Morgan H James, Jennifer E Fragale, Shayna L O'Connor, Benjamin A Zimmer, Gary Aston-Jones
An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report co-abusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators...
October 19, 2020: Neuropharmacology
Mojdeh Samzadeh, Ewa Papuć, Marzena Furtak-Niczyporuk, Konrad Rejdak
The effects of status epilepticus on the orexin/hypocretin system have yet to be investigated. The present study aimed to assay orexin-A/hypocretin-1 in the cerebrospinal fluid (CSF) of patients after generalized convulsive status epilepticus (GCSE). The study groups included 20 GCSE patients, 24 patients diagnosed with epilepsy but remaining in remission (ER), and 25 normal controls (CTR). Diagnostic lumbar puncture was performed in GCSE patients within 3-10 days of seizure cessation, as well as in the ER and to CTR subjects...
October 19, 2020: Journal of Clinical Medicine
Erin J Campbell, Mitchell Kri Hill, Xavier J Maddern, Shubo Jin, Terence Y Pang, Andrew J Lawrence
BACKGROUND: The lateral hypothalamic orexin (hypocretin) system has a well-established role in the motivation for reward. This has particular relevance to substance use disorders since orexin-1 receptors play a critical role in alcohol-seeking behavior, acting at multiple nodes in relapse-associated networks. AIMS: This study aimed to further our understanding of the role of orexin-1 receptor signaling within the lateral hypothalamus and bed nucleus of the stria terminalis, specifically in context-induced relapse to alcohol-seeking following punishment-imposed abstinence...
October 16, 2020: Journal of Psychopharmacology
Leila Kachooei-Mohaghegh-Yaghoobi, Fatemeh Rezaei-Rad, Khosro Sadeghniiat-Haghighi, Mahdi Zamani
Introduction: Narcolepsy is a chronic neurological and a genetic disorder of autoimmune origin, which is characterized by five main symptoms, including excessive day time sleepiness, sudden loss of muscle tone or cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. While there are several diagnostic tests for Narcolepsy such as MSLT (mean sleep latency test), polysomnography and low range of hypocretin in cerebrospinal fluid (CSF), sensitivity and specificity in these methodologies are not sufficient enough...
October 12, 2020: International Journal of Neuroscience
Yutaka Natori, Eisaku Sasaki, Shu Soeda, Shigenori Furukawa, Yusuke Azami, Emi Tokuda, Takashi Kanbayashi, Shigehira Saji
BACKGROUND: Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients. CASE PRESENTATION: A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab...
October 2020: Journal for Immunotherapy of Cancer
Katherine E Odegaard, Victoria L Schaal, Alexander R Clark, Sneh Koul, Austin Gowen, Jagadesan Sankarasubramani, Peng Xiao, Chittibabu Guda, Steven J Lisco, Sowmya V Yelamanchili, Gurudutt Pendyala
Prescription opioid abuse during and after pregnancy is a rising public health concern. While earlier studies have documented that offspring exposed to opioids in utero have impaired neurodevelopment, a significant knowledge gap remains in comparing the overall development between offspring exposed in utero and postnatally. Adding a layer of complexity is the role of heredity in the overall development of these exposed offspring. To fill in these important knowledge gaps, the current study uses a preclinical rat model mimicking oxycodone (oxy) exposure in utero (IUO) and postnatally (PNO) to investigate comparative and intergenerational effects in the two different treatment groups...
September 23, 2020: Translational Psychiatry
Lauren A Stone, Matthew J Girgenti, Jiawei Wang, Dingjue Ji, Hongyu Zhao, John H Krystal, Ronald S Duman
BACKGROUND: The molecular pathology underlying posttraumatic stress disorder (PTSD) remains unclear mainly due to a lack of human PTSD postmortem brain tissue. The orexigenic neuropeptides ghrelin, neuropeptide Y, and hypocretin have been recently implicated in modulating negative affect. Drawing from the largest functional genomics study of human PTSD postmortem tissue, we investigated whether there were molecular changes of these and other appetitive molecules. Further, we explored the interaction between PTSD and body mass index (BMI) on gene expression...
