Hypocretin

Stress is considered to be an important cause of disrupted sleep and insomnia. However, controlled and experimental studies in rodents indicate that effects of stress on sleep–wake regulation are complex and may strongly depend on the nature of the stressor. While most stressors are associated with at least a brief period of arousal and wakefulness, the subsequent amount and architecture of recovery sleep can vary dramatically across conditions even though classical markers of acute stress such as corticosterone are virtually the same. Sleep after stress appears to be highly influenced by situational variables including whether the stressor was controllable and/or predictable, whether the individual had the possibility to learn and adapt, and by the relative resilience and vulnerability of the individual experiencing stress. There are multiple brain regions and neurochemical systems linking stress and sleep, and the specific balance and interactions between these systems may ultimately determine the alterations in sleep–wake architecture. Factors that appear to play an important role in stress-induced wakefulness and sleep changes include various monominergic neurotransmitters, hypocretins, corticotro-pin releasing factor, and prolactin. In addition to the brain regions directly involved in stress responses such as the hypothalamus, the locus coeruleus, and the amygdala, differential effects of stressor controllability on behavior and sleep may be mediated by the medial prefrontal cortex. These various brain regions interact and influence each other and in turn affect the activity of sleep–wake controlling centers in the brain. Also, these regions likely play significant roles in memory processes and participate in the way stressful memories may affect arousal and sleep. Finally, stress-induced changes in sleep-architecture may affect sleep-related neuronal plasticity processes and thereby contribute to cognitive dysfunction and psychiatric disorders.

Purpose of Review
The complex nature of narcolepsy symptoms, along with the use of stimulants and anticataplectic medications, poses diagnostic difficulties in terms of underlying neuropsychiatric comorbidities. This study reviews recent evidence for the association between narcolepsy and neuropsychiatric disorders. We also critically analyze studies that have addressed the neuropsychiatric correlates of patients with narcolepsy, with a discussion of the possible pathophysiological mechanisms linking narcolepsy and neuropsychiatric disorders.
Recent Findings
Neuropsychiatric manifestations are common among patients with narcolepsy as narcolepsy and some neuropsychiatric disorders share common clinical features. This may create challenges in making the correct diagnosis, and hence result in a delay in starting appropriate treatment. Comorbid neuropsychiatric manifestations in patients with narcolepsy include depression, anxiety, psychosis, rapid eye movement (REM) sleep behavior disorder, and cognitive impairment. Although hypocretin deficiency has been proposed as a pathophysiological mechanism underlying both narcolepsy and neuropsychiatric disorders, further research is necessary to identify the exact mechanisms.
Summary
Narcolepsy patients often manifest comorbid neuropsychiatric symptoms, which makes the diagnosis difficult. Therefore, it is essential to address neuropsychiatric symptoms in the clinical care of patients with narcolepsy.

Background: Autoimmunity has been proposed as a cause of narcolepsy. A few studies have assessed comorbid autoimmune diseases in patients with narcolepsy, with conflicting
results; however, no study has assessed autoimmune diseases in Arab narcolepsy patients. This study aimed to assess the coexistence of immune-mediated conditions such as allergies,
autoimmune diseases, and autoinflammatory diseases in patients with narcolepsy type 1 (with cataplexy) (NT1) and narcolepsy type 2 (without cataplexy) (NT2).
Methods: Personal and family history of autoimmune/autoinflammatory and allergic disorders was collected using a questionnaire in 80 consecutive Saudi patients with narcolepsy
(46 NT1 and 24 NT2), who were diagnosed according to the International Classification of Sleep Disorders, Third Edition. The control group comprised 222 adults from the general population.
Results: Comorbid autoimmune/autoinflammatory diseases were reported by 21.4% of the NT1 patients, and 12.2% of the controls, with no significant difference between cases and controls in a model adjusted for confounding covariates. However, allergic disorders were significantly more prevalent among NT1 patients. Both comorbid autoimmune/autoinflammatory and allergic disorders were significantly more prevalent among NT2 patients
compared to controls. No differences in demographic and clinical characteristics were detected between narcolepsy patients with and without autoimmune/autoinflammatory diseases.
Conclusion: NT1 is not associated with increased comorbid autoimmune diseases in the studied sample of Saudi patients. However, autoimmune diseases are associated with NT2, and allergic disorders are associated with both NT1 and NT2. These findings suggest the existence of dysregulation in the immune system of narcolepsy patients that requires further research.

Did hypocretin receptor 2 auto-antibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.’s findings.

BACKGROUND AND PURPOSE:
Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home-cage food consumption in rodents. However, the role of these receptors in operant food self-administration or relapse to food seeking in animal models is unknown.

