|
1
|
Amodeo LR, Wills DN, Benedict J, Ehlers CL. Effects of daridorexant on rest/wake activity patterns and drinking in adult rats exposed to chronic ethanol vapor in adolescence. Alcohol 2025; 124:35-46. [PMID: 39870333 DOI: 10.1016/j.alcohol.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025]
Abstract
Disturbance in sleep and activity rhythms are significant health risks associated with alcohol use during adolescence. Many investigators support the theory of a reciprocal relationship between disrupted circadian rhythms, sleep patterns, and alcohol usage. However, in human studies it is difficult to disentangle other factors (i.e. lifestyle, psychiatric, genetic) when determining what is causal in the relationship between substance use and sleep/activity disruptions. To this end, we used an animal model of adolescent alcohol exposure whereby male and female Wistar rats are exposed to 5 weeks of intermittent alcohol vapor during adolescence (P22-P57). Five days after ethanol vapor rats were allowed to select to drink alcohol or water in a two-bottle choice procedure for a period of 5 h, 4 days a week for 6 weeks. Activity data was collected using a "Fitbit-like" device during vapor exposure, during acute withdrawal, and after 3 weeks of protracted withdrawal. Significant changes in rest/wake activity and circadian measures were seen during 24-h withdrawal and after 3 weeks of withdrawal. Four weeks following withdrawal, the effects of the dual orexin antagonist, Daridorexant, (DAX 30 mg, 100 mg, or vehicle control), on alcohol drinking and rest and activity rhythms were assessed over a 24 h period. Both daridorexant doses led to changes in circadian measures and rest/wake activity patterns. These results showed that daridorexant reduced activity, but it did not improve rest quality as measured by the mean inactive episode duration and inactive fragmentation ratio. Additionally, we did not find a significant difference in drinking behavior in animals treated with the orexin antagonist. Thus, it appears that data from this animal model do not support the use of this drug to improve adolescent alcohol-induced sleep disturbance and/or to decrease alcohol drinking.
Collapse
Affiliation(s)
- L R Amodeo
- Department of Psychology, California State University San Bernardino, San Bernardino, CA 92407, USA
| | - D N Wills
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - J Benedict
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - C L Ehlers
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
| |
Collapse
|
|
2
|
Flores-Ramirez FJ, Illenberger JM, Martin-Fardon R. Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior. Neurobiol Stress 2024; 33:100695. [PMID: 39640001 PMCID: PMC11617300 DOI: 10.1016/j.ynstr.2024.100695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 10/28/2024] [Accepted: 11/18/2024] [Indexed: 12/07/2024] Open
Abstract
A major challenge for the treatment of alcohol use disorder (AUD) is relapse to alcohol use, even after protracted periods of self-imposed abstinence. Stress significantly contributes to the chronic relapsing nature of AUD, given its long-lasting ability to elicit intense craving and precipitate relapse. As individuals transition to alcohol dependence, compensatory allostatic mechanisms result in insults to hypothalamic-pituitary-adrenal axis function, mediated by corticotropin-releasing factor (CRF), which is subsequently hypothesized to alter brain reward pathways, influence affect, elicit craving, and ultimately perpetuate problematic drinking and relapse vulnerability. Orexin (OX; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and has been shown to interact with CRF. Interestingly, most hypothalamic cells that express Ox mRNA also express Pdyn mRNA. Both dynorphin and OX are located in the same synaptic vesicles, and they are co-released. The infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) has emerged as being directly involved in the compulsive nature of alcohol consumption during dependence. The IL is a CRF-rich region that receives OX projections from the hypothalamus and where OX receptor mRNA has been detected. Although not thoroughly understood, anatomical and behavioral pharmacology data suggest that CRF, OX, and dynorphin may interact, particularly in the IL, and that functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects that may render them vulnerable to relapse. The present review presents evidence of the role of the IL in AUD and discusses functional interactions between CRF, OX, and dynorphin in this structure and how they are related to exacerbated alcohol drinking and seeking.
Collapse
Affiliation(s)
- Francisco J. Flores-Ramirez
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Psychology, California State University, San Marcos, CA, USA
| | | | - Rémi Martin-Fardon
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| |
Collapse
|
|
3
|
Chen ZK, Liu YY, Zhou JC, Chen GH, Liu CF, Qu WM, Huang ZL. Insomnia-related rodent models in drug discovery. Acta Pharmacol Sin 2024; 45:1777-1792. [PMID: 38671193 PMCID: PMC11335876 DOI: 10.1038/s41401-024-01269-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/24/2024] [Indexed: 04/28/2024]
Abstract
Despite the widespread prevalence and important medical impact of insomnia, effective agents with few side effects are lacking in clinics. This is most likely due to relatively poor understanding of the etiology and pathophysiology of insomnia, and the lack of appropriate animal models for screening new compounds. As the main homeostatic, circadian, and neurochemical modulations of sleep remain essentially similar between humans and rodents, rodent models are often used to elucidate the mechanisms of insomnia and to develop novel therapeutic targets. In this article, we focus on several rodent models of insomnia induced by stress, diseases, drugs, disruption of the circadian clock, and other means such as genetic manipulation of specific neuronal activity, respectively, which could be used to screen for novel hypnotics. Moreover, important advantages and constraints of some animal models are discussed. Finally, this review highlights that the rodent models of insomnia may play a crucial role in novel drug development to optimize the management of insomnia.
Collapse
Affiliation(s)
- Ze-Ka Chen
- Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yuan-Yuan Liu
- Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ji-Chuan Zhou
- Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Gui-Hai Chen
- Department of Neurology (Sleep Disorders), the Affiliated Chaohu Hospital of Anhui Medical University, Hefei, 238000, China
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
| | - Wei-Min Qu
- Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Zhi-Li Huang
- Department of Pharmacology, School of Basic Medical Sciences; State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science; Joint International Research Laboratory of Sleep; and Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
4
|
Kukkonen JP, Jacobson LH, Hoyer D, Rinne MK, Borgland SL. International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology. Pharmacol Rev 2024; 76:625-688. [PMID: 38902035 DOI: 10.1124/pharmrev.123.000953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 06/02/2024] [Accepted: 06/06/2024] [Indexed: 06/22/2024] Open
Abstract
The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX1 and OX2 Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.
Collapse
Affiliation(s)
- Jyrki P Kukkonen
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland (J.P.K., M.K.R.); Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne (D.H., L.H.J.), The Florey (D.H., L.H.J.), Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.); and Department of Physiology and Pharmacology, University of Calgary, Calgary Canada (S.L.B.)
| | - Laura H Jacobson
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland (J.P.K., M.K.R.); Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne (D.H., L.H.J.), The Florey (D.H., L.H.J.), Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.); and Department of Physiology and Pharmacology, University of Calgary, Calgary Canada (S.L.B.)
| | - Daniel Hoyer
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland (J.P.K., M.K.R.); Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne (D.H., L.H.J.), The Florey (D.H., L.H.J.), Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.); and Department of Physiology and Pharmacology, University of Calgary, Calgary Canada (S.L.B.)
| | - Maiju K Rinne
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland (J.P.K., M.K.R.); Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne (D.H., L.H.J.), The Florey (D.H., L.H.J.), Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.); and Department of Physiology and Pharmacology, University of Calgary, Calgary Canada (S.L.B.)
| | - Stephanie L Borgland
- Department of Pharmacology, Medicum, University of Helsinki, Helsinki, Finland (J.P.K., M.K.R.); Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne (D.H., L.H.J.), The Florey (D.H., L.H.J.), Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.); and Department of Physiology and Pharmacology, University of Calgary, Calgary Canada (S.L.B.)
| |
Collapse
|
|
5
|
Bennett HC, Zhang Q, Wu YT, Manjila SB, Chon U, Shin D, Vanselow DJ, Pi HJ, Drew PJ, Kim Y. Aging drives cerebrovascular network remodeling and functional changes in the mouse brain. Nat Commun 2024; 15:6398. [PMID: 39080289 PMCID: PMC11289283 DOI: 10.1038/s41467-024-50559-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 07/15/2024] [Indexed: 08/02/2024] Open
Abstract
Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brain vascular tracing shows an overall ~10% decrease in vascular length and branching density with ~7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling reveals increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities show selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We find increased blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice demonstrates reduced baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.
Collapse
Affiliation(s)
- Hannah C Bennett
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Qingguang Zhang
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA
- Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA
| | - Yuan-Ting Wu
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
- Department of Neurosurgery, Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Steffy B Manjila
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Uree Chon
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
- Neurosciences Graduate Program, Stanford University, Stanford, CA, 94305, USA
| | - Donghui Shin
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Daniel J Vanselow
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Hyun-Jae Pi
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Patrick J Drew
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA
- Department of Biomedical Engineering, Biology, and Neurosurgery, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Yongsoo Kim
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA.
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA.
| |
Collapse
|
|
6
|
Shan L, Wu Y, Lao J, Ma M, Luo X, Zheng K, Hu W, Kang Y, Wang F, Liu Y, Xu Y, Jin X. The positive impact of smoking on poor sleep quality is moderated by IGF1 levels in cerebrospinal fluid: a case-control study among Chinese adults. Front Psychiatry 2024; 15:1392732. [PMID: 38800060 PMCID: PMC11116786 DOI: 10.3389/fpsyt.2024.1392732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024] Open
Abstract
Objective Previous research indicates associations between cigarette smoking, insulin-like growth factor-1 (IGF1), and sleep disturbances. This study aimed to examine the association between smoking and sleep quality and investigate the moderating role of IGF1. Methods This case-control study involved 146 Chinese adult males (53 active smokers and 93 non-smokers) from September 2014 to January 2016. Sleep quality and disturbances were evaluated using the Pittsburgh Sleep Quality Index (PSQI), which includes seven scales. Pearson correlation analysis and logistic regression analysis were utilized to examine the link between IGF1 levels in cerebrospinal fluid (CSF) and PSQI scores. The effect of IGF1 was assessed using the moderation effect and simple slope analysis, with adjustments made for potential confounders. Results Active smokers exhibited significantly higher global PSQI scores and lower IGF1 levels in CSF compared to non-smokers. A significant negative correlation was observed between IGF1 and PSQI scores (â = -0.28, P < 0.001), with a stronger association in non-smokers (Pearson r = -0.30) compared to smokers (Pearson r = -0.01). Smoking was associated with higher global PSQI scores (â = 0.282, P < 0.001), and this association was moderated by IGF1 levels in CSF (â = 0.145, P < 0.05), with a stronger effect at high IGF1 levels (Bsimple = 0.402, p < 0.001) compared to low IGF1 levels (Bsimple = 0.112, p = 0.268). Four subgroup analysis revealed similar results for sleep disturbances (Bsimple = 0.628, P < 0.001), with a marginal moderation effect observed on subjective sleep quality (Bsimple = 0.150, P = 0.070). However, independent associations rather than moderating effects were observed between IGF1 and sleep efficiency and daytime disturbance. Conclusion We provided evidence to demonstrate the moderation effect of IGF1 on the relationship between smoking and sleep in CSF among Chinese adult males.