September 19, 2020: International Journal of Neuropsychopharmacology
James B Jaggard, Evan Lloyd, Anders Yuiska, Adam Patch, Yaouen Fily, Johanna E Kowalko, Lior Appelbaum, Erik R Duboue, Alex C Keene
Environmental perturbation can drive behavioral evolution and associated changes in brain structure and function. The Mexican fish species, Astyanax mexicanus , includes eyed river-dwelling surface populations and multiple independently evolved populations of blind cavefish. We used whole-brain imaging and neuronal mapping of 684 larval fish to generate neuroanatomical atlases of surface fish and three different cave populations. Analyses of brain region volume and neural circuits associated with cavefish behavior identified evolutionary convergence in hindbrain and hypothalamic expansion, and changes in neurotransmitter systems, including increased numbers of catecholamine and hypocretin/orexin neurons...
September 2020: Science Advances
Thomas Roth
​​ Excessive daytime sleepiness (EDS) is a hallmark symptom of narcolepsy. The second major symptom, cataplexy, is present only in a subgroup of patients with narcolepsy. Fortunately, existing pharmacologic interventions are effective in reducing EDS for many patients, but elimination of EDS for most patients has not been achieved. Some interventions also show efficacy in cataplexy. Nonpharmacologic strategies should also be discussed with patients to provide optimal narcolepsy management. Clinicians must monitor EDS during ongoing treatment so that residual symptoms can be addressed with adjustment to the regimen...
September 8, 2020: Journal of Clinical Psychiatry
Shi-Bin Li, Jeremy C Borniger, Hiroshi Yamaguchi, Julien Hédou, Brice Gaudilliere, Luis de Lecea
The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRHPVN ) and hypocretin neurons in the lateral hypothalamus (HcrtLH ). CRHPVN neurons directly innervate HcrtLH neurons, and optogenetic stimulation of LH-projecting CRHPVN neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the crh gene in CRHPVN neurons abolishes hyperarousal induced by stimulating LH-projecting CRHPVN neurons...
September 2020: Science Advances
Anelia Dietmann, Michael P Horn, Mink S Schinkelshoek, Rolf Fronczek, Anke Salmen, Panagiotis Bargiotas, Gert J Lammers, Ramin Khatami, Claudio L A Bassetti
Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF)...
August 7, 2020: Sleep Medicine
Berit Hjelde Hansen, Hilde T Juvodden, Sebjørg Hesla Nordstrand, Rannveig Viste, Per M Thorsby, David Swanson, Kristian B Nilsen, Terje Nærland, Stine Knudsen-Heier
OBJECTIVES: To characterize attention deficit-hyperactivity disorder (ADHD) symptoms in unmedicated post-H1N1 narcolepsy type 1 (NT1) youths, and explore associations between ADHD symptoms and the narcolepsy phenotype. METHODS: A total of 50 consecutively enrolled post-H1N1 NT1 youths (7-20 years, 62% females, 98% HLA-DQB1∗06:02-positive, 98% CSF hypocretin-1 deficient, 88% vaccinated) were assessed after two weeks off medication for ADHD (ADHD diagnosis pre/post-narcolepsy, parent-rated ADHD symptoms) and narcolepsy-phenotyped (semi-structured interview, Stanford Sleep Questionnaire, Epworth Sleepiness Scale, polysomnography (PSG), Multiple Sleep Latency Test (MSLT))...
June 18, 2020: Sleep Medicine
Kangyu Jin, Jing Lu, Zhebin Yu, Zhe Shen, Haimei Li, Tingting Mou, Yi Xu, Manli Huang
BACKGROUND: Cognitive impairment has long challenged the patients with major depressive disorder (MDD), hypocretins and inflammation have recently been implicated in cognitive function. However, limited studies have compressively assessed their associations with cognitive impairment in MDD. METHODS: A total of 100 MDD patients and 100 healthy controls (HC) were recruited for this study. They were tested with HAMD, HAMA, and MCCB scales. The plasma level of selected inflammatory factors (IL-1β, IL-6, and TNF-α) and hypocretin-1 were determined using enzyme-linked immunosorbent assay (ELISA)...
