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1.
Cell ; 184(24): 5886-5901.e22, 2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34822784

RESUMEN

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Receptor Muscarínico M1/agonistas , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Inhibidores de la Colinesterasa/farmacología , Cricetulus , Cristalización , Modelos Animales de Enfermedad , Perros , Donepezilo/farmacología , Electroencefalografía , Femenino , Células HEK293 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Primates , Ratas , Receptor Muscarínico M1/química , Transducción de Señal , Homología Estructural de Proteína
2.
Proc Natl Acad Sci U S A ; 120(13): e2214171120, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36947514

RESUMEN

Sleep/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake control and potential promise as a therapeutic target for the treatment of insomnia.


Asunto(s)
Electroencefalografía , Péptidos Opioides , Ratas , Ratones , Animales , Sueño , Sueño REM/fisiología , Nociceptina
3.
J Sleep Res ; : e14037, 2023 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-37731248

RESUMEN

Aversive symptoms, including insomnia experienced during opioid withdrawal, are a major drive to relapse; however, withdrawal-associated sleep symptomatology has been little explored in preclinical models. We describe here a model of opioid withdrawal in mice that resembles the sleep phenotype characteristic of withdrawal in humans. Male and female C57BL/6 mice were instrumented with telemeters to record electroencephalogram, electromyogram, activity and subcutaneous temperature. All mice received two treatments separated by a 16-day washout period: (1) saline (volume: 10 ml kg-1 ); or (2) ascending doses of morphine (5, 10, 20, 40 and 80 mg kg-1 ; volume: 10 ml kg-1 ) for 5 days at Zeitgeber time 1 and Zeitgeber time 13. Recordings for the first 71 hr after treatment discontinuation (withdrawal days 1-3) and for 24 hr on withdrawal days 5 and 7 were scored for sleep/wake state, and sleep architecture and electroencephalogram spectral data were analysed. Morphine was acutely wake- and activity-promoting, and non-rapid eye movement and rapid eye movement sleep were increased during the dark phase on withdrawal day 2 in both sexes. While non-rapid eye movement delta power (0.5-4.0 Hz), a measure of sleep intensity, was reduced during the light phase on withdrawal day 1 and the dark phase on withdrawal day 2 in both sexes, female mice also exhibited changes in the duration and the number of bouts of sleep/wake states. These observations of fragmented sleep on withdrawal days 1-3 suggest poorer sleep consolidation and a more pronounced withdrawal-associated sleep phenotype in female than in male mice. These data may indicate a greater sensitivity to morphine, a more distinct aversive sleep phenotype and/or a faster escalation to dependence in female mice.

4.
J Sleep Res ; 32(4): e13839, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36808670

RESUMEN

The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO-DTA mice. TAK-925 (1-10 mg/kg, s.c.) and ARN-776 (1-10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc ) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the second hour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6 h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and Tsc , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists.


Asunto(s)
Cataplejía , Narcolepsia , Animales , Masculino , Ratones , Cataplejía/tratamiento farmacológico , Narcolepsia/tratamiento farmacológico , Receptores de Orexina/uso terapéutico , Orexinas , Sueño/fisiología , Vigilia/fisiología
5.
Proc Natl Acad Sci U S A ; 110(50): 20272-7, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24191004

RESUMEN

Although the neural circuitry underlying homeostatic sleep regulation is little understood, cortical neurons immunoreactive for neuronal nitric oxide synthase (nNOS) and the neurokinin-1 receptor (NK1) have been proposed to be involved in this physiological process. By systematically manipulating the durations of sleep deprivation and subsequent recovery sleep, we show that activation of cortical nNOS/NK1 neurons is directly related to non-rapid eye movement (NREM) sleep time, NREM bout duration, and EEG δ power during NREM sleep, an index of preexisting homeostatic sleep drive. Conversely, nNOS knockout mice show reduced NREM sleep time, shorter NREM bouts, and decreased power in the low δ range during NREM sleep, despite constitutively elevated sleep drive. Cortical NK1 neurons are still activated in response to sleep deprivation in these mice but, in the absence of nNOS, they are unable to up-regulate NREM δ power appropriately. These findings support the hypothesis that cortical nNOS/NK1 neurons translate homeostatic sleep drive into up-regulation of NREM δ power through an NO-dependent mechanism.


