Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders
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Hypocretins are hypothalamic neuropeptides acting on the regulation of several physiological functions, the most important being the control of arousal. Hypocretin 1 and hypocretin 2 are derived from the same precursor and both bind to the orexin receptors. The hypocretinergic system has been a target of several studies that try to understand its function on the regulation of mood and behavior. The hypocretinergic system has a direct relationship with the pathways related to emotions and reward system, besides the interaction with the stress circuit. This article aims to analyze the relationship of hypocretins with anxiety, stress and depression, through a review of the existing literature.
KeywordsHypocretin Anxiety Depression Stress
OXR1 expression is observed in various brain regions, including the prefrontal and infralimbic cortex, hippocampus, amygdala, dorsal striatum nucleus, paraventricular thalamic nucleus, anterior hypothalamus, dorsal raphe and locus coeruleus [4, 5]. The OXR2 subtype is found in the amygdala, the nucleus of the dorsal striatum, paraventricular thalamic nucleus, dorsal raphe and peduncle–pontine nuclei and accumbens [4, 5]. Recent studies suggest that OXR1 is involved in various functions, especially regulation of emotion, reward system and autonomic function , while OXR2 is mainly involved in the regulation of wakefulness . This divergence in receptor functions is also observed in the regulation of mood and affect, having an important role in depression, anxiety and stress .
The hypocretinergic system is modulated by multiple endocrine signals and neural inputs from other areas, suggesting that this system is influenced by internal and external stimuli and is involved in several physiological functions, including the sleep–wake cycle, energetic metabolism, behavioral and neuroendocrinological responses to stress and reward system [9, 10, 11]. Diseases such as depression and anxiety, as well as conditions such as stress would affect this system, which will have the potential to modulate mood through its neuroanatomical projections and the expression of its receptors in certain brain regions .
Dysregulation of sleep/wake cycle predisposes to metabolic and psychiatric disorders . The evidences of the role of the hypocretinergic system on the modulation of several physiological functions and mental diseases emerged after the discovery of this system, 15 years ago . But the exact mechanism how this modulation occurs is not well known. In the last decade, a significant advance was made on the complex interactions between brain systems that control the transition of sleep and wake states . Recently, a lot of research has been done with OXR1 and OXR2 antagonists, promising therapeutic target and encouraging investments of the pharmaceutic industry on basics researches. The database of these pre-clinical studies is limited and the involvement of the hypocretinergic system is still questionable . Thus, the objective of the present study was to critically discuss the relationship between orexin and psychiatric disorders. Here, a literature search was conducted using the databases PubMed, ISI Web of Knowledge and PsycInfo combining the following terms: “hypocretin”, “depression”, “stress” and “schizophrenia”. All articles were published in English and without temporal restriction. Additional references were identified through hand search of the selected articles.
2 Hypocretin as Regulator of Waking State
3 Psychiatric Disorders Regulated by Hypocretins
The hypocretinergic system has been related with narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness [3, 31, 32, 33, 34, 35]. However, recent evidence has suggested that the hypocretinergic system is linked with other health issues, such as obesity, mood and other psychiatric disorders [28, 29, 36, 37, 38, 39]. This system has a close relationship (functional and anatomical) with pathways that regulate the autonomic system, mood, emotions and the reward system .
3.1 Mood Regulated by Hypocretins
The relationship between hypocretin and mood disorders, specifically depression, has received special attention in recent years with divergent findings among various authors. There has been an association between OXR1 gene polymorphism and mood disorders and high hypocretin levels correlated with positive content emotions and social interaction. In addition, non-genetic factors such as chronic stress also cause hypocretin to be involved in the pathogenesis of depression . The projection of hypocretinergic neurons to the hippocampus explains the involvement of this system in the learning and memory-related process of depression, known as learned helplessness [1, 2, 4, 40].
It is possible that dysregulation of the hypothalamic–pituitary–adrenal axis (HPA), which is often associated with major depression, is in part an inability of the paraventricular thalamic nucleus to adapt to chronic stress. More recent studies demonstrate that exposure to a stressor stimulus over a long period of time would lead to a downregulation of hypocretinergic activity. This early exposure to stress would increase the levels of hypocretin 1 in the hypothalamic regions and the expression of OXR1 in the frontal cortex; thus, there would be a consequent reduction in the synaptic availability of hypocretin (hypocretinergic dysfunction) . In contrast, in the case of patients with depression and their reduction after treatment with anti-depressant sertraline, Salomon et al.  demonstrated the opposite effect, reporting high levels of hypocretin 1 in CSF, unlike Schmidt et al. , who did not show any association between depression and cerebrospinal fluid levels of hypocretin.
Two hypotheses explain these divergent findings. First, we must consider that depression is a naturally heterogenic disease, influenced by environmental, genetic and comorbid factors [4, 8]. Second, recent studies report divergent roles for hypocretin receptors, and both exert functions that counterbalanced brain regions involved in mood regulation, such as the hippocampus, frontal tegmental area and prefrontal cortex [4, 8]. In the study by Scott et al. , knockout mice for OXR1 presented decrease in depressive symptoms, whereas knockout mice for OXR2 showed an increase of these symptoms.