August 14, 2020: Journal of Affective Disorders
Irwin Gill, Aishling Sheils, Elaine Reade, Siobhan O'Malley, Aoife Carey, Maeve Muldoon, Abigail Wagle, Catherine Crowe, Bryan Lynch
AIM: To describe the population of young people in Ireland diagnosed with narcolepsy with regards to vaccine exposure, symptomatology, investigation results and experience of medical treatment. METHOD: Retrospective review of medical records at the single tertiary referral centre for young people with narcolepsy in Ireland. RESULTS: Sixty-seven patients were diagnosed with narcolepsy between July 2006 and July 2017. Sixty-one (91%) of these developed symptoms after receiving the Pandemrix vaccine...
August 4, 2020: European Journal of Paediatric Neurology: EJPN
Natalie J Michael, Joel K Elmquist
Orexin/hypocretin neurons located in the lateral hypothalamus play a critical role in the maintenance of arousal and contribute to the regulation of multiple homeostatic and behavioral processes. In this issue of the JCI, Tan and Hang et al. report that feeding a high-fat diet to mice compromised the function of the orexin system, leading to impairments in reward-seeking and active coping mechanisms. The researchers observed changes at the cellular and circuit levels suggesting that reduced excitability of orexin neurons affects behavior through induction of a hypoarousal state...
August 17, 2020: Journal of Clinical Investigation
Jennifer E Fragale, Morgan H James, Gary Aston-Jones
The orexin (hypocretin) system plays a critical role in motivated drug taking. Cocaine self-administration with the intermittent access (IntA) procedure produces a robust addiction-like state that is orexin-dependent. Here, we sought to determine the role of the orexin system in opioid addiction using IntA self-administration of fentanyl. Different groups of male rats were either given continuous access in 1-h period (short access [ShA]), 6-h period (long access [LgA]), or IntA (5 min of access separated by 25 min of no access for 6 h) to fentanyl for 14 days...
August 14, 2020: Addiction Biology
Emily C Barker, Julie Flygare, Shalini Paruthi, Katherine M Sharkey
Narcolepsy is a neurological disorder of the sleep-wake cycle characterized by excessive daytime sleepiness (EDS), cataplexy, nighttime sleep disturbances, and REM-sleep-related phenomena (sleep paralysis, hallucinations) that intrude into wakefulness. Dysfunction of the hypocretin/orexin system has been implicated as the underlying cause of narcolepsy with cataplexy. In most people with narcolepsy, symptom onset occurs between the ages of 10 and 35 years, but because the disorder is underrecognized and testing is complex, delays in diagnosis and treatment are common...
2020: Nature and Science of Sleep
Krister Melén, Pinja Jalkanen, Jyrki P Kukkonen, Markku Partinen, Hanna Nohynek, Arja Vuorela, Outi Vaarala, Tobias L Freitag, Seppo Meri, Ilkka Julkunen
Narcolepsy type 1, likely an immune-mediated disease, is characterized by excessive daytime sleepiness and cataplexy. The disease is strongly associated with human leukocyte antigen (HLA) DQB1∗06:02. A significant increase in the incidence of childhood and adolescent narcolepsy was observed after a vaccination campaign with AS03-adjuvanted Pandemrix influenza vaccine in Nordic and several other countries in 2010 and 2011. Previously, it has been suggested that a surface-exposed region of influenza A nucleoprotein, a structural component of the Pandemrix vaccine, shares amino acid residues with the first extracellular domain of the human OX2 orexin/hypocretin receptor eliciting the development of autoantibodies...
2020: Journal of translational autoimmunity
Hui Feng, Si-Yi Wen, Qi-Cheng Qiao, Yu-Jie Pang, Sheng-Yun Wang, Hao-Yi Li, Jiao Cai, Kai-Xuan Zhang, Jing Chen, Zhi-An Hu, Fen-Lan Luo, Guan-Zhong Wang, Nian Yang, Jun Zhang
The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings...
July 21, 2020: Nature Communications
Celia Garau, Craig Blomeley, Denis Burdakov
Hypothalamic orexin/hypocretin neurons integrate multiple sensory cues and project brain-wide to orchestrate multiple innate behaviours. Their loss impairs many context-appropriate actions, but the motivational characteristics of orexin cell activity remain unclear. We and others previously approached this question by artificial orexin stimulation, which could induce either rewarding (positive valence) and aversive (negative valence) brain activity. It is unknown to what extent such approaches replicate natural/endogenous orexin signals, which rapidly fluctuate during wakefulness...
July 15, 2020: Journal of Physiology
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