Asunto(s)
Ondas Encefálicas/fisiología , Corteza Cerebral/fisiología , Interneuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Sueño/fisiología , Animales , Recuento de Células , Electroencefalografía , Electromiografía , Inmunohistoquímica , Ratones , Ratas , Ratas Sprague-Dawley
6.
J Neurosci ; 34(19): 6485-94, 2014 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-24806675

RESUMEN

γ-Hydroxybutyrate (GHB) is an approved therapeutic for the excessive sleepiness and sudden loss of muscle tone (cataplexy) characteristic of narcolepsy. The mechanism of action for these therapeutic effects is hypothesized to be GABAB receptor dependent. We evaluated the effects of chronic administration of GHB and the GABAB agonist R-baclofen (R-BAC) on arousal state and cataplexy in two models of narcolepsy: orexin/ataxin-3 (Atax) and orexin/tTA; TetO diphtheria toxin mice (DTA). Mice were implanted for EEG/EMG monitoring and dosed with GHB (150 mg/kg), R-BAC (2.8 mg/kg), or vehicle (VEH) bid for 15 d-a treatment paradigm designed to model the twice nightly GHB dosing regimen used by human narcoleptics. In both models, R-BAC increased NREM sleep time, intensity, and consolidation during the light period; wake bout duration increased and cataplexy decreased during the subsequent dark period. GHB did not increase NREM sleep consolidation or duration, although NREM delta power increased in the first hour after dosing. Cataplexy decreased from baseline in 57 and 86% of mice after GHB and R-BAC, respectively, whereas cataplexy increased in 79% of the mice after VEH. At the doses tested, R-BAC suppressed cataplexy to a greater extent than GHB. These results suggest utility of R-BAC-based therapeutics for narcolepsy.


Asunto(s)
Cataplejía/tratamiento farmacológico , Agonistas del GABA/uso terapéutico , Narcolepsia/tratamiento farmacológico , Receptores de GABA-B/efectos de los fármacos , Sueño/efectos de los fármacos , Oxibato de Sodio/uso terapéutico , Animales , Nivel de Alerta/efectos de los fármacos , Nivel de Alerta/fisiología , Ataxina-3 , Interpretación Estadística de Datos , Toxina Diftérica/genética , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Electromiografía/efectos de los fármacos , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Neuropéptidos/genética , Proteínas Nucleares/genética , Orexinas , Proteínas Represoras/genética , Sueño REM/efectos de los fármacos
7.
J Pharmacol Exp Ther ; 353(1): 213-33, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25665805

RESUMEN

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.


Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Imidazoles/farmacología , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Regulación Alostérica , Animales , Ansiolíticos/farmacocinética , Ansiolíticos/uso terapéutico , Antidepresivos/farmacocinética , Antidepresivos/uso terapéutico , Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Células Cultivadas , Cricetulus , Depresión/metabolismo , Depresión/psicología , Agonismo Inverso de Drogas , Electroencefalografía , Femenino , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Macaca fascicularis , Masculino , Ratones , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ensayo de Unión Radioligante , Ratas Sprague-Dawley , Ratas Wistar , Receptor del Glutamato Metabotropico 5/metabolismo , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/fisiopatología
8.
Brain ; 136(Pt 7): 2159-72, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23801738

RESUMEN

Deficits in sleep and circadian organization have been identified as common early features in patients with Huntington's disease that correlate with symptom severity and may be instrumental in disease progression. Studies in Huntington's disease gene carriers suggest that alterations in the electroencephalogram may reflect underlying neuronal dysfunction that is present in the premanifest stage. We conducted a longitudinal characterization of sleep/wake and electroencephalographic activity in the R6/2 mouse model of Huntington's disease to determine whether analogous electroencephalographic 'signatures' could be identified early in disease progression. R6/2 and wild-type mice were implanted for electroencephalographic recordings along with telemetry for the continuous recording of activity and body temperature. Diurnal patterns of activity and core body temperature were progressively disrupted in R6/2 mice, with a large reduction in the amplitude of these rhythms apparent by 13 weeks of age. The diurnal variation in sleep/wake states was gradually attenuated as sleep became more fragmented and total sleep time was reduced relative to wild-type mice. These genotypic differences were augmented at 17 weeks and evident across the entire 24-h period. Quantitative electroencephalogram analysis revealed anomalous increases in high beta and gamma activity (25-60 Hz) in all sleep/wake states in R6/2 mice, along with increases in theta activity during both non-rapid eye movement and rapid eye movement sleep and a reduction of delta power in non-rapid eye movement sleep. These dramatic alterations in quantitative electroencephalographic measures were apparent from our earliest recording (9 weeks), before any major differences in diurnal physiology or sleep/wake behaviour occurred. In addition, the homeostatic response to sleep deprivation was greatly attenuated with disease progression. These findings demonstrate the sensitivity of quantitative electroencephalographic analysis to identify early pathophysiological alterations in the R6/2 model of Huntington's disease and suggest longitudinal studies in other preclinical Huntington's disease models are needed to determine the generality of these observations as a potential adjunct in therapeutic development.


