that in JP, specific motor and cognitive impairments are related to increased low-frequency oscillatory neuronal network activity. Zolpidem is unique amongst hypnotic drugs in its ability to desynchronize such pathological low-frequency activity, thereby restoring cognitive function

Evaluation and Management of Sleep Disorders in the Hand Surgery Patient.

Despite posing a significant public health threat, sleep disorders remain poorly understood and often underdiagnosed and mismanaged. Although sleep disorders are seemingly unrelated, hand surgeons should be mindful of these because numerous conditions of the upper extremity have known associations with sleep disturbances that can adversely affect patient function and satisfaction. In addition, patients with sleep disorders are at significantly higher risk for severe, even life-threatening medical comorbidities, further amplifying the role of hand surgeons in the recognition of this condition

Drug Use on Mont Blanc: A Study Using Automated Urine Collection

Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance

Trends in long-term prescribing of dependence forming medicines

Using patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. Aim This descriptive research used patient-level primary care data to estimate the extent to which antidepressant medicines are prescribed to people continuously for long periods of time. The study also drew on survey data and data on the number of prescriptions dispensed. Findings - The number of antidepressant prescriptions dispensed each year in England doubled between 2008 and 2018 - Survey data show that the proportion of adults reporting use of antidepressants in the past year increased in the 1990s, and again between 2007 and 2014 - The average length of time that antidepressants are continuously prescribed to people for has increased over time. - Some types of antidepressants (for example, tricyclics and other antidepressants) tend to be prescribed for longer periods than other types (such as SSRIs). - In 2014, one in twelve prescribing periods for tricyclics and other antidepressants lasted for three years or more Methods The analyses in this report are descriptive and show the overall prevalence of long-term prescribing in each year. We used a sample of around 50,000 patients prescribed at least one antidepressant medicine between 2000 and 2017. This was drawn from the Clinical Practice Research Datalink (CPRD). The CPRD contains data about prescriptions issued by GPs (including the length and size of prescription) and characteristics of the patients prescribed to (such as their age, sex, and area where they live). Medicines were grouped for analysis into: tricyclics, selective serotonin reuptake inhibitors (SSRIs), and other ADMs. The length of individual prescriptions and continuous prescribing periods were derived using information on consultation dates, the quantity of tablets prescribed, and the numeric daily dose

Effects of filtration sterilization on the stability of ketamine, selected benzodiazepines and metabolites in female urine

Benzodiazepines (Benzos) and ketamine (K) are compounds that have been encountered in Drug-Facilitated Sexual Assault (DFSA) cases. Due to the intimate nature of these crimes, evidence collection is often postponed due to delays and/or reluctance in reporting these crimes. Further delays in analysis may be encountered in laboratories with large caseloads and/or backlogs. Drug identification in biological samples is important to determine whether victims knowingly or unknowingly took an impairing substance, however, the results could be negative due to chemical degradation over a long storage period. The purpose of this project was to study if degradation could be prevented with a new preservation method at the time of collection. Urine samples were prepared by the addition of K and metabolites and selected benzos and metabolites that were subjected to different sample pre-treatment techniques, and were analyzed after storage at room temperature (25°C), refrigerator (4°C) and freezer (-20°). The samples were either pre-treated with preservative (0.5% toluene) or filtration sterilization (sterile filter kit) within two hours after sample collection, and a control group with no pre-treatment was incorporated into the study for comparison. The changes in concentrations over 50 days (Benzos group) and 210 days (K group) were evaluated between different pre-treated methods and different temperature conditions. Sample that were treated with 0.5% toluene showed the most degradation: 44% of oxazepam and 96% of diazepam degraded over 10 days, and 80% of dehydronorketamine degraded after storage of 150 days regardless the temperature conditions. Clonazepam and flunitrazepam concentrations were reduced by 80% of the original concentration when stored at room temperature for 10 days. The major benzodiazepines evaluated in this study were stable when stored in the freezer. In K group, ketamine and norketamine that were stored at room temperature and refrigerated over 210 days were stable, however, degradation was observed after 150 days when the samples were stored in the freezer. There was no statistically different change observed among the samples pre-treated with or without filtration sterilization. Each sample pH was measured and it was determined that those stored at room temperature had an average pH of 8.5, while samples stored in the refrigerator and freezer had an average pH of 6.7 and 6.5, respectively. This finding revealed that pH could be the major factor affecting compound degradation rather than the bacterial contamination with high pH contributing to degradation, and low pH potentially preventing sample lost

Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem

Background: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). Methods: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). Results: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. Conclusion: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS