Orexin, stress, and anxiety/panic states

doi:10.1016/B978-0-444-59489-1.00009-4

Progress in Brain Research

Volume 198, 2012, Pages 133-161

https://doi.org/10.1016/B978-0-444-59489-1.00009-4 Get rights and content

Abstract

A panic response is an adaptive response to deal with an imminent threat and consists of an integrated pattern of behavioral (aggression, fleeing, or freezing) and increased cardiorespiratory and endocrine responses that are highly conserved across vertebrate species. In the 1920s and 1940s, Philip Bard and Walter Hess, respectively, determined that the posterior regions of the hypothalamus are critical for a “fight-or-flight” reaction to deal with an imminent threat. Since the 1940s it was determined that the posterior hypothalamic panic area was located dorsal (perifornical hypothalamus: PeF) and dorsomedial (dorsomedial hypothalamus: DMH) to the fornix. This area is also critical for regulating circadian rhythms and in 1998, a novel wake-promoting neuropeptide called orexin (ORX)/hypocretin was discovered and determined to be almost exclusively synthesized in the DMH/PeF perifornical hypothalamus and adjacent lateral hypothalamus. The most proximally emergent role of ORX is in regulation of wakefulness through interactions with efferent systems that mediate arousal and energy homeostasis. A hypoactive ORX system is also linked to narcolepsy. However, ORX role in more complex emotional responses is emerging in more recent studies where ORX is linked to depression and anxiety states. Here, we review data that demonstrates ORX ability to mobilize a coordinated adaptive panic/defense response (anxiety, cardiorespiratory, and endocrine components), and summarize the evidence that supports a hyperactive ORX system being linked to pathological panic and anxiety states.

Section snippets

Orexin/hypocretin discovery and loss of function linked to narcolepsy

Orexins (ORXs) are hypothalamic neuropeptides that were simultaneously discovered in 1998 by two different research groups (de Lecea et al., 1998, Sakurai et al., 1998). They determined that there are two forms of ORXs, ORX-A and ORX-B (also, respectively, known as hypocretin 1 and 2), that are produced from a common prepro-ORX precursor that are endogenous ligands for the G-protein-coupled ORX1 and ORX2 receptors (see inset in Fig. 1a). The ORX1 receptor has greater affinity for ORX-A than

Efferent targets of orexin neurons

Although ORX neuronal projections are present throughout the brain, they are particularly dense in areas of the brain that mobilize different components of a panic response (Nambu et al., 1999, Peyron et al., 1998) such as the (1) stress and arousal systems—medial prefrontal cortex (mPFC; Gabbott et al., 2005, Kim and Whalen, 2009), cingulate cortex and monoaminergic systems (e.g., noradrenergic locus ceruleus (LC; Itoi and Sugimoto, 2010), serotonergic dorsal raphe nucleus (DRN; Lowry et al.,

Orexin role in mobilizing an integrative anxiety–panic response

ORX role in increasing anxiety states and coordinating an integrative panic/defense response in the presence of an imminent threat or following local disinhibition of the neurons in the PeF region that contains the ORX neurons, is a concept that has emerged slowly in comparison to studies indicating that the ORX system plays a role in sleep–wake cycle, feeding, and reward regulation. In the first 5 years following ORX discovery, initial physiology studies began demonstrating that ORX was

Orexin role in panic disorder

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks, which are unexpected bursts of severe anxiety that are accompanied by multiple physical symptoms with at least four characteristic symptoms such as tachycardia, hyperventilation, dyspnea, locomotor agitation, etc. (DSM-IV, 1994), and hence often referred to as “spontaneous.” Although initially occurring in “spontaneous” manner, panic attacks in patients with panic disorder can be reliably induced in the

Concluding remarks

Under nonstressful condition, ORX main role appears to be maintaining wakefulness and increasing vigilance and arousal during routine goal-oriented behavior. However, when confronted with threatening stress-related challenge, ORX also mobilizes an adaptive and integrative stress response that is comprised of anxiety-associated behavior, cardiorespiratory, and endocrine responses. There is also emerging evidence that the dysregulation of the ORX system contributes to pathologies associated with

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Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.
Enhanced low-gamma band power in the hippocampus and prefrontal cortex in a rat model of depression is reversed by orexin-1 receptor antagonism
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The hippocampal-prefrontal cortex network dynamics is reported to be involved in various cognitive functions and in different mood disturbances including depression. It has been suggested that blocking orexin-1 receptors can be beneficial in depression. The purpose of this study is to determine whether orexin-1 receptor antagonists have an impact on changes in brain oscillations in the hippocampus and prefrontal cortex in a rat model of depression. Forty-eight male Wistar rats were divided into six experimental groups: control, chronic mild stress (CMS), acute SB-334867, a selective orexin-1 receptor antagonist, treated rats (SB), chronic SB-treated (CSB), CMS+SB, and CMS+CSB. Two stainless steel recording electrodes were placed in the coordinates of the hippocampus (HPC) and the prefrontal cortex (PFC). After behavioral verification of the model, local field potentials were recorded at 1 kHz sampling frequency. The absolute power of different frequency bands was obtained using the Fast Fourier Transform (FFT) function, and the power spectral density (PSD) of each frequency band was calculated for each animal. In the CMS- treated animals, the low-gamma band power increased both in the HPC and PFC (p ≤ 0.05), which were reversed by chronic SB-334867 treatment (p ≤ 0.05). The alterations in theta, and high-gamma band power were not significant in CMS treated rats, while acute and chronic SB-334867 treatment diminished the theta and high-gamma band power (p ≤ 0.05), respectively. The hippocampal-prefrontal coherence decreased in the delta (p ≤ 0.01), theta (p ≤ 0.01), and alpha (p ≤ 0.05) band range of the CMS exposed rats. It is concluded that CMS boosts the low-gamma band power, which is reversed by CSB treatment. The low-frequency band coherence is attenuated after CMS treatment.
Mechanisms of pathogenesis and environmental moderators in preclinical models of compulsive-like behaviours
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Obsessive-compulsive and related disorders (OCRD) is an emergent class of psychiatric illnesses that contributes substantially to the global mental health disease burden. In particular, the prototypical illness, obsessive-compulsive disorder (OCD), has a profoundly deleterious effect on the quality of life of those with lived experience. Both clinical and preclinical studies have investigated the genetic and environmental influences contributing to the pathogenesis of obsessive-compulsive and related disorders. Significant progress has been made in recent years in our understanding of the genetics of OCD, along with the critical role of common environmental triggers (e.g., stress). Some of this progress can be attributed to the sophistication of rodent models used in the field, particularly genetic mutant models, which demonstrate promising construct, face, and predictive validity. However, there is a paucity of studies investigating how these genetic and environmental influences interact to precipitate the behavioural, cellular, and molecular changes that occur in OCD. In this review, we assert that preclinical studies offer a unique opportunity to carefully manipulate environmental and genetic factors, and in turn to interrogate gene-environment interactions and relevant downstream sequelae. Such studies may serve to provide a mechanistic framework to build our understanding of the pathogenesis of complex neuropsychiatric disorders such as OCD. Furthermore, understanding gene-environment interactions and pathogenic mechanisms will facilitate precision medicine and other future approaches to enhance treatment, reduce side-effects of therapeutic interventions, and improve the lives of those suffering from these devastating disorders.
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Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies. Advancing our understanding of the role of biological sex in the responses to sleep loss stands to greatly improve our ability to understand and treat health consequences of insufficient sleep. As such, this review discusses sex differences in response to sleep deprivation, with a focus on the sympathetic nervous system stress response and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We review sex differences in several stress-related consequences of sleep loss, including inflammation, learning and memory deficits, and mood related changes. Focusing on women's health, we discuss the effects of sleep deprivation during the peripartum period. In closing, we present neurobiological mechanisms, including the contribution of sex hormones, orexins, circadian timing systems, and astrocytic neuromodulation, that may underlie potential sex differences in sleep deprivation responses.
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Stress suppresses the sense of pain, a physiological phenomenon known as stress-induced analgesia (SIA). Brain orexin peptides regulate many physiological functions, including wakefulness and nociception. The contribution of the orexinergic system within the nucleus accumbens (NAc) in the modulation of antinociception induced by forced swim stress (FSS) remains unclear. The present study addressed the role of intra-accumbal orexin receptors in the antinociceptive responses induced by FSS during the persistent inflammatory pain model in the rat. Stereotaxic surgery was performed unilaterally on 106 adult male Wistar rats weighing 250–305 g. Different doses (1, 3, 10, and 30 nmol/ 0.5 μl DMSO) of orexin-1 receptor (OX1r) antagonist (SB334867) or OX2 receptor antagonist (TCS OX2 29) were administered into the NAc five minutes before exposure to FSS for a 6-min period. The formalin test was carried out using formalin injection (50 μl; 2.5%) into the rat's hind paw plantar surface, which induces biphasic pain-related responses. The first phase begins immediately after formalin infusion and takes 3–5 min. Subsequently, the late phase begins 15–20 min after formalin injection and takes 20–40 min. The findings demonstrated that intra-accumbal microinjection of SB334867 or TCS OX2 29 attenuated the FSS-induced antinociception in both phases of the formalin test, with the TCS OX2 29 showing higher potency. Moreover, the effect of TCS OX2 29 was more significant during the early phase of the formalin test. The results suggest that OX1 and OX2 receptors in the NAc might modulate the antinociceptive responses induced by the FSS.