Collapse
Affiliation(s)
- Ligang Shan
- Department of Anesthesiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
| | - Yuyu Wu
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jiaying Lao
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mingwei Ma
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xingguang Luo
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Ke Zheng
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, China
| | - Weiming Hu
- Department of Psychiatry, The Third Hospital of Quzhou, Quzhou, China
| | - Yimin Kang
- Psychosomatic Medicine Research Division, Inner Mongolia Medical University, Hohhot, China
| | - Fan Wang
- Beijing Huilongguan Hospital, Peking University, Beijing, China
| | - Yanlong Liu
- School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yali Xu
- Infection Control Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaoya Jin
- Infection Control Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| |
Collapse
|
|
7
|
Kron JOZJ, Keenan RJ, Hoyer D, Jacobson LH. Orexin Receptor Antagonism: Normalizing Sleep Architecture in Old Age and Disease. Annu Rev Pharmacol Toxicol 2024; 64:359-386. [PMID: 37708433 DOI: 10.1146/annurev-pharmtox-040323-031929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/16/2023]
Abstract
Sleep is essential for human well-being, yet the quality and quantity of sleep reduce as age advances. Older persons (>65 years old) are more at risk of disorders accompanied and/or exacerbated by poor sleep. Furthermore, evidence supports a bidirectional relationship between disrupted sleep and Alzheimer's disease (AD) or related dementias. Orexin/hypocretin neuropeptides stabilize wakefulness, and several orexin receptor antagonists (ORAs) are approved for the treatment of insomnia in adults. Dysregulation of the orexin system occurs in aging and AD, positioning ORAs as advantageous for these populations. Indeed, several clinical studies indicate that ORAs are efficacious hypnotics in older persons and dementia patients and, as in adults, are generally well tolerated. ORAs are likely to be more effective when administered early in sleep/wake dysregulation to reestablish good sleep/wake-related behaviors and reduce the accumulation of dementia-associated proteinopathic substrates. Improving sleep in aging and dementia represents a tremendous opportunity to benefit patients, caregivers, and health systems.
Collapse
Affiliation(s)
- Jarrah O-Z J Kron
- The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia;
| | - Ryan J Keenan
- The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia;
- Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Daniel Hoyer
- The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia;
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia;
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
| | - Laura H Jacobson
- The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia;
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia;
| |
Collapse
|
|
8
|
Eisen A, Vucic S, Mitsumoto H. History of ALS and the competing theories on pathogenesis: IFCN handbook chapter. Clin Neurophysiol Pract 2023; 9:1-12. [PMID: 38213309 PMCID: PMC10776891 DOI: 10.1016/j.cnp.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/07/2023] [Accepted: 11/28/2023] [Indexed: 01/13/2024] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the human motor system, first described in the 19th Century. The etiology of ALS appears to be multifactorial, with a complex interaction of genetic, epigenetic, and environmental factors underlying the onset of disease. Importantly, there are no known naturally occurring animal models, and transgenic mouse models fail to faithfully reproduce ALS as it manifests in patients. Debate as to the site of onset of ALS remain, with three competing theories proposed, including (i) the dying-forward hypothesis, whereby motor neuron degeneration is mediated by hyperexcitable corticomotoneurons via an anterograde transsynaptic excitotoxic mechanism, (ii) dying-back hypothesis, proposing the ALS begins in the peripheral nervous system with a toxic factor(s) retrogradely transported into the central nervous system and mediating upper motor neuron dysfunction, and (iii) independent hypothesis, suggesting that upper and lower motor neuron degenerated independently. Transcranial magnetic stimulation studies, along with pathological and genetic findings have supported the dying forward hypothesis theory, although the science is yet to be settled. The review provides a historical overview of ALS, discusses phenotypes and likely pathogenic mechanisms.
Collapse
Affiliation(s)
- Andrew Eisen
- Division of Neurology, Department of Medicine, University of British Columbia, Canada
| | - Steve Vucic
- Director Brain and Nerve Research Center, Clinical School, University of Sydney, Australia
| | - Hiroshi Mitsumoto
- Wesley J. Howe Professor of Neurology, Columbia University, The Neurological Institute of New York, and New York-Presbyterian Hospital/Columbia University Medical Center, United States
| |
Collapse
|
|
9
|
Zhou M, Li Y. Effect of different doses of almorexant on learning and memory in 8-month-old APP/PS1 (AD) mice. Peptides 2023; 167:171044. [PMID: 37330110 DOI: 10.1016/j.peptides.2023.171044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/09/2023] [Accepted: 06/09/2023] [Indexed: 06/19/2023]
Abstract
OBJECTIVE To explore the effects of different doses of almorexant (an dual orexin receptor antagonist) on learning and memory in Alzheimer's disease (AD) mice. METHODS Forty-four APP/PS1 (model of Alzheimer's disease; AD) mice were randomly divided into 4 groups: the control group (CON) and those that received 10mg/kg almorexant (low dose; LOW), 30mg/kg almorexant (medium dose; MED) and 60mg/kg almorexant (high dose; HIGH). During the 28-day intervention period, mice received an intraperitoneal injection at the beginning of the light period (6:00 am). The effects of different doses of almorexant on learning and memory and 24-hour sleep-wake behaviour were assessed by immunohistochemical staining. The above continuous variables are expressed as the mean ± standard deviation (SD), and then univariate regression analysis and generalized estimating equations were performed to compare the groups; these results are expressed as the mean difference (MD) and 95% confidence interval (CI). The statistical software used STATA 17.0 MP. RESULTS Forty-one mice completed the experiment (3 died: 2 mice in the HIGH group and 1 mouse in the CON group). Compared with the CON group, the LOW group (MD=6,803s, 95% CI: 4,470 to 9,137s), MED group (MD=14,473s, 95% CI: 12,140 to 16,806s) and the HIGH group (MD=24,505s, 95% CI: 22,052 to 26,959s) had significantly longer sleep durations. The Y maze results showed that LOW group (MD=0.14,95%CI: 0.078 to 0.20) and MED group (MD=0.14,95%CI = 0.074 to 0.20) mice compared to the CON group, and the low-medium dose of Almorexant did not damage the short-term learning and memory performance of APP / PS1 (AD) mice.Compared with the CON, LOW, and MED groups, the HIGH group exhibited a significant decrease in the Aβ plaque-positive area in the cortex (MD= -0.030, 95% CI: -0.035 to -0.025; MD=-0.049, 95% CI: -0.054 to -0.044; and MD=-0.07, 95% CI: -0.076 to -0.066, respectively). CONCLUSION The moderate dose of almorexant (30mg/kg) prolonged the sleep duration of APP/PS1 (AD) mice to a greater extent than the low dose (10mg/kg) without altering learning and memory. The MED mice showed a good sleep response and a small residual effect on the next day. High-dose (60mg / kg) almorexant impaired behavioral learning and memory performance in mice.Compared to the CON group and the LOW group, the MED group exhibited improved working memory. Thus, treatment with almorexant may reduce β-amyloid deposition in AD, slowing neurodegeneration. Additional studies are needed to determine the mechanism of action.
Collapse
Affiliation(s)
- Mengzhen Zhou
- Department of Neurology, Qianfo Mountain Hospital affiliated to Shandong First Medical University ，Jinan, Shandong, China.
| | - Yanran Li
- Department of Neurology, Qianfo Mountain Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
| |
Collapse
|
|
10
|
Bennett HC, Zhang Q, Wu YT, Chon U, Pi HJ, Drew PJ, Kim Y. Aging drives cerebrovascular network remodeling and functional changes in the mouse brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.23.541998. [PMID: 37305850 PMCID: PMC10257218 DOI: 10.1101/2023.05.23.541998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall ~10% decrease in vascular length and branching density, and light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity in aged brains. Vasculature and pericyte densities showed significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. Moreover, in vivo imaging in awake mice identified delays in neurovascular coupling and disrupted blood oxygenation. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging.
Collapse
Affiliation(s)
- Hannah C Bennett
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
- Equal contribution
| | - Qingguang Zhang
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA
- Equal contribution
| | - Yuan-Ting Wu
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Uree Chon
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Hyun-Jae Pi
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
| | - Patrick J Drew
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA
- Biomedical Engineering, Biology, and Neurosurgery, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Yongsoo Kim
- Department of Neural and Behavioral Sciences, The Pennsylvania State University, Hershey, PA, 17033, USA
- Center for Neural Engineering, Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA, 16802, USA
- Lead contact
| |
Collapse
|
|
11
|
Tereshchenko SY. Neurobiological risk factors for problematic social media use as a specific form of Internet addiction: A narrative review. World J Psychiatry 2023; 13:160-173. [PMID: 37303928 PMCID: PMC10251362 DOI: 10.5498/wjp.v13.i5.160] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/13/2023] [Accepted: 04/07/2023] [Indexed: 05/19/2023] Open
Abstract
Problematic social media use (PSMU) is a behavioral addiction, a specific form of problematic Internet use associated with the uncontrolled use of social networks. It is typical mostly for modern adolescents and young adults, which are the first generations fully grown up in the era of total digitalization of society. The modern biopsychosocial model of the formation of behavioral addictions, postulating the impact of a large number of biological, psychological, and social factors on addictive behavior formation, may be quite applicable to PSMU. In this narrative review, we discussed neurobiological risk factors for Internet addiction with a focus on current evidence on the association between PSMU and structural/ functional characteristics of the brain and autonomic nervous system, neurochemical correlations, and genetic features. A review of the literature shows that the vast majority of the mentioned neurobiological studies were focused on computer games addiction and generalized Internet addiction (without taking into account the consumed content). Even though a certain number of neuroimaging studies have been conducted for PSMU, there is practically no research on neuropeptide and genetic associations for PSMU to date. This fact points to the extremely high relevance of such studies.
Collapse
Affiliation(s)
- Sergey Yu Tereshchenko
- Department of Child's Physical and Mental Health, Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences”, Research Institute of Medical Problems of the North, Krasnoyarsk 660022, Russia
| |
Collapse
|
|
12
|
Zhou M, Tang S. Effect of a dual orexin receptor antagonist on Alzheimer's disease: Sleep disorders and cognition. Front Med (Lausanne) 2023; 9:984227. [PMID: 36816725 PMCID: PMC9929354 DOI: 10.3389/fmed.2022.984227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 11/18/2022] [Indexed: 02/04/2023] Open
Abstract
Orexin is a neuropeptide produced by the lateral hypothalamus that plays an important role in regulating the sleep-wake cycle. The overexpression of the orexinergic system may be related to the pathology of sleep/wakefulness disorders in Alzheimer's disease (AD). In AD patients, the increase in cerebrospinal fluid orexin levels is associated with parallel sleep deterioration. Dual orexin receptor antagonist (DORA) can not only treat the sleep-wakefulness disorder of AD but also improve the performance of patients with cognitive behavior disorder. It is critical to clarify the role of the orexin system in AD, study its relationship with cognitive decline in AD, and evaluate the safety and efficacy of DORA.
Collapse
Affiliation(s)
- Mengzhen Zhou
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Shi Tang
- Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China,*Correspondence: Shi Tang
| |
Collapse
|
|
13
|
Zhou M, Tang J, Li S, Li Y, Zhao M. Orexin dual receptor antagonists, zolpidem, zopiclone, eszopiclone, and cognitive research: A comprehensive dose-response meta-analysis. Front Hum Neurosci 2023; 16:1029554. [PMID: 36699960 PMCID: PMC9869688 DOI: 10.3389/fnhum.2022.1029554] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/31/2022] [Indexed: 01/11/2023] Open
Abstract
Background About one-third of adults have trouble sleeping, ranging from occasional difficulty to chronic insomnia, along with difficulty maintaining sleep. Many studies reported that the long-term use of hypnotics can cause brain dysfunction and damage cognition. Objective The objective of the study is to evaluate whether low, medium, and high doses of orexin dual receptor antagonists (DORA), zopiclone (ZOP), eszopiclone (ESZ), and zolpidem (ZST) can impair cognition. Methods From the beginning through September 20, 2022, PubMed, Embase, Scopus, the Cochrane Library, and Google Scholar were searched. Randomized controlled trials (RCTs) assessing the therapeutic effects of DORA, eszopiclone, and zopiclone for sleep and cognitive function were included. The primary outcomes were indices related to the cognitive profile, including memory, alertness, execution and control function, and attention and orientation. The secondary outcomes were indices related to sleep and adverse events. The standard mean difference (SMD) was generated for continuous variables. Certain data were captured from figures by GetData 2.26 and analyzed using RStudio 4.2. Results Finally, a total of 8,702 subjects were included in 29 studies. Compared with the placebo, the DSST (Digit Symbol Substitution Test) scores of low, medium, and high doses of DORA were SMD = 0.77; 95% CI: 0.33-1.20; SMD = 1.58; 95% CI: 1.11-2.05; and SMD = 0.85; 95% CI: 0.33-1.36, respectively. The DSST scores of zolpidem at low, medium, and high doses were SMD = -0.39; 95% CI: 0.85-0.07; SMD = -0.88, 95% CI: -2.34-0.58; and SMD = -0.12, 95% CI: -0.85-0.60, respectively. Zopiclone's DSST scale score was SMD = -0.18; 95% CI: -0.54-0.18. In addition, the total sleep time (TST) of low, medium, and high doses of DORA was SMD = 0.28, 95% CI: -0.15-0.70; SMD = 1.36, 95% CI: 0.87-1.86; and SMD = 2.59, 95% CI: 1.89-3.30, respectively. The TST of zolpidem with low, medium, and high doses was SMD = 1.01, 95% CI: 0.18-1.83; SMD = 1.94, 95% CI: 0.46-3.43; and SMD = 1.71, 95% CI: 0.86-2.56, respectively. The TST of low, medium, and high doses of eszopiclone was relatively SMD = 2.03, 95% CI: -0.21-4.27; SMD = 2.38, 95% CI: 1.35-3.42; and SMD = 1.71, 95% CI: 0.60-2.82. Zopiclone's TST was SMD = 2.47, 95% CI: 1.36-3.58. Conclusion We recommend DORA as the best intervention for insomnia because it is highly effective in inducing and maintaining sleep without impairing cognition. Although zolpidem has a more pronounced effect on maintaining sleep, it is best to reduce its use because of its side effects. Eszopiclone and zopiclone improved sleep quality, but their safety in cognition remains to be verified.
Collapse
Affiliation(s)
- Mengzhen Zhou
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Jiyou Tang
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China,*Correspondence: Jiyou Tang
| | - Shasha Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Yaran Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Mengke Zhao
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical University, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning, China
| |
Collapse
|
|
14
|
Illenberger JM, Flores-Ramirez FJ, Matzeu A, Mason BJ, Martin-Fardon R. Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats. Front Pharmacol 2023; 14:1127735. [PMID: 37180716 PMCID: PMC10172671 DOI: 10.3389/fphar.2023.1127735] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 04/17/2023] [Indexed: 05/16/2023] Open
Abstract
Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse. Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0-20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD. Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females. Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.
Collapse
|
|
15
|
Shakerinava P, Sayarnezhad A, Karimi-Haghighi S, Mesgar S, Haghparast A. Antagonism of the orexin receptors in the ventral tegmental area diminished the stress-induced analgesia in persistent inflammatory pain. Neuropeptides 2022; 96:102291. [PMID: 36155089 DOI: 10.1016/j.npep.2022.102291] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/26/2022] [Accepted: 09/13/2022] [Indexed: 10/14/2022]
Abstract
As a part of descending pain inhibitory system, orexin (OXs) in the ventral tegmental area (VTA) are implicated in nociceptive responses. The current study aimed to evaluate the role of OX receptors (OXRs) in the VTA in stress-induced analgesia in persistent inflammatory pain. Ninety-nine adult male Wistar rats underwent forced swim stress (FSS) following intra-VTA infusion of various doses of SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol/0.3 μL) as an OX1R or OX2R antagonist, respectively. The nociceptive threshold was evaluated using the formalin test as an animal model of persistent inflammatory pain. Current results demonstrated FSS as acute stress produced analgesic responses in the persistent inflammatory pain. Moreover, either OX1R or OX2R antagonist infusion in the VTA hindered the FSS-induced analgesia in both early and late phases. The inhibitory effect of SB334768 in the FSS-induced analgesia was stronger than TCS OX2 29 in both early and late phases of the formalin test. Neither SB334768 nor TCS OX2 29 alone affects pain-related behaviors in formalin tests. Intra-VTA microinjection of each treatment could not modify locomotion in rats. The findings suggest that OX1R and OX2R in the VTA are implicated in FSS-induced analgesia mechanisms.
Collapse
Affiliation(s)
- Pedram Shakerinava
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Sayarnezhad
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeideh Karimi-Haghighi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Community Based Psychiatric Care Research Center, School of Nursing and Midwifery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somaye Mesgar
- Neurobiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
16
|
Kourosh-Arami M, Gholami M, Alavi-Kakhki SS, Komaki A. Neural correlates and potential targets for the contribution of orexin to addiction in cortical and subcortical areas. Neuropeptides 2022; 95:102259. [PMID: 35714437 DOI: 10.1016/j.npep.2022.102259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 05/14/2022] [Accepted: 05/15/2022] [Indexed: 02/01/2023]
Abstract
The orexin (hypocretin) is one of the hypothalamic neuropeptides that plays a critical role in some behaviors including feeding, sleep, arousal, reward processing, and drug addiction. This variety of functions can be described by a united function for orexins in translating states of heightened motivation, for example during physiological requirement states or following exposure to reward opportunities, into planned goal-directed behaviors. An addicted state is characterized by robust activation of orexin neurons from the environment, which triggers downstream circuits to facilitate behavior directed towards obtaining the drug. Two orexin receptors 1 (OX1R) and 2 (OX2R) are widely distributed in the brain. Here, we will introduce and describe the cortical and subcortical brain areas involved in addictive-like behaviors and the impact of orexin on addiction.
Collapse
Affiliation(s)
- Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Masoumeh Gholami
- Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Seyed Sajjad Alavi-Kakhki
- Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Alireza Komaki
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
17
|
Stoops WW, Strickland JC, Hatton KW, Hays LR, Rayapati AO, Lile JA, Rush CR. Suvorexant maintenance enhances the reinforcing but not subjective and physiological effects of intravenous cocaine in humans. Pharmacol Biochem Behav 2022; 220:173466. [PMID: 36152876 PMCID: PMC9588557 DOI: 10.1016/j.pbb.2022.173466] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/19/2022] [Indexed: 10/14/2022]
Abstract
Preclinical research has sought to understand the role of the orexin system in cocaine addiction given the connection between orexin producing cells in the lateral hypothalamus and brain limbic areas. Exogenous administration of orexin peptides increased cocaine self-administration whereas selective orexin-1 receptor antagonists reduced cocaine self-administration in non-human animals. The first clinically available orexin antagonist, suvorexant (a dual orexin-1 and orexin-2 receptor antagonist), attenuated motivation for cocaine and cocaine conditioned place preference, as well as cocaine-associated impulsive responding, in rodents. This study aimed to translate those preclinical findings and determine whether suvorexant maintenance altered the pharmacodynamic effects of cocaine in humans. Seven non-treatment seeking subjects with cocaine use disorder completed this within-subject human laboratory study, and a partial data set was obtained from one additional subject. Subjects were maintained for at least three days on 0, 5, 10 and 20 mg oral suvorexant administered at 2230 h daily in random order. Subjects completed experimental sessions in which cocaine self-administration of 0, 10 and 30 mg/70 kg of intravenous cocaine was evaluated on a concurrent progressive ratio drug versus money choice task. Subjective and physiological effects of cocaine were also determined. Cocaine functioned as a reinforcer and produced prototypic dose-related subjective and physiological effects (e.g., increased ratings of "Stimulated" and heart rate). Suvorexant (10, 20 mg) increased self-administration of 10 mg/70 kg cocaine and decreased oral temperature but did not significantly alter any other effects of cocaine. Future research may seek to evaluate the effects of orexin-1 selective antagonists in combination with cocaine.