Asunto(s)
Ondas Encefálicas/fisiología , Ritmo Circadiano/fisiología , Enfermedad de Huntington/complicaciones , Fases del Sueño/fisiología , Trastornos del Sueño-Vigilia/etiología , Análisis de Varianza , Animales , Temperatura Corporal/genética , Ondas Encefálicas/genética , Ritmo Circadiano/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electroencefalografía , Electromiografía , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Estudios Longitudinales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/genética , Proteínas del Tejido Nervioso/genética , Fenotipo , Privación de Sueño/fisiopatología , Fases del Sueño/genética , Análisis Espectral , Repeticiones de Trinucleótidos/genética , Vigilia/genética
9.
Sleep ; 45(12)2022 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-35182424

RESUMEN

Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. female orexin-tTA; TetO-DTA mice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, subcutaneous temperature, gross motor activity, and video recordings were conducted for 24-h at baseline and 1, 2, 4, and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Subcutaneous temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the "Delta State", characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use.


Asunto(s)
Cataplejía , Narcolepsia , Animales , Ratones , Masculino , Femenino , Orexinas/genética , Narcolepsia/genética , Sueño/fisiología , Neuronas , Fenotipo , Vigilia/fisiología
10.
Sleep ; 43(10)2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-32303763

RESUMEN

STUDY OBJECTIVES: Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. METHODS: Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). RESULTS: ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. CONCLUSIONS: The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.


Asunto(s)
Hipnóticos y Sedantes , Piridinas , Acetamidas , Animales , Cognición , Método Doble Ciego , Femenino , Humanos , Hipnóticos y Sedantes/efectos adversos , Isoquinolinas , Masculino , Receptores de Orexina , Orexinas/farmacología , Desempeño Psicomotor , Piridinas/efectos adversos , Adulto Joven , Zolpidem/farmacología
11.
Neuropsychopharmacology ; 44(8): 1485-1493, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30954024

RESUMEN

Trace amine-associated receptor 1 (TAAR1) is a G-protein coupled receptor with affinity for the trace amines. TAAR1 agonists have pro-cognitive, antidepressant-, and antipsychotic-like properties in both rodents and non-human primates (NHPs). TAAR1 agonism also increases wakefulness and suppresses rapid-eye movement (REM) sleep in mice and rats and reduces cataplexy in two mouse models of narcolepsy. We investigated the effects of TAAR1 agonism in Cynomolgus macaques, a diurnal species that exhibits consolidated night-time sleep, and evaluated the effects of TAAR1 agonists on cognition using a working memory (WM) paradigm in this species. Adult male Cynomolgus macaques (n = 6) were surgically implanted to record the electroencephalogram (EEG), electromyogram, and locomotor activity (LMA) and the efficacy of the TAAR1 partial agonist RO5263397 (0.1,1,10 mg/kg, p.o.) on sleep/wake, EEG spectra, and LMA was determined. In a second experiment, the acute effects of RO5263397 (0.1,1,10 mg/kg, p.o.) were assessed on a delayed-match-to-sample test of WM in adult male macaques (n = 7). RO5263397 (10 mg/kg) administered at lights off, when sleep pressure was high, promoted wakefulness and reduced both REM and non-REM sleep without inducing hyperlocomotion. RO5263397 (10 mg/kg) also increased delta/theta activity during all vigilance states. RO5263397 had no effect on WM at either short (2 sec) or long (10 sec) delay intervals. The wake-enhancing and REM-suppressing effects of R05263397 shown here in a diurnal primate are consistent with previous results in nocturnal rodents. These effects and the associated alterations in EEG spectra occurred without inducing hyperlocomotion or affecting WM, encouraging further study of TAAR1 agonists as potential narcolepsy therapeutics.


