The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons\' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal.

Alteration of motor control during REM sleep has been extensively described in sleep disorders, in particular in isolated REM sleep behavior disorder (iRBD) and narcolepsy type 1 (NT1). NT1 is caused by the loss of orexin/hypocretin (ORX) neurons. Unlike in iRBD, the RBD comorbid symptoms of NT1 is not associated with alpha-synucleinopathies. To determine whether the chronic absence of ORX neuropeptides is sufficient to induce RBD symptoms, we analyzed during REM sleep the EMG signal of the prepro-hypocretin knockout mice (ORX-/-), a recognized mouse model of NT1. Then, we evaluated the severity of motor alterations by comparing EMG data of ORX-/- mice to those of mice with a targeted suppression of the sublaterodorsal glutamatergic neurotransmission, a recognized rodent model of iRBD. We found a significant alteration of tonic and phasic components of EMG during REM sleep in ORX-/- mice, with more phasic events and more REM sleep episodes without atonia compared to the control wild-type mice. However, these phasic events were fewer, shorter and less complex in ORX-/- mice compared to the RBD-like ORX-/- mice. We thus show that ORX-deficiency, as seen in NT1, is sufficient to impair muscle atonia during REM sleep with a moderate severity of alteration as compared to isolated RBD mice. As described in NT1 patients, we report a major inter-individual variability in the severity and the frequency of RBD symptoms in ORX-deficient mice.

The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shown that the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanisms of the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration of OXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.

Failure to recover from repeated hypercapnia and hypoxemia (HH) challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/- mice. Here, we developed two gas challenges consisting of repeated HH exposures and used whole body plethysmography to determine whether Kcna1-/- mice have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreating Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our preclinical data suggest that those at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.

Orexinergic neurons are critically involved in regulating arousal, wakefulness, and appetite. Their dysfunction has been associated with sleeping disorders, and non-peptide drugs are currently being developed to treat insomnia and narcolepsy. Yet, no light-regulated agents are available to reversibly control their activity. To meet this need, a photoswitchable peptide analogue of the endogenous neuroexcitatory peptide orexin-B was designed, synthesized, and tested in vitro and in vivo. This compound - photorexin - is the first photo-reversible ligand reported for orexin receptors. It allows dynamic control of activity in vitro (including almost the same efficacy as orexin-B, high nanomolar potency, and subtype selectivity to human OX2 receptors) and in vivo in zebrafish larvae by direct application in water. Photorexin induces dose- and light-dependent changes in locomotion and a reduction in the successive induction reflex that is associated with sleep behavior. Molecular dynamics calculations indicate that trans and cis photorexin adopt similar bent conformations and that the only discriminant between their structures and activities is the positioning of the N-terminus. This, in the case of the more active trans isomer, points towards the OX2 N-terminus and extra-cellular loop 2, a region of the receptor known to be involved in ligand binding and recognition consistent with a \"message-address\" system. Thus, our approach could be extended to several important families of endogenous peptides, such as endothelins, nociceptin, and dynorphins among others, that bind to their cognate receptors through a similar mechanism: a \"message\" domain involved in receptor activation and signal transduction, and an \"address\" sequence for receptor occupation and improved binding affinity.

In addition to well-known symptoms such as sleepiness and cataplexy, many people with narcolepsy have impaired cognition, reporting inattention, poor memory and other concerns. Unfortunately, research on cognition in narcolepsy has been limited. Strong evidence demonstrates difficulties with sustained attention, but evidence for executive dysfunction and impaired memory is mixed. Animal research provides some insights into how loss of the orexin neurons in narcolepsy type 1 may give rise to impaired cognition via dysfunction of the prefrontal cortex, and cholinergic and monoaminergic systems. This paper reviews some of these clinical and preclinical findings, provides a neurobiological framework to understand these deficits, and highlights some of the many key unanswered questions.

Pupil size is a widely used metric of brain state. It is one of the few signals originating from the brain that can be readily monitored with low-cost devices in basic science, clinical, and home settings. It is, therefore, important to investigate and generate well-defined theories related to specific interpretations of this metric. What exactly does it tell us about the brain? Pupils constrict in response to light and dilate during darkness, but the brain also controls pupil size irrespective of luminosity. Pupil size fluctuations resulting from ongoing \"brain states\" are used as a metric of arousal, but what is pupil-linked arousal and how should it be interpreted in neural, cognitive, and computational terms? Here, we discuss some recent findings related to these issues. We identify open questions and propose how to answer them through a combination of well-defined tasks, neurocomputational models, and neurophysiological probing of the interconnected loops of causes and consequences of pupil size.

BACKGROUND: 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.
OBJECTIVE: 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.

The onset of narcolepsy type 1 (NT1) occurs after 50 years of age in less than 2% of the cases. In older adults, the diagnosis is often delayed due to the presence of neurological degenerative and inflammatory comorbidities and overlapping sleep disorders. We report the case of a 63-year-old man with a 5-year history of excessive daytime sleepiness (EDS) and a 2-year diagnosis of obstructive sleep apnea syndrome (OSAS), which. OSAS was confirmed by respiratory polygraphy that showed an apnea-hypopnea index (AHI) of 71 events/hour of sleep associated with significant nocturnal hypoxemia (lowest oxygen saturation: 53%), which lead to the initiation of continuous positive airway pressure (CPAP) treatment. Cognitive complaints, unexplained spells of dizziness, and lack of improvement in EDS with CPAP led to further diagnostic investigation of infectious, inflammatory, and neurodegenerative disorders. Low hypocretin levels in the cerebrospinal fluid (CSF) confirmed the diagnosis of NT1, and the patient\'s symptoms improved with the treatment with pitolisant. Though exceptional in older adults, NT1 should be suspected in the presence of atypical EDS with neurological complaints, unexplained dizzy spells, or OSAS that resists the CPAP treatment. Low levels of hypocretin in the CSF are highly specific and rule out other neurological and sleep disorders.

Cataplexy is the sudden loss of muscle tone often provoked by emotion such as laughter or excitement. Cataplexy is one of the essential diagnostic features of Narcolepsy type 1 (NT1). We describe two cases of isolated cataplexy with different outcomes, highlighting the diagnostic and prognostic challenges. There is conflicting literature as to whether it is a legitimate standalone diagnosis or an early warning sign of narcolepsy. Our cases do not fit with current diagnostic criteria for narcolepsy, yet still share some clinical or laboratory features. These ambiguous cases question what the mechanistic relationship between narcolepsy and cataplexy may be.