Collapse
Affiliation(s)
- William W Stoops
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA; Center on Drug and Alcohol Research, University of Kentucky College of Medicine, 845 Angliana Avenue, Lexington, KY 40508, USA.
| | - Justin C Strickland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA
| | - Kevin W Hatton
- Department of Anesthesiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536, USA
| | - Lon R Hays
- Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA
| | - Abner O Rayapati
- Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA
| | - Joshua A Lile
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA
| | - Craig R Rush
- Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Lexington, KY 40536-0086, USA; Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY 40509-1810, USA; Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY 40506-0044, USA
| |
Collapse
|
|
18
|
Abstract
The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.
Collapse
Affiliation(s)
- Laura H Jacobson
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Daniel Hoyer
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
| | - Luis de Lecea
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA
| |
Collapse
|
|
19
|
Dale NC, Hoyer D, Jacobson LH, Pfleger KDG, Johnstone EKM. Orexin Signaling: A Complex, Multifaceted Process. Front Cell Neurosci 2022; 16:812359. [PMID: 35496914 PMCID: PMC9044999 DOI: 10.3389/fncel.2022.812359] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/07/2022] [Indexed: 11/15/2022] Open
Abstract
The orexin system comprises two G protein-coupled receptors, OX1 and OX2 receptors (OX1R and OX2R, respectively), along with two endogenous agonists cleaved from a common precursor (prepro-orexin), orexin-A (OX-A) and orexin-B (OX-B). For the receptors, a complex array of signaling behaviors has been reported. In particular, it becomes obvious that orexin receptor coupling is very diverse and can be tissue-, cell- and context-dependent. Here, the early signal transduction interactions of the orexin receptors will be discussed in depth, with particular emphasis on the direct G protein interactions of each receptor. In doing so, it is evident that ligands, additional receptor-protein interactions and cellular environment all play important roles in the G protein coupling profiles of the orexin receptors. This has potential implications for our understanding of the orexin system's function in vivo in both central and peripheral environments, as well as the development of novel agonists, antagonists and possibly allosteric modulators targeting the orexin system.
Collapse
Affiliation(s)
- Natasha C. Dale
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, VIC, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Perth, WA, Australia
| | - Daniel Hoyer
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States
| | - Laura H. Jacobson
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Kevin D. G. Pfleger
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, VIC, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Perth, WA, Australia
- Dimerix Limited, Nedlands, WA, Australia
| | - Elizabeth K. M. Johnstone
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Nedlands, WA, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Melbourne, VIC, Australia
- Australian Research Council Centre for Personalised Therapeutics Technologies, Perth, WA, Australia
- School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| |
Collapse
|
|
20
|
Keenan RJ, Daykin H, Chu J, Cornthwaite-Duncan L, Allocca G, Hoyer D, Jacobson LH. Differential sleep/wake response and sex effects following acute suvorexant, MK-1064 and zolpidem administration in the rTg4510 mouse model of tauopathy. Br J Pharmacol 2022; 179:3403-3417. [PMID: 35112344 PMCID: PMC9302982 DOI: 10.1111/bph.15813] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 01/06/2022] [Accepted: 01/28/2022] [Indexed: 12/02/2022] Open
Abstract
Background and Purpose Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep‐promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy‐related disorders. Experimental Approach This study examined polysomnographic recordings in 6‐6.5‐month‐old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg−1), MK‐1064 (30 mg·kg−1) or zolpidem (10 mg·kg−1), administered at the commencement of the active phase. Key Results Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK‐1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK‐1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK‐1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. Conclusions and Implications Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK‐1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.
Collapse
Affiliation(s)
- Ryan J Keenan
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Heather Daykin
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Jiahui Chu
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Linda Cornthwaite-Duncan
- Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Giancarlo Allocca
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Somnivore Inc. Ltd. Pty, Bacchus Marsh, Victoria, Australia
| | - Daniel Hoyer
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
| | - Laura H Jacobson
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria, Australia
| |
Collapse
|
|
21
|
Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone. Brain Sci 2022; 12:brainsci12020150. [PMID: 35203914 PMCID: PMC8870430 DOI: 10.3390/brainsci12020150] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 01/13/2023] Open
Abstract
Orexin peptides comprise two neuropeptides, orexin A and orexin B, that bind two G-protein coupled receptors (GPCRs), orexin receptor 1 (OXR1) and orexin receptor 2 (OXR2). Although cell bodies that produce orexin peptides are localized in a small area comprising the lateral hypothalamus and adjacent regions, orexin-containing fibres project throughout the neuraxis. Although orexins were initially described as peptides that regulate feeding behaviour, research has shown that orexins are involved in diverse functions that range from the modulation of autonomic functions to higher cognitive functions, including reward-seeking, behaviour, attention, cognition, and mood. Furthermore, disruption in orexin signalling has been shown in mood disorders that are associated with low hedonic tone or anhedonia, including depression, anxiety, attention deficit hyperactivity disorder, and addiction. Notably, projections of orexin neurons overlap circuits involved in the modulation of hedonic tone. Evidence shows that orexins may potentiate hedonic behaviours by increasing the feeling of pleasure or reward to various signalling, whereas dysregulation of orexin signalling may underlie low hedonic tone or anhedonia. Further, orexin appears to play a key role in regulating behaviours in motivationally charged situations, such as food-seeking during hunger, or drug-seeking during withdrawal. Therefore, it would be expected that dysregulation of orexin expression or signalling is associated with changes in hedonic tone. Further studies investigating this association are warranted.
Collapse
|
|
22
|
Orexin-A Regulates Follicular Growth, Proliferation, Cell Cycle and Apoptosis in Mouse Primary Granulosa Cells via the AKT/ERK Signaling Pathway. Molecules 2021; 26:molecules26185635. [PMID: 34577105 PMCID: PMC8467508 DOI: 10.3390/molecules26185635] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/08/2021] [Accepted: 09/12/2021] [Indexed: 11/16/2022] Open
Abstract
Granulosa cells (GCs) are essential for follicular growth, development, and atresia. The orexin-A (OXA) neuropeptide is widely involved in the regulation of various biological functions. OXA selectively binds to orexin receptor type 1 (OX1R) and mediates all its biological actions via OX1R. This study aimed to explore the expression of OXA and OX1R and their regulatory role in GCs proliferation, cell cycle progression, apoptosis, oocyte maturation, and underlying molecular mechanisms of these processes and elucidate its novel signaling pathway. Western blotting and RT-qPCR showed that OXA and OX1R were expressed during different developmental stages of GCs, and siRNA transfection successfully inhibited the expression of OX1R at the translational and transcriptional levels. Flow cytometry revealed that OX1R knockdown upregulated GCs apoptosis and triggered S-phase arrest in cell cycle progression. RT-qPCR and Western blotting showed significantly reduced expression of Bcl-2 and elevated expression of Bax, caspase-3, TNF-α, and P21 in OX1R-silenced GCs. Furthermore, the CCK-8 assay showed that knockdown of OX1R suppressed GCs proliferation by downregulating the expression of PCNA, a proliferation marker gene, at the translational and transcriptional levels. Western blotting revealed that knockdown of OX1R resulted in a considerable decrease of the phosphorylation level of the AKT and ERK1/2 proteins, indicating that the AKT/ERK1/2 pathway is involved in regulating GCs proliferation and apoptosis. In addition, OX1R silencing enhanced the mRNA expression of GDF9 and suppressed the mRNA expression of BMP15 in mouse GCs. Collectively, these results reveal a novel regulatory role of OXA in the development of GCs and folliculogenesis by regulating proliferation, apoptosis, and cell cycle progression. Therefore, OXA can be a promising therapeutic agent for female infertility.
Collapse
|
|
23
|
Hopkins K, Mukherjee S, Ponce D, Mangum J, Jacobson LH, Hoyer D. Development of a LC-ESI-MRM method for the absolute quantification of orexin A in the CSF of individual mice. MEDICINE IN DRUG DISCOVERY 2021. [DOI: 10.1016/j.medidd.2021.100102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
|
24
|
At the intersection of sleep deficiency and opioid use: mechanisms and therapeutic opportunities. Transl Res 2021; 234:58-73. [PMID: 33711513 PMCID: PMC8217216 DOI: 10.1016/j.trsl.2021.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/17/2021] [Accepted: 03/06/2021] [Indexed: 12/18/2022]
Abstract
Due to the ongoing opioid epidemic, innovative scientific perspectives and approaches are urgently needed to reduce the unprecedented personal and societal burdens of nonmedical and recreational opioid use. One promising opportunity is to focus on the relationship between sleep deficiency and opioid use. In this review, we examine empirical evidence: (1) at the interface of sleep deficiency and opioid use, including hypothesized bidirectional associations between sleep efficiency and opioid abstinence; (2) as to whether normalization of sleep deficiency might directly or indirectly improve opioid abstinence (and vice versa); and (3) regarding mechanisms that could link improvements in sleep to opioid abstinence. Based on available data, we identify candidate sleep-restorative therapeutic approaches that should be examined in rigorous clinical trials.
Collapse
|
|
25
|
Boof ML, Dingemanse J, Lederer K, Fietze I, Ufer M. Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea. Sleep 2021; 44:6030922. [PMID: 33305817 DOI: 10.1093/sleep/zsaa275] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/30/2020] [Indexed: 11/14/2022] Open
Abstract
In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant - placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: -1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: -0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.
Collapse
Affiliation(s)
- Marie-Laure Boof
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | | | - Ingo Fietze
- Advanced Sleep Research GmbH, Berlin, Germany
| | - Mike Ufer
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
26
|
Sun Y, Tisdale RK, Kilduff TS. Hypocretin/Orexin Receptor Pharmacology and Sleep Phases. FRONTIERS OF NEUROLOGY AND NEUROSCIENCE 2021; 45:22-37. [PMID: 34052813 DOI: 10.1159/000514963] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 02/02/2021] [Indexed: 12/15/2022]
Abstract
The hypocretins/orexins are two excitatory neuropeptides, alternately called HCRT1 or orexin-A and HCRT2 or orexin-B, that are the endogenous ligands for two G-protein-coupled receptors, HCRTR1/OX1R and HCRTR2/OX2R. Shortly after the discovery of this system, degeneration of hypocretin/orexin-producing neurons was implicated in the etiology of the sleep disorder narcolepsy. The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry. The broad projections of the hypocretin/orexin-producing neurons, along with differential expression of the two receptors in the projection fields of these neurons, suggest distinct roles for these receptors. While HCRTR1/OX1R is associated with regulation of motivation, reward, and autonomic functions, HCRTR2/OX2R is strongly linked to sleep-wake control. The association of hypocretin/orexin with these physiological processes has led to intense interest in the therapeutic potential of compounds targeting these receptors. Agonists and antagonists for the hypocretin/orexin receptors have shown potential for the treatment of disorders of excessive daytime somnolence and nocturnal hyperarousal, respectively, with the first antagonists approved by the US Food and Drug Administration (FDA) in 2014 and 2019 for the treatment of insomnia. These and related compounds have also been useful tools to advance hypocretin/orexin neurobiology.