Asunto(s)
Cognición/efectos de los fármacos , Oxazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Vigilia/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Macaca fascicularis , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos
12.
Artículo en Inglés | MEDLINE | ID: mdl-31236518

RESUMEN

Most preclinical sleep studies are conducted in nocturnal rodents that have fragmented sleep in comparison to humans who are primarily diurnal, typically with a consolidated sleep period. Consequently, we sought to define basal sleep characteristics, sleep/wake architecture and electroencephalographic (EEG) activity in a diurnal non-human primate (NHP) to evaluate the utility of this species for pharmacological manipulation of the sleep/wake cycle. Adult, 9-11 y.o. male cynomolgus macaques (n = 6) were implanted with telemetry transmitters to record EEG and electromyogram (EMG) activity and Acticals to assess locomotor activity under baseline conditions and following injections either with vehicle or the caffeine (CAF; 10 mg/kg, i.m.) prior to the 12 h dark phase. EEG/EMG recordings (12-36 h in duration) were analyzed for sleep/wake states and EEG spectral composition. Macaques exhibited a sleep state distribution and architecture similar to previous NHP and human sleep studies. Acute administration of CAF prior to light offset enhanced wakefulness nearly 4-fold during the dark phase with consequent reductions in both NREM and REM sleep, decreased slow wave activity during wakefulness, and increased higher EEG frequency activity during NREM sleep. Despite the large increase in wakefulness and profound reduction in sleep during the dark phase, no sleep rebound was observed during the 24 h light and dark phases following caffeine administration. Cynomolgus macaques show sleep characteristics, EEG spectral structure, and respond to CAF in a similar manner to humans. Consequently, monitoring EEG/EMG by telemetry in this species may be useful both for basic sleep/wake studies and for pre-clinical assessments of drug-induced effects on sleep/wake.

13.
Front Neurosci ; 13: 207, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30936820

RESUMEN

Manual scoring of polysomnography data is labor-intensive and time-consuming, and most existing software does not account for subjective differences and user variability. Therefore, we evaluated a supervised machine learning algorithm, SomnivoreTM, for automated wake-sleep stage classification. We designed an algorithm that extracts features from various input channels, following a brief session of manual scoring, and provides automated wake-sleep stage classification for each recording. For algorithm validation, polysomnography data was obtained from independent laboratories, and include normal, cognitively-impaired, and alcohol-treated human subjects (total n = 52), narcoleptic mice and drug-treated rats (total n = 56), and pigeons (n = 5). Training and testing sets for validation were previously scored manually by 1-2 trained sleep technologists from each laboratory. F-measure was used to assess precision and sensitivity for statistical analysis of classifier output and human scorer agreement. The algorithm gave high concordance with manual visual scoring across all human data (wake 0.91 ± 0.01; N1 0.57 ± 0.01; N2 0.81 ± 0.01; N3 0.86 ± 0.01; REM 0.87 ± 0.01), which was comparable to manual inter-scorer agreement on all stages. Similarly, high concordance was observed across all rodent (wake 0.95 ± 0.01; NREM 0.94 ± 0.01; REM 0.91 ± 0.01) and pigeon (wake 0.96 ± 0.006; NREM 0.97 ± 0.01; REM 0.86 ± 0.02) data. Effects of classifier learning from single signal inputs, simple stage reclassification, automated removal of transition epochs, and training set size were also examined. In summary, we have developed a polysomnography analysis program for automated sleep-stage classification of data from diverse species. Somnivore enables flexible, accurate, and high-throughput analysis of experimental and clinical sleep studies.