3.2 Anxiety Regulated by Hypocretins
The subnuclei of the basolateral and central amygdala, the prefrontal cortex and the paraventricular thalamic nucleus are regions known to be involved in anxiety and all have hypocretinergic connections . The application of hypocretin 1 or 2 in the central sub-nucleus of the amygdala, rich in hypocretinergic projections, excites the neurons of this region producing an increase in anxious behavior [2, 11]. On the other hand, inhibition of glutamate and the action of OXR2 in the basolateral region would lead to a relief in anxiety. Studies have shown an increase in the release of hypocretin in the amygdala and in the cerebrospinal fluid of anxiety patients, suggesting a possible hyperactivity state of the hypocretinergic system in these patients [2, 11]. In these studies, the levels of hypocretin increased during wakefulness and fell during sleep, but the highest peak was during an acute emotional state, whether positive or negative.
The pre-limbic region of the prefrontal cortex would be, for anatomical and functional reasons, a potential area for the action of hypocretin in the regulation of anxiety, but no study has demonstrated this relationship. Heydendael et al.  have demonstrated that the stimulation of hypocretinergic receptors in the paraventricular thalamic nucleus produces fear and anxiety-like behavior and the blockade of these receptors in the same area has anxiolytic effects.
3.3 Stress Regulated by Hypocretins
The role of hypocretin in chronic stress occurs through the depolarization of neurons present in the paraventricular thalamic nucleus (PVN), a site rich in type 1 and 2 receptors. This nucleus plays an important role in the regulation of the neuroendocrine system and in the behavioral adaptation after a severe stressor stimulus. In chronic stress, it is necessary to reduce the circadian rhythm of body temperature and the activation of the hypothalamic–pituitary–adrenal (HPA) axis, and may also be the link between circadian cycle disorders, chronic stress and depression, mainly through the hypocretinergic pathways [4, 6].
Hypocretin would activate the HPA axis, including corticotrophin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone, stimulating stress behavior [9, 46]. The hypocretinergic system, in addition to receiving inputs from CRH-producing pathways, also sends projections that stimulate the brain regions responsible for the production of this hormone . This evidence suggests that these two systems are involved in stress management, although acting in different brain areas. While the CRH acts on the motor cortex, the prefrontal cortex, the dorsal portions of the caudate and putamen nuclei, the cingulate and amygdala, the hypocretin act on the nucleus accumbens, dorsal thalamus, amygdala, ventral hippocampus and frontal cortex . The region that has the largest neural network of CRH stimulation to the hypocretinergic neurons is the nucleus of the dorsal striatum (BNST), belonging to the limbic system .
3.4 Other Psychiatric Disorders Regulated by Hypocretins
Regarding psychiatric disorders, schizophrenia affects approximately 1% of the world’s population. This disease has been managed by using pharmacological means including compounds that interact with monoaminergic transmission [47, 48, 49, 50]. Recent data have suggested the putative role of hypocretin in modulation of schizophrenia . For example, Sansa and coworkers  reported that patients with schizophrenia showed positive correlation with human leukocyte antigen (HLA) DQB1*06:02. Importantly, narcolepsy with cataplexy has been strongly associated with the same HLA . Thus, it is likely that hypocretin might be present in patients with schizophrenia. Further studies have confirmed this observation. For instance, the plasma levels of hypocretin 1 in 127 patients with schizophrenia were determined. In patients, the clinical symptoms on the Positive and Negative Syndrome Scale for schizophrenia as well as executive function by the Wisconsin Card Sorting test (WCST) were assessed. Basically, it was found that patients with schizophrenia had higher levels of hypocretin 1 compared to healthy controls and schizophrenic patients tended to have lower perseverative errors and higher failures to maintain set in the WCST . These findings corroborated with previous studies  and the results are in concordance with posterior observations [37, 54]. Beyond the neurobiological role of hypocretin on the modulation of sleep–wake cycle, an accumulative body of evidence has suggested the putative influence of this peptidergic system in schizophrenia. Thus, a novel and interesting approach for targeting hypocretin for the development of novel antipsychotic medications remains to be elucidated.
4 Orexin Receptor Antagonists
New drugs involving the hypocretinergic system are being studied. Several different chemical structures can bind to one or both hypocretin receptors; when the antagonist binds to a single receptor, it is called SORAs, and dual antagonists are called DORAs. Four DORAs have undergone clinical trials: almorexant, suvorexant, filorexant and SB-649868. Only suvorexant went through phase 3 and it was filed in the USA and Japan as a new treatment for insomnia in 2013. It selectively blocks neuropeptides hypocretin 1 and 2 from binding to the orexin receptor types 1 and 2, suppressing wakefulness [10, 55]. The tight regulation of the sleep/wake cycle is critical for mental well-being and drugs that acts in this cycle could have a place in psychiatry. Significant progress has been made in the knowledge of the contribution of the orexin system to mental health; for example, several studies indicate that orexin antagonists, in particular selective OXR1 antagonist, can reduce drug seeking [4, 55]. There is data indicating that depression may be associated with decreased orexin system function, and this knowledge raises concerns for the long-term use of orexin antagonists. Therefore, a greater understanding of the changes to orexin receptor expression in the brain areas will be necessary to predict the outcomes of therapeutic manipulation of orexin signaling .
Hypocretin is involved in the modulation of several neurobiological systems, both central and peripheral, but the exact mechanism by which this modulation occurs is not well known. Growing interest has been seen toward this system and its role in modulating anxious and depressive behavior. Advances in orexin antagonists may lead to the development of new molecules for the treatment of sleep disorders and psychiatric conditions. New researches need to be done to understand all mechanisms involved in psychiatric disorders and the hypocretinergic system.
Compliance with Ethical Standards
All data reported in this paper are from public repositories.
Conflict of interest
The authors declare no conflict of interest.
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