Collapse
Affiliation(s)
- Yu Sun
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California, USA
| | - Ryan K Tisdale
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California, USA
| | - Thomas S Kilduff
- Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California, USA
| |
Collapse
|
|
27
|
Oberrauch S, Metha JA, Brian ML, Barnes SA, Featherby TJ, Lawrence AJ, Hoyer D, Murawski C, Jacobson LH. Reward motivation and cognitive flexibility in tau null-mutation mice. Neurobiol Aging 2021; 100:106-117. [PMID: 33524848 DOI: 10.1016/j.neurobiolaging.2020.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 11/05/2020] [Accepted: 12/15/2020] [Indexed: 01/21/2023]
Abstract
The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau-/-) and wild-type mice using progressive ratio and reversal learning tasks. Tau-/- mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau-/- mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies.
Collapse
Affiliation(s)
- Sara Oberrauch
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia; Department of Pharmacology & Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Jeremy A Metha
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia; Department of Pharmacology & Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia; Department of Finance, Brain, Mind & Markets Laboratory, The University of Melbourne, Melbourne, Victoria, Australia
| | - Maddison L Brian
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia; Department of Pharmacology & Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Samuel A Barnes
- Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Travis J Featherby
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia
| | - Andrew J Lawrence
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia
| | - Daniel Hoyer
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia; Department of Pharmacology & Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Carsten Murawski
- Department of Finance, Brain, Mind & Markets Laboratory, The University of Melbourne, Melbourne, Victoria, Australia
| | - Laura H Jacobson
- The Florey Institute of Neuroscience and Mental Health, Parkville Campus, University of Melbourne, Parkville, Australia; Department of Pharmacology & Therapeutics, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia; Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Victoria, Australia.
| |
Collapse
|
|
28
|
Keenan RJ, Oberrauch S, Bron R, Nowell CJ, Challis LM, Hoyer D, Jacobson LH. Decreased Orexin Receptor 1 mRNA Expression in the Locus Coeruleus in Both Tau Transgenic rTg4510 and Tau Knockout Mice and Accompanying Ascending Arousal System Tau Invasion in rTg4510. J Alzheimers Dis 2021; 79:693-708. [PMID: 33361602 DOI: 10.3233/jad-201177] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Sleep/wake disturbances (e.g., insomnia and sleep fragmentation) are common in neurodegenerative disorders, especially Alzheimer's disease (AD) and frontotemporal dementia (FTD). These symptoms are somewhat reminiscent of narcolepsy with cataplexy, caused by the loss of orexin-producing neurons. A bidirectional relationship between sleep disturbance and disease pathology suggests a detrimental cycle that accelerates disease progression and cognitive decline. The accumulation of brain tau fibrils is a core pathology of AD and FTD-tau and clinical evidence supports that tau may impair the orexin system in AD/FTD. This hypothesis was investigated using tau mutant mice. OBJECTIVE To characterize orexin receptor mRNA expression in sleep/wake regulatory brain centers and quantify noradrenergic locus coeruleus (LC) and orexinergic lateral hypothalamus (LH) neurons, in tau transgenic rTg4510 and tau-/- mice. METHODS We used i n situ hybridization and immunohistochemistry (IHC) in rTg4510 and tau-/- mice. RESULTS rTg4510 and tau-/- mice exhibited a similar decrease in orexin receptor 1 (OX1R) mRNA expression in the LC compared with wildtype controls. IHC data indicated this was not due to decreased numbers of LC tyrosine hydroxylase-positive (TH) or orexin neurons and demonstrated that tau invades TH LC and orexinergic LH neurons in rTg4510 mice. In contrast, orexin receptor 2 (OX2R) mRNA levels were unaffected in either model. CONCLUSION The LC is strongly implicated in the regulation of sleep/wakefulness and expresses high levels of OX1R. These findings raise interesting questions regarding the effects of altered tau on the orexin system, specifically LC OX1Rs, and emphasize a potential mechanism which may help explain sleep/wake disturbances in AD and FTD.
Collapse
Affiliation(s)
- Ryan J Keenan
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Sara Oberrauch
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Romke Bron
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Cameron J Nowell
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Leesa M Challis
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Daniel Hoyer
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Laura H Jacobson
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.,Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.,Melbourne Dementia Research Centre, University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| |
Collapse
|
|
29
|
Boof ML, Dingemanse J, Brunke M, Esselmann A, Heymer P, Kestermann O, Lederer K, Fietze I, Ufer M. Effect of the novel dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease. J Sleep Res 2021; 30:e13248. [PMID: 33417730 DOI: 10.1111/jsr.13248] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/06/2020] [Accepted: 11/12/2020] [Indexed: 01/29/2023]
Abstract
In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double-blind, placebo-controlled, two-period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase-III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO2 ) during total sleep time (TST) after last dosing. Night-time respiratory function and sleep were further evaluated based on the apnea-hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant - placebo) for SpO2 during TST as it was 0.18% (90% confidence interval: -0.21 to 0.57). There was also no difference from placebo for SpO2 during non-rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night-time respiratory function and improves sleep in patients with moderate COPD.
Collapse
Affiliation(s)
- Marie-Laure Boof
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Mareile Brunke
- Klinische Forschung Hannover-Mitte GmbH, Hannover, Germany
| | | | - Peter Heymer
- Klinische Forschung Dresden GmbH, Dresden, Germany
| | | | | | | | - Mike Ufer
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
30
|
Vernia F, Di Ruscio M, Ciccone A, Viscido A, Frieri G, Stefanelli G, Latella G. Sleep disorders related to nutrition and digestive diseases: a neglected clinical condition. Int J Med Sci 2021; 18:593-603. [PMID: 33437194 PMCID: PMC7797530 DOI: 10.7150/ijms.45512] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023] Open
Abstract
Sleep disturbances often result from inappropriate lifestyles, incorrect dietary habits, and/or digestive diseases. This clinical condition, however, has not been sufficiently explored in this area. Several studies have linked the circadian timing system to the physiology of metabolism control mechanisms, energy balance regulation, and nutrition. Sleep disturbances supposedly trigger digestive disorders or conversely represent specific clinical manifestation of gastrointestinal (GI) diseases. Poor sleep may worsen the symptoms of GI disorders, affecting the quality of life. Conversely, short sleep may influence dietary choices, as well as meal timing, and the circadian system drives temporal changes in metabolic patterns. Emerging evidence suggests that patients with inappropriate dietary habits and chronic digestive disorders often sleep less and show lower sleep efficiency, compared with healthy individuals. Sleep disturbances may thus represent a primary symptom of digestive diseases. Further controlled trials are needed to fully understand the relationship between sleep disturbances, dietary habits, and GI disorders. It may be also anticipated that the evaluation of sleep quality may prove useful to drive positive interventions and improve the quality of life in a proportion of patients. This review summarizes data linking sleep disorders with diet and a series of disease including gastro-esophageal reflux disease, peptic disease, functional gastrointestinal disorders, inflammatory bowel diseases, gut microbiota alterations, liver and pancreatic diseases, and obesity. The evidence supporting the complex interplay between sleep dysfunction, nutrition, and digestive diseases is discussed.
Collapse
Affiliation(s)
- Filippo Vernia
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Mirko Di Ruscio
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Antonio Ciccone
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Angelo Viscido
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Giuseppe Frieri
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Gianpiero Stefanelli
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| | - Giovanni Latella
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health, and Environmental Sciences, University of L'Aquila, Piazza S. Tommasi, 1- Coppito, 67100 L'Aquila, Italy
| |
Collapse
|
|
31
|
Muehlan C, Vaillant C, Zenklusen I, Kraehenbuehl S, Dingemanse J. Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders. Expert Opin Drug Metab Toxicol 2020; 16:1063-1078. [DOI: 10.1080/17425255.2020.1817380] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Clemens Muehlan
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Cedric Vaillant
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Isabelle Zenklusen
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Stephan Kraehenbuehl
- Department of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
32
|
Clark JW, Brian ML, Drummond SP, Hoyer D, Jacobson LH. Effects of orexin receptor antagonism on human sleep architecture: A systematic review. Sleep Med Rev 2020; 53:101332. [DOI: 10.1016/j.smrv.2020.101332] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 03/09/2020] [Accepted: 03/16/2020] [Indexed: 10/24/2022]
|
|
33
|
Sadat-Shirazi MS, Soltani H, Nikpour N, Haghshenas M, Khalifeh S, Mokri A, Zarrindast MR. Alteration of orexin-A and PKCα in the postmortem brain of pure-opioid and multi-drug abusers. Neuropeptides 2020; 83:102074. [PMID: 32741526 DOI: 10.1016/j.npep.2020.102074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/18/2020] [Accepted: 07/19/2020] [Indexed: 02/09/2023]
Abstract
Finding changes induced by the drug of abuse is one of the most important approaches to design new drugs for the treatment of substance use disorders (SUD). Postmortem study is the most reliable method for detecting alteration in the brain of SUD patients. Recently, the role of orexinergic system in SUD is in consideration. In the current study, we evaluated the level of orexin-A in the CSF and protein kinase Cα (PKCα) in the brain of pure-opioid (POA) and multi-drug abusers (MDA). A total of 56 POA, 45 MDA, and 13 matched control brains were collected from the legal medicine center, Tehran, Iran. The CSF was gathered from the third ventricle immediately after opening the skull and kept at -80 °C. The medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), orbitofrontal cortex (OFC), nucleus accumbens (NAc), and amygdala were dissected from fresh brain, frozen with liquid nitrogen and kept at -80 °C. The level of orexin-A evaluated in the CSF. Using western blotting, the level of PKCα assessed in the brain. Obtained data revealed that the level of orexin-A increased in POA and MDA compared with the control group (p < 0.05). In addition, the level of PKCα increased in the prefrontal cortex and amygdala of the abusers compared with the control group, although we did not detect changes in the level of PKCα in the NAc. Along with animal studies, the current results showed that the level of orexin increased in the CSF of drug abusers, which might be related to increases in the activation of lateral hypothalamic orexinergic neurons faced with the drug of abuse. Enhancement in the level of PKCα in the drug reward circuits might be adaptational changes induced by orexin and drugs of abuse.