14.
Sleep ; 31(1): 34-44, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18220076

RESUMEN

STUDY OBJECTIVES: Serotonin (5-HT) has long been implicated in the control of sleep and wakefulness. This study evaluated the hypnotic efficacy of the 5-HT6 antagonist RO4368554 (RO) and the 5-HT2A receptor antagonist MDL100907 (MDL) relative to zolpidem. DESIGN: A randomized, repeated-measures design was utilized in which Wistar rats received intraperitoneal injections of RO (1.0, 3.0, and 10 mg/kg), MDL (0.1, 1.0 and 3.0 mg/kg), zolpidem (10 mg/kg), or vehicle in the middle of the dark (active) period. Electroencephalogram, electromyogram, body temperature (Tb) and locomotor activity were analyzed for 6 hours after injection. MEASUREMENTS AND RESULTS: RO, MDL, and zolpidem all produced significant increases in sleep and decreases in waking, compared with vehicle control. All 3 doses of MDL produced more consolidated sleep, increased non-rapid eye movement sleep (NREM) sleep, and increased electroencephalographic delta power during NREM sleep. The highest dose of RO (10.0 mg/kg) produced significant increases in sleep and decreases in waking during hour 2 following dosing. These increases in sleep duration were associated with greater delta power during NREM sleep. ZO Zolpidem induced sleep with the shortest latency and significantly increased NREM sleep and delta power but also suppressed rapid eye movement sleep sleep; in contrast, neither RO nor MDL affected rapid eye movement sleep. Whereas RO did not affect Tb, both zolpidem and MDL reduced Tb relative to vehicle-injected controls. CONCLUSIONS: These results support a role for 5-HT2A receptor modulation in NREM sleep and suggest a previously unrecognized role for 5-HT6 receptors in sleep-wake regulation.


Asunto(s)
Fluorobencenos/farmacología , Indoles/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT2 , Sueño REM/efectos de los fármacos , Vigilia/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley
16.
Neuropsychopharmacology ; 42(6): 1305-1314, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-27658486

RESUMEN

Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (Tb), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased Tb without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.


Asunto(s)
Conducta Animal/fisiología , Ondas Encefálicas/fisiología , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Oxazoles/farmacología , Receptores Acoplados a Proteínas G/fisiología , Fases del Sueño/fisiología , Vigilia/fisiología , Animales , Conducta Animal/efectos de los fármacos , Ondas Encefálicas/efectos de los fármacos , Cafeína/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Masculino , Ratones , Ratones Noqueados , Oxazoles/administración & dosificación , Receptores Acoplados a Proteínas G/agonistas , Fases del Sueño/efectos de los fármacos , Vigilia/efectos de los fármacos
17.
eNeuro ; 3(2)2016.
Artículo en Inglés | MEDLINE | ID: mdl-27022631

RESUMEN

Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network.


Asunto(s)
Acetamidas/farmacología , Área Hipotalámica Lateral/fisiología , Isoquinolinas/farmacología , Locus Coeruleus/fisiología , Orexinas/metabolismo , Sueño REM/efectos de los fármacos , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Electroencefalografía , Electromiografía , Agonistas de Receptores de GABA-A/farmacología , Histamina/metabolismo , Área Hipotalámica Lateral/efectos de los fármacos , Área Hipotalámica Lateral/lesiones , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/lesiones , Masculino , Norepinefrina/metabolismo , Orexinas/antagonistas & inhibidores , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Inactivadoras de Ribosomas Tipo 1/toxicidad , Saporinas , Telemetría , Vigilia/efectos de los fármacos , Zolpidem
18.
Neuropsychopharmacology ; 41(4): 1144-55, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26289145

RESUMEN

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.


Asunto(s)
Acetamidas/administración & dosificación , Encéfalo/fisiología , Isoquinolinas/administración & dosificación , Neuronas/fisiología , Antagonistas de los Receptores de Orexina/administración & dosificación , Piridinas/administración & dosificación , Fases del Sueño/efectos de los fármacos , Vigilia/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Electroencefalografía , Electromiografía , Histamina/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Orexinas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/metabolismo , Zolpidem
19.
Sleep ; 39(2): 379-91, 2016 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-26446107