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Chapter 9 - Orexin, stress, and anxiety/panic states

Abstract

Section snippets

Orexin/hypocretin discovery and loss of function linked to narcolepsy

Efferent targets of orexin neurons

Orexin role in mobilizing an integrative anxiety–panic response

Orexin role in panic disorder

Concluding remarks

Psychoneuroendocrinology

Behavioural Brain Research

Brain Research

Neuroscience

Biological Psychiatry

Brain Research

Biological Psychiatry

Brain Research

European Neuropsychopharmacology

European Journal of Pharmacology

Neuroscience Research

Cell

Brain Research

Biological Psychiatry

Brain Research

Neuroscience

Pharmacology, Biochemistry, and Behavior

Journal of Chemical Neuroanatomy

Neurobiology of Aging

Respiratory Physiology & Neurobiology

Brain Res.

Behav Brain Res.

Brain Research

Journal of the Autonomic Nervous System

Brain Research

European Journal of Pharmacology

Journal of Behavior Therapy and Experimental Psychiatry

Neuron

Trends in Neurosciences

Neuroscience

Behavioural Brain Research

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

Nature

Effects of unilateral lesions of retrotrapezoid nucleus on breathing in awake rats

Journal of Applied Physiology

GABA-mediated control of hypocretin- but not melanin-concentrating hormone-immunoreactive neurones during sleep in rats

The Journal of Physiology

Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurones in conscious rats

Journal of Neuroendocrinology

Synaptic correlates of fear extinction in the amygdala

Nature Neuroscience

Effect of local inhibition of gamma-aminobutyric acid uptake in the dorsomedial hypothalamus on extracellular levels of gamma-aminobutyric acid and on stress-induced tachycardia: A study using microdialysis

The Journal of Pharmacology and Experimental Therapeutics

Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology

Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: Focus on orexin targets involved in control of food and water intake

The European Journal of Neuroscience

Behavioral and cardiovascular effects of 7.5% CO2 in human volunteers

Depression and Anxiety

Stimulation of lateral septum CRF2 receptors promotes anorexia and stress-like behaviors: Functional homology to CRF1 receptors in basolateral amygdala

The Journal of Neuroscience

Evidence-based guidelines for the pharmacological treatment of anxiety disorders: Recommendations from the British Association for Psychopharmacology

Journal of Psychopharmacology

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders-First revision

The World Journal of Biological Psychiatry

A diencephalic mechanism for the expression of rage with special reference to the sympathetic nervous system

Am J Physiol.

Some forebrain mechanisms involved in the expression of rage with special reference to suppression of angry behavior

Res Publ Assoc Res Nerv Ment Dis.

Orexins (hypocretins) directly excite tuberomammillary neurons

The European Journal of Neuroscience

Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline)

The Journal of Neuroscience

Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology

Orexin (hypocretin) neurons contain dynorphin

The Journal of Neuroscience

Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms

The Journal of Neuroscience

Behavioral and cardiovascular effects of 7.5% CO₂ in human volunteers