Collapse
Affiliation(s)
| | - Haniyeh Soltani
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Nikpour
- Department of Microbiology, Pasteur Institute of Iran, Tehran, Iran
| | - Masoud Haghshenas
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
| | - Solmaz Khalifeh
- Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir-Almomenin Hospital, Islamic Azad University, Tehran, Iran
| | - Azarakhsh Mokri
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad-Reza Zarrindast
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir-Almomenin Hospital, Islamic Azad University, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Institute, Tehran University of Medical Science, Tehran, Iran.
| |
Collapse
|
|
34
|
PSPH-D-18-00526: Effect of a dual orexin receptor antagonist (DORA-12) on sleep and event-related oscillations in rats exposed to ethanol vapor during adolescence. Psychopharmacology (Berl) 2020; 237:2917-2927. [PMID: 31659377 PMCID: PMC7186151 DOI: 10.1007/s00213-019-05371-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 09/12/2019] [Accepted: 09/30/2019] [Indexed: 02/07/2023]
Abstract
RATIONALE Sleep difficulties are one of the problems associated with adolescent binge drinking. However, the mechanisms underlying adolescent alcohol-associated sleep disturbances and potential targets for therapy remain under investigated. Orexin receptor antagonists may have therapeutic value in the treatment of insomnia, yet the use of this class of drugs in the treatment of sleep disturbances following adolescent alcohol exposure has not been studied. OBJECTIVES This study employed a model whereby ethanol vapor exposure occurred for 5 weeks during adolescence (AIE), and waking event-related oscillations (EROs) and EEG sleep were subsequently evaluated in young adult rats. The ability of two doses (10, 30 mg/kg PO) of a dual orexin receptor antagonist (DORA-12) to modify sleep, EEG, and EROs was investigated in AIE rats and controls. RESULTS Adolescent vapor exposure was found to produce a fragmentation of sleep, in young adults, that was partially ameliorated by DORA-12. DORA-12 also produced increases in delta and theta power in waking EROs recorded before sleep, and deeper sleep as indexed by increases in delta and theta power in the sleep EEG in both ethanol and control rats. Rats given DORA-12 also fell asleep faster than vehicle-treated rats as measured by a dose-dependent reduction in the latency to both the first slow wave and REM sleep episodes. CONCLUSIONS This study showed that DORA-12 can affect the sleep disturbance that is associated with a history of adolescent ethanol exposure and also has several other sleep-promoting effects that are equivalent in both ethanol and control rats.
Collapse
|
|
35
|
Skillman B, Kerrigan S. CYP450-Mediated metabolism of suvorexant and investigation of metabolites in forensic case specimens. Forensic Sci Int 2020; 312:110307. [PMID: 32473525 DOI: 10.1016/j.forsciint.2020.110307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 01/10/2023]
Abstract
Suvorexant (Belsomra®) is a sedative hypnotic that was approved for use in 2015. It has a novel mechanism of action and was the first dual orexin receptor antagonist (DORA) to be approved for the treatment of sleep disorders. Sedative hypnotics often feature prominently in forensic investigations such as impaired driving and drug-facilitated sexual assault (DFSA) cases. As such, suvorexant is a drug of interest and its identification in forensic toxicology investigations is of significance. However, limited studies have been published to date and the disposition or importance of its metabolites has been largely uninvestigated. In this report, we investigate the enzymes responsible for metabolism and explore the prevalence of metabolites in blood from a series of thirteen forensic investigations. Recombinant cytochrome P450 enzymes (rCYPs) were used to generate phase I metabolites for suvorexant in vitro, and metabolites were identified using liquid chromatography-quadrupole/time-of-flight-mass spectrometry (LC-Q/TOF-MS). Four rCYP isoenzymes (3A4, 2C19, 2D6, and 2C9) were found to contribute to suvorexant metabolism. The only metabolite identified in blood or plasma arose from hydroxylation of the benzyl triazole moiety (M9). This metabolite was identified in seventeen blood and plasma specimens from twelve medicolegal death investigations and one impaired driving investigation. In the absence of a commercially available reference material, the metabolite was confirmed using rCYP-generated in vitro controls using high resolution mass spectrometry.
Collapse
Affiliation(s)
- Britni Skillman
- Sam Houston State University, Department of Forensic Science, 1003 Bowers Blvd., Huntsville, TX 77341, United States
| | - Sarah Kerrigan
- Sam Houston State University, Department of Forensic Science, 1003 Bowers Blvd., Huntsville, TX 77341, United States.
| |
Collapse
|
|
36
|
Maehara S, Yuge N, Higashi C, Ota T, Furukawa J, Takeuchi T. Pharmacological characterization of a novel potent, selective, and orally active orexin 2 receptor antagonist, SDM-878. Neuropsychopharmacol Rep 2020; 40:182-189. [PMID: 32337858 PMCID: PMC7722660 DOI: 10.1002/npr2.12105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/25/2020] [Accepted: 03/04/2020] [Indexed: 12/28/2022] Open
Abstract
Aims Recently, we identified a novel orexin 2 (OX2) receptor antagonist, SDM‐878 (2‐(3‐(2‐(1H‐pyrazol‐1‐yl)nicotinoyl)‐3,8‐diazabicyclo[3.2.1]octan‐8‐yl)‐3‐methoxyisonicotinonitrile). The purpose of the present study is to characterize the in vitro and in vivo pharmacological effects of SDM‐878. Methods The in vitro potency and selectivity of SDM‐878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX1), human orexin 2 (OX2), rat OX1, and rat OX2receptors. Then, the plasma half‐life, oral bioavailability, and brain penetration of SDM‐878 were examined in rats. The in vivo effect of SDM‐878 in rats was tested using electroencephalography (EEG). The target engagement of SDM‐878 in the rat brain was examined using the antagonistic effect against hyperlocomotion caused by the intracerebroventricular administration of the OX2 receptor agonist, ADL‐OXB ([Ala11, d‐Leu15]‐orexin B). Results SDM‐878 showed potent inhibitory activities for human and rat OX2 receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000‐fold selectivity against the OX1receptor. In rat studies, SDM‐878 exhibited a relatively short half‐life in plasma, oral bioavailability, and good brain penetration. These data indicate that SDM‐878 is a potent, selective, orally active, and brain‐penetrable OX2receptor antagonist. In behavioral studies using rats, SDM‐878 (100 mg/kg) antagonized hyperlocomotion caused by intracerebroventricular administration of ADL‐OXB. SDM‐878 exhibited a potent sleep‐promoting effect at the same dose (100 mg/kg) in a rat EEG study. Conclusion Our results suggest that SDM‐878 is likely to be a good pharmacological tool for investigating the role of the OX2receptor and may have therapeutic potential for the treatment of insomnia. We identified a novel potent, selective, orally active, and brain‐penetrable orexin 2 receptor antagonist, SDM‐878. SDM‐878 exhibited a potent sleep‐promoting effect in rats and may have therapeutic potential for the treatment of insomnia.![]()
Collapse
Affiliation(s)
- Shunsuke Maehara
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| | - Natsuko Yuge
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| | - Chika Higashi
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| | - Takumi Ota
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| | - Junji Furukawa
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| | - Takashi Takeuchi
- Biology Laboratory, Discovery Research, Mochida Pharmaceutical Co., Ltd., Gotemba, Japan
| |
Collapse
|
|
37
|
Orexins role in neurodegenerative diseases: From pathogenesis to treatment. Pharmacol Biochem Behav 2020; 194:172929. [PMID: 32315694 DOI: 10.1016/j.pbb.2020.172929] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022]
Abstract
Orexin is a neurotransmitter that mainly regulates sleep/wake cycle. In addition to its sleep cycle regulatory role, it is involved in regulation of attention, energy homeostasis, neurogenesis and cognition. Several evidences has shown the involvement of orexin in narcolepsy, but there are also growing evidences that shows the disturbance in orexin system in neurodegenerative diseases including Alzheimer's, Parkinson's, Epilepsy, Huntington's diseases and Amyotrophic lateral sclerosis. Pathogenesis and clinical symptoms of these disorders can be partly attributed from orexin system imbalance. However, there are controversial reports on the exact relationship between orexin and these neurodegenerative diseases. Therefore, the aim of this review is to summarize the current evidences regarding the role of orexin in these neurodegenerative diseases.
Collapse
|
|
38
|
Sanchez-Alavez M, Benedict J, Wills DN, Ehlers CL. Effect of suvorexant on event-related oscillations and EEG sleep in rats exposed to chronic intermittent ethanol vapor and protracted withdrawal. Sleep 2020; 42:5304584. [PMID: 30715515 DOI: 10.1093/sleep/zsz020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/07/2018] [Indexed: 01/27/2023] Open
Abstract
STUDY OBJECTIVES Insomnia is a prominent complaint in patients with alcohol use disorders (AUD). However, despite the importance of sleep in the maintenance of sobriety, treatment options for sleep disturbance associated with a history of AUD are currently limited. Recent clinical trials have demonstrated that suvorexant, a dual Hct/OX receptor antagonist, normalizes sleep in patients with primary insomnia; yet, its potential for the treatment of sleep pathology associated with AUD has not been investigated in either preclinical or clinical studies. METHODS This study employed a model whereby ethanol vapor exposure or control conditions were administered for 8 weeks to adult rats. Waking event-related oscillations (EROs) and EEG sleep were evaluated at baseline before exposure and again following 24 hr of withdrawal from the exposure. Subsequently, the ability of vehicle (VEH) and two doses (10, 30 mg/kg IP) of suvorexant to modify EROs, sleep, and the sleep EEG was investigated. RESULTS After 24 hr following EtOH withdrawal, the ethanol-treated group had increases in waking ERO θ and β activity, more fragmented sleep (shorter duration and increased frequency of slow wave (SW) and rapid eye movement [REM] sleep episodes), and increased θ and β power in REM and SW sleep. Suvorexant induced a dose-dependent decrease in the latency to REM and SW sleep onsets but also produced REM and SW sleep fragmentation and increased β energy in waking EROs when compared with VEH. CONCLUSIONS Taken together, these studies suggest that suvorexant has overall sleep-promoting effects, but it may exacerbate some aspects of sleep and EEG pathology.