EXPERIMENTAL APPROACH:
In Experiment 1, we trained food-restricted rats (16-20 g per day) to lever press for high-fat (35%) pellets (3-6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg(-1), i.p) on pellet self-administration. In Experiment 2, we trained rats to self-administer the food pellets, and following extinction of the food-reinforced responding, we tested the effect of hypocretin 1 (3 and 6 mug, i.c.v) on reinstatement of food-seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non-contingent pellet exposure (pellet-priming) or the pharmacological stressor yohimbine (2 mg kg(-1), i.p).

KEY RESULTS:
SB 334867 attenuated high-fat pellet self-administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet-priming or yohimbine.

CONCLUSIONS AND IMPLICATIONS:
These data indicate that during dieting, hypocretin 1 receptors contribute to operant high-fat pellet self-administration, but not to relapse to food seeking induced by acute re-exposure to the food itself or by the induction of a stress-like state.

The complex nature of narcolepsy symptoms, along with the use of stimulants and anticataplectic medications, poses diagnostic difficulties in terms of underlying neuropsychiatric comorbidities. This study reviews recent evidence for the association between narcolepsy and neuropsychiatric disorders. We also critically analyze studies that have addressed the neuropsychiatric correlates of patients with narcolepsy, with a discussion of the possible pathophysiological mechanisms linking narcolepsy and neuropsychiatric disorders. Neuropsychiatric manifestations are common among patients with narcolepsy as narcolepsy and some neuropsychiatric disorders share common clinical features. This may create challenges in making the correct diagnosis, and hence result in a delay in starting appropriate treatment. Comorbid neuropsychiatric manifestations in patients with narcolepsy include depression, anxiety, psychosis, rapid eye movement (REM) sleep behavior disorder, and cognitive impairment. Although hypocretin deficiency has been proposed as a pathophysiological mechanism underlying both narcolepsy and neuropsychiatric disorders, further research is necessary to identify the exact mechanisms. Narcolepsy patients often manifest comorbid neuropsychiatric symptoms, which makes the diagnosis difficult. Therefore, it is essential to address neuropsychiatric symptoms in the clinical care of patients with narcolepsy.

ABSTRACT: Hypocretin regulates brain reward function and cocaine consumption in rats. The hypocretinergic (Hcrt) system is implicated in energy homeostasis, feeding and sleep regulation. Hypocretinergic cell bodies are located in the lateral hypothalamus (LH) and project throughout the brain. The aim of the present studies was to investigate the role of the Hcrt system in regulating brain reward function and the reinforcing properties of cocaine in rats. Intracranial self-stimulation (ICSS) thresholds provide an accurate measure of brain reward function in rats. Here we show that a single injection of Hcrt-1 (5 µg icv) induced persistent, long-lasting elevations in ICSS thresholds in drug-naïve rats. Indeed, Hrct-1 elevated ICSS thresholds for 36 h, with peak elevations between 6 and 12 hours after injection. Hrct-1-induced threshold elevations were attenuated by an antibody known to neutralize the binding of hcrt-1 to its receptors. Taken together, these observations suggest that Hrct-1 negatively regulates brain reward function in rats. Because Hrct-1 negatively regulates brain reward function, we hypothesized that it may attenuate the increased brain reward function usually observed after cocaine consumption, and thereby alter cocaine self-administration behavior. A daily injection of Hrct-1 (1 µg icv), for 4 consecutive days, slightly increased cocaine self-administration (0.25 mg/infusion) in rats. Overall, these data demonstrate that Hrct-1 negatively regulates brain reward function, and as such may indirectly alter cocaine self-administration. Given the well-established role of hypocretin neurons in regulating feeding behavior and sleep, we hypothesize that hypocretinergic regulation of brain reward function may provide a mechanism by which appropriate and competing behaviors (e.g. sleep or feeding) may be engaged to maintain energy homeostasis.

The species of the cetacean and artiodactyl suborders, which constitute the order Cetartiodactyla, exhibit very different sleep phenomenology, with artiodactyls showing typical bihemispheric slow wave and REM sleep, while cetaceans show unihemispheric slow wave sleep and appear to lack REM sleep. The aim of this study was to determine whether cetaceans and artiodactyls have differently organized orexinergic arousal systems by examining the density of orexinergic innervation to the cerebral cortex, as this projection will be involved in various aspects of cortical arousal. This study provides a comparison of orexinergic bouton density in the cerebral cortex of twelve cetartiodactyl species (ten artiodactyls and two cetaceans) by means of immunohistochemical staining and stereological analysis.  It was found that the morphology of the axonal projections of the orexinergic system to the cerebral cortex was similar across all species, as the presence, size and proportion of large and small orexinergic boutons were similar. Despite this, orexinergic bouton density was lower in the cerebral cortex of the cetaceans studied compared to the artiodactyls studied, even when corrected for brain mass, neuron density, glial density and glial: neuron ratio. Principal component analysis indicates that glial density appears to be a major determinant for the observed differences between artiodactyl and cetacean cortical orexinergic bouton density.