RESUMEN

STUDY OBJECTIVES: Patients with Huntington's disease (HD) show a high prevalence of sleep disorders that typically occur prior to the onset of motoric symptoms and neurodegeneration. Our understanding of the pathophysiological alterations in premanifest HD is limited, hindering the ability to measure disease modification in response to treatment. We used a full-length knock-in HD model to determine early changes in the electroencephalogram (EEG) and sleep that may predict the onset and progression of the disease. METHODS: A 10-month longitudinal study was designed to determine the effect of the HD mutation on the EEG and sleep/wake changes in heterozygous (HET) and homozygous (HOM) zQ175 mice and wild-type (WT) littermates from 8 to 48 w of age. Mice were instrumented with tethered headmounts to record EEG/electromyography signals. Telemeters were implanted to continuously measure locomotor activity (LMA) and body temperature (Tb). Sleep deprivation (SDep) was performed at 8, 12, 16, 24, 32, and 48 w of age. RESULTS: The HD mutation disrupted the EEG field potential from 8-12 w in an age- and mutant huntington dose-dependent manner, prior to changes in sleep/wake states, LMA, and Tb. Prominent effects of the HD mutation on the EEG included a progressive reduction in low frequency power, a slowing of rapid eye movement peak theta frequency, and the emergence of state-dependent beta/gamma oscillations. There was no effect of genotype on the relative increase in nonrapid eye movement delta power or sleep time in response to SDep. CONCLUSIONS: The expression of the Huntington's disease (HD) mutation results in complex EEG alterations that occur prior to deficits in behavioral measures and are one of the earliest phenotypes uncovered in this mouse model. Despite these EEG changes, homeostatic responses to sleep loss were preserved in HET and HOM zQ175 mice. Greater insight into the localization and response of these EEG alterations to novel therapies may enable early intervention and improve outcomes for patients with HD.


Asunto(s)
Modelos Animales de Enfermedad , Progresión de la Enfermedad , Electroencefalografía , Técnicas de Sustitución del Gen , Enfermedad de Huntington/genética , Enfermedad de Huntington/fisiopatología , Proteínas del Tejido Nervioso/genética , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/fisiopatología , Envejecimiento , Animales , Temperatura Corporal , Ondas Encefálicas , Electromiografía , Genotipo , Humanos , Proteína Huntingtina , Enfermedad de Huntington/complicaciones , Estudios Longitudinales , Masculino , Ratones , Actividad Motora , Mutación/genética , Fenotipo , Privación de Sueño/fisiopatología , Sueño REM/fisiología , Vigilia/fisiología
20.
Neuropsychopharmacology ; 40(3): 632-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25139062

RESUMEN

Cortical interneurons, immunoreactive for neuronal nitric oxide synthase (nNOS) and the receptor NK1, express the functional activity marker Fos selectively during sleep. NREM sleep 'pressure' is hypothesized to accumulate during waking and to dissipate during sleep. We reported previously that the proportion of Fos(+) cortical nNOS/NK1 neurons is correlated with established electrophysiological markers of sleep pressure. As these markers covary with the amount of NREM sleep, it remained unclear whether cortical nNOS/NK1 neurons are activated to the same degree throughout NREM sleep or whether the extent of their activation is related to the sleep pressure that accrued during the prior waking period. To distinguish between these possibilities, we used hypnotic medications to control the amount of NREM sleep in rats while we varied prior wake duration and the resultant sleep pressure. Drug administration was preceded by 6 h of sleep deprivation (SD) ('high sleep pressure') or undisturbed conditions ('low sleep pressure'). We find that the proportion of Fos(+) cortical nNOS/NK1 neurons was minimal when sleep pressure was low, irrespective of the amount of time spent in NREM sleep. In contrast, a large proportion of cortical nNOS/NK1 neurons was Fos(+) when an equivalent amount of sleep was preceded by SD. We conclude that, although sleep is necessary for cortical nNOS/NK1 neuron activation, the proportion of cells activated is dependent upon prior wake duration.


Asunto(s)
Corteza Cerebral/fisiología , Homeostasis/fisiología , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/fisiología , Receptores de Neuroquinina-1/fisiología , Fases del Sueño/fisiología , Acetamidas/farmacología , Animales , Corteza Cerebral/efectos de los fármacos , Isoquinolinas/farmacología , Masculino , Neuronas/inmunología , Óxido Nítrico Sintasa de Tipo I/inmunología , Piridinas/farmacología , Ratas , Receptores de Neuroquinina-1/inmunología , Privación de Sueño/fisiopatología , Fases del Sueño/efectos de los fármacos , Zolpidem
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