Collapse
Affiliation(s)
| | - Jessica Benedict
- Department of Neurosciences, The Scripps Research Institute, La Jolla, CA
| | - Derek N Wills
- Department of Neurosciences, The Scripps Research Institute, La Jolla, CA
| | - Cindy L Ehlers
- Department of Neurosciences, The Scripps Research Institute, La Jolla, CA
| |
Collapse
|
|
39
|
Roehrs T, Withrow D, Koshorek G, Verkler J, Bazan L, Roth T. Sleep and pain in humans with fibromyalgia and comorbid insomnia: double-blind, crossover study of suvorexant 20 mg versus placebo. J Clin Sleep Med 2020; 16:415-421. [PMID: 31992394 PMCID: PMC7075085 DOI: 10.5664/jcsm.8220] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/08/2019] [Accepted: 11/08/2019] [Indexed: 11/13/2022]
Abstract
STUDY OBJECTIVES The chronic pain disorder, fibromyalgia, is associated with sleep disturbance, typically sleep maintenance. No studies have evaluated the effect of sleep medication on pain sensitivity in this population. Suvorexant, an orexin antagonist approved for treatment of insomnia, was evaluated for effects on both sleep and the pain of fibromyalgia. METHODS Women age 21 to 65 years with fibromyalgia and comorbid insomnia (n = 10) were treated, double-blind, for 9 nights each with suvorexant, 20 mg and placebo in counterbalanced order. All were in good psychiatric and stable physical health and met American College of Rheumatology 2010 criteria for fibromyalgia and Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition criteria for insomnia. Screening 8-hour polysomnography (PSG) was used to rule out other sleep disorders. On nights 8 and 9 of each treatment 8-hour PSG were collected and on days 1 and 8 pain sensitivity was assessed at 1100 and 1500 hours by measuring finger withdrawal latency (FWL) to a radiant heat stimulus at 5 randomly presented intensity levels. RESULTS Suvorexant versus placebo increased total sleep time (7.2 versus 6.7 hours, P < .05) and reduced wake after sleep onset (37 versus 67 minutes, P < .04) with no night effects or interaction. Latency to persistent sleep and sleep stage measures were not altered. FWL on both am and pm tests varied as a function of intensity (P < .001). Average FWL (over 5 intensities and both days) was increased relative to placebo on both the am (13.9 versus 13.1 seconds) and pm tests (15.8 versus 14.1 seconds, P < .03) following suvorexant the previous night. CONCLUSIONS Suvorexant 20 mg in patients with fibromyalgia, improved sleep time and reduced next-day pain sensitivity on assessments of FWL to a radiant heat stimulus. CLINICAL TRIAL REGISTRY Registry: ClinicalTrials.gov; Name: A double-blind cross-over, study to compare the hypnotic, daytime sleepiness/fatigue, and pain effects of nighttime administration of suvorexant 20 mg versus placebo in patients with fibromyalgia and comorbid insomnia; Identifier: NCT02684136; URL: https://clinicaltrials.gov/ct2/show/NCT02684136.
Collapse
Affiliation(s)
- Timothy Roehrs
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
- Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, Michigan
| | - Dana Withrow
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
| | - Gail Koshorek
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
| | - Jelena Verkler
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
| | - Luisa Bazan
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
| | - Thomas Roth
- Henry Ford Health System, Sleep Disorders and Research Center, Detroit, Michigan
- Department of Psychiatry and Behavioral Neurosciences, School of Medicine, Wayne State University, Detroit, Michigan
| |
Collapse
|
|
40
|
Muehlan C, Boehler M, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Clinical pharmacology of the dual orexin receptor antagonist ACT-541468 in elderly subjects: Exploration of pharmacokinetics, pharmacodynamics and tolerability following single-dose morning and repeated-dose evening administration. J Psychopharmacol 2020; 34:326-335. [PMID: 31642731 DOI: 10.1177/0269881119882854] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The dual orexin receptor antagonist ACT-541468 showed sedative pharmacodynamic effects during initial clinical testing in adult subjects. The present study explored pharmacokinetics, pharmacodynamics and tolerability in healthy elderly subjects. METHODS Double-blind, placebo-controlled, randomised, single-ascending dose study in 24 male/female elderly (65-80 years, 5, 15 and 25 mg in the morning, 6/2 active/placebo per group). Additionally, 10 subjects (8/2 active/placebo) received 25 mg for 7 days in the evening. Pharmacokinetics, pharmacodynamics (saccadic peak velocity, adaptive tracking, body sway, visual analogue scales according to Bowdle and Bond and Lader, Karolinska Sleepiness Scale) and tolerability were assessed. In particular, pharmacodynamics results are to be interpreted exploratorily. RESULTS Absorption was quick with a median time to maximum concentration of ∼ 1.0 h. The mean elimination half-life was 8.5-9.8 h, the area under the curve and the maximum plasma concentration increased proportionally with dose. Following repeated evening administration of 25 mg, minimal accumulation was observed. There were no pharmacodynamic effects at 5 mg. At 15 mg, saccadic peak velocity (degree/s; SD) was reduced (69; 38), while other variables showed no effects. At 25 mg, effects on all objective pharmacodynamic parameters were observed. At 8-12 h post-dose, there were no differences to placebo and no next-day effects on pharmacodynamic variables after evening administration. Elderly subjects reported fewer adverse events compared to adults in previous studies. CONCLUSION ACT-541468 in elderly subjects was well tolerated and pharmacokinetics and pharmacodynamics are compatible with a drug for the treatment of insomnia. Clinicaltrials.gov: NCT02571855.
Collapse
Affiliation(s)
- Clemens Muehlan
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Margaux Boehler
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Sander Brooks
- Centre for Human Drug Research (CHDR), Leiden, The Netherlands
| | - Rob Zuiker
- Centre for Human Drug Research (CHDR), Leiden, The Netherlands
| | - Joop van Gerven
- Centre for Human Drug Research (CHDR), Leiden, The Netherlands
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| |
Collapse
|
|
41
|
Hoyer D, Allen A, Jacobson LH. Hypnotics with novel modes of action. Br J Clin Pharmacol 2020; 86:244-249. [PMID: 31756268 PMCID: PMC7015741 DOI: 10.1111/bcp.14180] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 10/25/2019] [Accepted: 11/01/2019] [Indexed: 12/19/2022] Open
Abstract
Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABAA receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug-drug interactions with e.g. alcohol, less memory impairment and dependence potential compared to classical hypnotics.
Collapse
Affiliation(s)
- Daniel Hoyer
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleVictoriaAustralia
- The Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
- Department of Molecular MedicineThe Scripps Research InstituteLa JollaCAUSA
| | - Andrew Allen
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleVictoriaAustralia
| | - Laura H. Jacobson
- Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health SciencesThe University of MelbourneParkvilleVictoriaAustralia
- The Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
| |
Collapse
|
|
42
|
Koob GF, Colrain IM. Alcohol use disorder and sleep disturbances: a feed-forward allostatic framework. Neuropsychopharmacology 2020; 45:141-165. [PMID: 31234199 PMCID: PMC6879503 DOI: 10.1038/s41386-019-0446-0] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/09/2019] [Accepted: 06/13/2019] [Indexed: 11/09/2022]
Abstract
The development of alcohol use disorder (AUD) involves binge or heavy drinking to high levels of intoxication that leads to compulsive intake, the loss of control in limiting intake, and a negative emotional state when alcohol is removed. This cascade of events occurs over an extended period within a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three heuristic stages map onto the dysregulation of functional domains of incentive salience/habits, negative emotional states, and executive function, mediated by the basal ganglia, extended amygdala, and frontal cortex, respectively. Sleep disturbances, alterations of sleep architecture, and the development of insomnia are ubiquitous in AUD and also map onto the three stages of the addiction cycle. During the binge/intoxication stage, alcohol intoxication leads to a faster sleep onset, but sleep quality is poor relative to nights when no alcohol is consumed. The reduction of sleep onset latency and increase in wakefulness later in the night may be related to the acute effects of alcohol on GABAergic systems that are associated with sleep regulation and the effects on brain incentive salience systems, such as dopamine. During the withdrawal/negative affect stage, there is a decrease in slow-wave sleep and some limited recovery in REM sleep when individuals with AUD stop drinking. Limited recovery of sleep disturbances is seen in AUD within the first 30 days of abstinence. The effects of withdrawal on sleep may be related to the loss of alcohol as a positive allosteric modulator of GABAA receptors, a decrease in dopamine function, and the overactivation of stress neuromodulators, including hypocretin/orexin, norepinephrine, corticotropin-releasing factor, and cytokines. During the preoccupation/anticipation stage, individuals with AUD who are abstinent long-term present persistent sleep disturbances, including a longer latency to fall asleep, more time awake during the night, a decrease in slow-wave sleep, decreases in delta electroencephalogram power and evoked delta activity, and an increase in REM sleep. Glutamatergic system dysregulation that is observed in AUD is a likely substrate for some of these persistent sleep disturbances. Sleep pathology contributes to AUD pathology, and vice versa, possibly as a feed-forward drive to an unrecognized allostatic load that drives the addiction process.
Collapse
Affiliation(s)
- George F Koob
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 6700B Rockledge Drive, Room 1209, MSC 6902, Bethesda, MD, 20892-6902, USA.
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, 20892-6902, USA.
| | - Ian M Colrain
- SRI Biosciences, SRI International, Menlo Park, CA, USA
- Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, Australia
| |
Collapse
|
|
43
|
Gamble MC, Katsuki F, McCoy JG, Strecker RE, McKenna JT. The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model. Sleep 2019; 43:5583907. [PMID: 31595304 DOI: 10.1093/sleep/zsz241] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/06/2019] [Indexed: 12/16/2022] Open
Abstract
AbstractInsomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally affecting mnemonic function, yet many hypnotic drugs (e.g. benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine whether the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze and then administered DORA-22 (10, 30, or 100 mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a 6-hr time period (at time points 0 and 3 hr), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption—wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared with vehicle treatment for one dose (30 mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg) and time spent in platform location and number of platform crossings (10 mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.
