International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology.

The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.

Acoustic Stimulation to Improve Slow-Wave Sleep in Alzheimer's Disease: A Multiple Night At-Home Intervention.

OBJECTIVES: To investigate the efficacy of closed-loop acoustic stimulation (CLAS) during slow-wave sleep (SWS) to enhance slow-wave activity (SWA) and SWS in patients with Alzheimer's disease (AD) across multiple nights and to explore associations between stimulation, participant characteristics, and individuals' SWS response. DESIGN: A 2-week, open-label at-home intervention study utilizing the DREEM2 headband to record sleep data and administer CLAS during SWS. SETTING AND PARTICIPANTS: Fifteen older patients with AD (6 women, mean age: 76.27 [SD = 6.06], mean MOCA-score: 16.07 [SD = 6.94]), living at home with their partner, completed the trial. INTERVENTION: Patients first wore the device for two baseline nights, followed by 14 nights during which the device was programmed to randomly either deliver acoustic stimulations of 50 ms pink noise (± 40 dB) targeted to the slow-wave up-phase during SWS or only mark the wave (sham). RESULTS: On a group level, stimulation significantly enhanced SWA and SWS with consistent SWS enhancement throughout the intervention. However, substantial variability existed in individual responses to stimulation. Individuals received more stimulations on nights with increased SWS compared to baseline than on nights with no change or a decrease. In individuals, having lower baseline SWS correlated with receiving fewer stimulations on average during the intervention. CONCLUSION: CLAS during SWS is a promising nonpharmacological method to enhance SWA and SWS in AD. However, patients with lower baseline SWS received fewer stimulations during the intervention, possibly resulting in less SWS enhancement. Individual variability in response to stimulation underscores the need to address personalized stimulation parameters in future research and therapy development.

The characteristic time scale of cultural evolution.

Numerous researchers from various disciplines have explored commonalities and divergences in the evolution of complex social formations. Here, we explore whether there is a "characteristic" time course for the evolution of social complexity in a handful of different geographic areas. Data from the Seshat: Global History Databank is shifted so that the overlapping time series can be fitted to a single logistic regression model for all 23 geographic areas under consideration. The resulting regression shows convincing out-of-sample predictions, and its period of extensive growth in social complexity can be identified via bootstrapping as a time interval of roughly 2,500 years. To analyze the endogenous growth of social complexity, each time series is restricted to a central time interval without major disruptions in cultural or institutional continuity, and both approaches result in a similar logistic regression curve. Our results suggest that these different areas have indeed experienced a similar course in the their evolution of social complexity, but that this is a lengthy process involving both internal developments and external influences.

Hypocretin-1 receptor antagonism improves inhibitory control during the Go/No-Go task in highly motivated, impulsive male mice.

RATIONALE: Motivation and inhibitory control are dominantly regulated by the dopaminergic (DA) and noradrenergic (NA) systems, respectively. Hypothalamic hypocretin (orexin) neurons provide afferent inputs to DA and NA nuclei and hypocretin-1 receptors (HcrtR1) are implicated in reward and addiction. However, the role of the HcrtR1 in inhibitory control is not well understood. OBJECTIVES: To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice. METHODS: n = 23 male C57Bl/6JArc mice were trained in a go/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5 mg/kg, per os) or vehicle were then administered 30 min before go/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals. RESULTS: HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task. CONCLUSIONS: These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations.

Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice.

BACKGROUND AND PURPOSE: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown. EXPERIMENTAL APPROACH: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg-1 ·day-1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX2 ) receptor antagonist MK-1064 (40 mg·kg-1 ·day-1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry. KEY RESULTS: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX2 receptor signalling. CONCLUSIONS AND IMPLICATIONS: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.

A contemporary training concept in critical care cardiology.

Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.