Collapse
Affiliation(s)
- Mackenzie C Gamble
- Boston VA Research Institute, Inc., Jamaica Plain, MA
- VA Boston Healthcare System, West Roxbury, MA
| | - Fumi Katsuki
- Boston VA Research Institute, Inc., Jamaica Plain, MA
- VA Boston Healthcare System, West Roxbury, MA
- Department of Psychiatry, Harvard Medical School, West Roxbury, MA
| | - John G McCoy
- Boston VA Research Institute, Inc., Jamaica Plain, MA
- VA Boston Healthcare System, West Roxbury, MA
- Neuroscience Program, Stonehill College, Easton, MA
| | - Robert E Strecker
- Boston VA Research Institute, Inc., Jamaica Plain, MA
- VA Boston Healthcare System, West Roxbury, MA
- Department of Psychiatry, Harvard Medical School, West Roxbury, MA
| | - James Timothy McKenna
- Boston VA Research Institute, Inc., Jamaica Plain, MA
- VA Boston Healthcare System, West Roxbury, MA
- Department of Psychiatry, Harvard Medical School, West Roxbury, MA
| |
Collapse
|
|
44
|
Muehlan C, Brooks S, Zuiker R, van Gerven J, Dingemanse J. Multiple-dose clinical pharmacology of ACT-541468, a novel dual orexin receptor antagonist, following repeated-dose morning and evening administration. Eur Neuropsychopharmacol 2019; 29:847-857. [PMID: 31221502 DOI: 10.1016/j.euroneuro.2019.05.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 05/22/2019] [Accepted: 05/29/2019] [Indexed: 01/06/2023]
Abstract
ACT-541468 is a dual orexin receptor antagonist with sleep-promoting effects in humans. Following entry-into-humans, its pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability following multiple-ascending oral dose (MAD) administration in the morning, and next-day residual effects after repeated evening administration were investigated in a double-blind, placebo-controlled, randomized study. 31 healthy male and female subjects in 3 dose-groups (10, 25, and 75 mg) received study drug in the morning for 5 days (MAD part), and 20 healthy subjects received 25 mg in the evening for 1 week (evening part). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analogue scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), Digit Symbol Substitution Test (DSST), and Simple Reaction Time Test (SRTT), safety, and tolerability were assessed. ACT-541468 was absorbed with a median tmax of 1.0-2.0 h across the 3 dose groups. The geometric mean elimination half-life (t½) on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality. No accumulation and no influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. No effects were observed at 10 mg. Administration of 25 and 75 mg during the day showed clear dose-dependent effects on the PD parameters, while next-day effects were absent after evening administration of 25 mg. The drug was safe and well tolerated. In conclusion, multiple-dose PK/PD of ACT-541468 were compatible with a drug designated to treat insomnia.
Collapse
Affiliation(s)
- Clemens Muehlan
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland.
| | - Sander Brooks
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL Leiden, the Netherlands
| | - Rob Zuiker
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL Leiden, the Netherlands
| | - Joop van Gerven
- Centre for Human Drug Research (CHDR), Zernikedreef 8, 2333 CL Leiden, the Netherlands
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| |
Collapse
|
|
45
|
Tereshchenko S, Kasparov E. Neurobiological Risk Factors for the Development of Internet Addiction in Adolescents. Behav Sci (Basel) 2019; 9:bs9060062. [PMID: 31207886 PMCID: PMC6616486 DOI: 10.3390/bs9060062] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
The sudden appearance and spread of Internet addiction in adolescent populations, in association with the rapid escalation of consumed Internet content and the broad availability of smartphones and tablets with Internet access, is posing a new challenge for classical addictology which requires urgent solutions. Like the majority of other psychopathological conditions, pathological Internet addiction depends upon a group of multifactor polygenic conditions. For each specific case, there is a unique combination of inherited characteristics (nervous tissue structure, secretion, degradation, and reception of neuromediators), and many are extra-environment factors (family-related, social, and ethnic-cultural). One of the main challenges in the development of the bio-psychosocial model of Internet addiction is to determine which genes and neuromediators are responsible for increased addiction susceptibility. This information will herald the start of a search for new therapeutic targets and the development of early prevention strategies, including the assessment of genetic risk levels. This review summarizes the literature and currently available knowledge related to neurobiological risk factors regarding Internet addiction in adolescents. Genetic, neurochemical and neuroimaging data are presented with links to actual pathogenetic hypotheses according to the bio-psychosocial model of IA forming.
Collapse
Affiliation(s)
- Sergey Tereshchenko
- Research Institute of Medical Problems of the North, Federal Research Center "Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences", Krasnoyarsk 660022, Russia.
| | - Edward Kasparov
- Research Institute of Medical Problems of the North, Federal Research Center "Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences", Krasnoyarsk 660022, Russia.
| |
Collapse
|
|
46
|
Landolt HP, Holst SC, Valomon A. Clinical and Experimental Human Sleep-Wake Pharmacogenetics. Handb Exp Pharmacol 2019; 253:207-241. [PMID: 30443785 DOI: 10.1007/164_2018_175] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, γ-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics.
Collapse
Affiliation(s)
- Hans-Peter Landolt
- Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
- Zürich Center for Interdisciplinary Sleep Research (ZiS), University of Zürich, Zürich, Switzerland.
| | - Sebastian C Holst
- Neurobiology Research Unit and Neuropharm, Department of Neurology, Rigshospitalet, Copenhagen, Denmark
| | - Amandine Valomon
- Wisconsin Institute for Sleep and Consciousness, University of Wisconsin Madison, Madison, WI, USA
| |
Collapse
|
|
47
|
Holst SC, Werth E, Landolt HP. [Pharmacotherapy of Sleep-Wake Disorders]. PRAXIS 2019; 108:131-138. [PMID: 30722734 DOI: 10.1024/1661-8157/a003189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Pharmacotherapy of Sleep-Wake Disorders Abstract. Sleep is a complex behavior, coordinated by many different brain regions and neurotransmitters. These neurochemical systems can be pharmacologically influenced to modulate wakefulness and sleep. Excessive daytime sleepiness (EDS) is often treated with dopaminergic drugs, which in mild cases range from caffeine via (ar)modafinil to amphetamine derivatives. Tricyclic antidepressants and melatonin-based drugs are also used to promote alertness, but to a lesser extent. The drugs used to promote sleep include GABA-ergic drugs such as benzodiazepines and Z-hypnotics as well as histamine H1 receptor antagonists. Exogenous melatonin or a pharmacological combination of melatonin receptor agonists and 5-HT2C receptor antagonists are also used in mild cases. Selective and dual orexin (hypocretin) receptor antagonists (DORA) as well as drugs binding to specific 5-HT receptors are currently being investigated as future sleep-promoting drugs. However, pharmacological treatment is not always the primary treatment option, insomnia is treated first-line with cognitive behavioral therapy, and continuous positive airway pressure is used to treat sleep apnea.
Collapse
Affiliation(s)
- Sebastian C Holst
- 1 Copenhagen University Hospital, Rigshospitalet, Department of Neurology and Neurobiology Research Unit, Kopenhagen, Dänemark
- 2 Sleep and Health Zürich (SHZ), Universität Zürich
| | - Esther Werth
- 2 Sleep and Health Zürich (SHZ), Universität Zürich
- 3 Klinik für Neurologie, Universitätsspital Zürich
| | - Hans-Peter Landolt
- 2 Sleep and Health Zürich (SHZ), Universität Zürich
- 4 Institut für Pharmakologie und Toxikologie, Universität Zürich
| |
Collapse
|
|
48
|
Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry 2018; 87:234-244. [PMID: 28734941 DOI: 10.1016/j.pnpbp.2017.07.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/15/2017] [Accepted: 07/15/2017] [Indexed: 01/21/2023]
Abstract
Pain is an unwelcome sleep partner. Pain tends to erode sleep quality and alter the sleep restorative process in vulnerable patients. It can contribute to next-day sleepiness and fatigue, affecting cognitive function. Chronic pain and the use of opioid medications can also complicate the management of sleep disorders such as insomnia (difficulty falling and/or staying asleep) and sleep-disordered breathing (sleep apnea). Sleep problems can be related to various types of pain, including sleep headache (hypnic headache, cluster headache, migraine) and morning headache (transient tension type secondary to sleep apnea or to sleep bruxism or tooth grinding) as well as periodic limb movements (leg and arm dysesthesia with pain). Pain and sleep management strategies should be personalized to reflect the patient's history and ongoing complaints. Understanding the pain-sleep interaction requires assessments of: i) sleep quality, ii) potential contributions to fatigue, mood, and/or wake time functioning; iii) potential concomitant sleep-disordered breathing (SDB); and more importantly; iv) opioid use, as central apnea may occur in at-risk patients. Treatments include sleep hygiene advice, cognitive behavioral therapy, physical therapy, breathing devices (continuous positive airway pressure - CPAP, or oral appliance) and medications (sleep facilitators, e.g., zolpidem; or antidepressants, e.g., trazodone, duloxetine, or neuroleptics, e.g., pregabalin). In the presence of opioid-exacerbated SDB, if the dose cannot be reduced and normal breathing restored, servo-ventilation is a promising avenue that nevertheless requires close medical supervision.
Collapse
Affiliation(s)
- Serguei Marshansky
- CIUSSS du Nord de l'Île de Montréal, Hôpital Sacré-Cœur, Québec, Canada; Hôpital Hôtel-Dieu du Centre Hospitalier de l'Université de Montréal (CHUM), Faculté de Médecine, Université de Montréal, Québec, Canada
| | - Pierre Mayer
- Hôpital Hôtel-Dieu du Centre Hospitalier de l'Université de Montréal (CHUM), Faculté de Médecine, Université de Montréal, Québec, Canada
| | - Dorrie Rizzo
- Jewish General, Université de Montréal, Montréal, Québec, Canada
| | - Marc Baltzan
- Faculty of Medicine, McGill University, Mount Sinai Hospital, Montréal, Canada
| | - Ronald Denis
- CIUSSS du Nord de l'Île de Montréal, Hôpital Sacré-Cœur, Québec, Canada
| | - Gilles J Lavigne
- CIUSSS du Nord de l'Île de Montréal, Hôpital Sacré-Cœur, Québec, Canada; Faculty of Dental Medicine, Université de Montréal, Department of Stomatology, CHUM, Montréal, Québec, Canada.
| |
Collapse
|
|
49
|
Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit. Brain Res 2018; 1731:146037. [PMID: 30481504 DOI: 10.1016/j.brainres.2018.11.032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 11/19/2018] [Accepted: 11/23/2018] [Indexed: 12/20/2022]
Abstract
Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a 'defense reaction' with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin → NALC → LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin → NALC → LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).
Collapse
|
|
50
|
Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hypocretin/Orexin receptor 1-KO mice. Sci Rep 2018; 8:15474. [PMID: 30341359 PMCID: PMC6195537 DOI: 10.1038/s41598-018-33069-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 09/21/2018] [Indexed: 11/08/2022] Open
Abstract
Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NALC) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NALC cells. To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1Dbh-CKO) mice’, and their control littermates’ electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1Dbh-CKO mice exhibited a weakened ability to lower infra-θ frequencies (1–7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55–80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15–45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ activities. Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors. Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-δ waves (0.75–2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal.
Collapse
|