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Gaulden AD, Tepe EA, Sia E, Rollins SS, McReynolds JR. Repeated footshock stress enhances cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1. Physiol Behav 2025; 293:114840. [PMID: 39922412 DOI: 10.1016/j.physbeh.2025.114840] [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] [Received: 07/19/2023] [Revised: 01/02/2025] [Accepted: 02/05/2025] [Indexed: 02/10/2025]
Abstract
Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model of rat self-administration that employs an electric footshock stressor at the time of cocaine self-administration, resulting in an enhancement of cocaine self-administration. This stress enhancement of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress enhances cocaine self-administration in male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine self-administration in both male and female rats. Male and female Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2 hr access was separated into four 30 min self-administration blocks separated by four 5 min drug free periods. Footshock stress significantly increased cocaine self-administration similarly in both male and female rats. Females displayed greater stress-enhanced time-out, non-reinforced responding, and stress-specific "front-loading" behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine self-administration in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine self-administration in stress-enhanced rats, similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes.
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Affiliation(s)
- Andrew D Gaulden
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Erin A Tepe
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Eleni Sia
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Sierra S Rollins
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Jayme R McReynolds
- Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States; Center for Addiction Research, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
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Sarfi M, Elahdadi Salmani M, Lashkarbolouki T, Goudarzi I. Divergent effects of noradrenergic activation and orexin receptor 1 blockade on hippocampal structure, anxiety-like behavior, and social interaction following chronic stress. Pharmacol Biochem Behav 2025; 250:173997. [PMID: 40073949 DOI: 10.1016/j.pbb.2025.173997] [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: 12/18/2024] [Revised: 03/06/2025] [Accepted: 03/07/2025] [Indexed: 03/14/2025]
Abstract
Chronic stress (Ch.S) has detrimental effects on the brain's structure and function, particularly in the hippocampus. The noradrenergic and orexinergic systems play crucial roles in the stress response and regulation of stress-related behaviors. This study aimed to investigate the interaction between noradrenergic activation and orexin receptor 1 inhibition on chronic stress-induced hippocampal alterations. The study conducted experiments on male Wistar rats, subjected to Ch.S, OXr1 blocking, noradrenergic activation, or a combination of these treatments. Plasma corticosterone level was measured using a fluorometric method. Behavioral assessment of social maze, elevated plus maze (EPM) and novel object recognition (NOR) test were performed. Then, the expression of prepro-orexin, OXr1, and glucocorticoid receptor (GR) was analyzed using semiquantitative RT-PCR. Neuronal populations were quantified through Nissl staining. The data revealed that all stress and yohimbine groups had elevated plasma corticosterone levels. Ch.S significantly altered behavior, impairing social interaction, disrupting object recognition memory and increasing anxiety-like responses in the EPM. OXr1 blocking reversed these stress-induced behavioral deficits, while yohimbine did not improve these behavioral outcomes. Chronic stress led to a significant increase in prepro-orexin, OXr1, and GR expression. While blocking OXr1 helped counteract these stress-induced changes, yohimbine failed to restore the expression levels. Ch.S reduced hippocampal neuronal populations, while OXr1 blocking partially reversed this effect, and yohimbine further recovered the reversal. These findings indicate that blocking hippocampal OXr1 can mitigate the adverse effects of chronic stress on both hippocampal structure and anxiety-like behaviors, while noradrenergic signaling appears to have differential effects on behavioral and cellular measures.
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Affiliation(s)
| | | | | | - Iran Goudarzi
- School of Biology, Damghan University, Damghan, Iran.
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Renda B, Leri F. The anxiogenic drug yohimbine is a reinforcer in male and female rats. Neuropsychopharmacology 2024; 50:432-443. [PMID: 39289489 PMCID: PMC11631961 DOI: 10.1038/s41386-024-01985-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024]
Abstract
The indole alkaloid yohimbine is an anxiogenic drug that activates stress-responsive systems in the brain. However, because yohimbine also elicits approach behaviors, this study employed male and female Sprague-Dawley rats to explore its potential reinforcing effects. Thus, it was first determined if intravenous (IV) infusions of yohimbine (0.25 mg/kg/infusion) could maintain lever pressing, whether intake could be modulated by dose/infusion, and if lever pressing would persist in the absence of yohimbine or yohimbine-paired cues. Next, to assess yohimbine's effect on memory consolidation, 0.3, 1.25 or 3 mg/kg yohimbine was administered post-training using an object recognition memory task. Finally, place conditioning assessed whether doses of yohimbine that elevate blood serum corticosterone levels (1.25 or 3 mg/kg) could elicit a conditioned place preference. It was found that both sexes acquired yohimbine IV self-administration, that intake was modulated by dose/infusion, and that lever pressing persisted during extinction and in the absence of the yohimbine-paired cue. As well, post-training injections of 1.25 mg/kg yohimbine enhanced consolidation of object memory, and 1.25 and 3 mg/kg elevated corticosterone levels and elicited a place preference in both sexes. Finally, in behavioral tests of psychomotor functions, acute yohimbine increased lever pressing for a visual cue and elevated locomotor activity. These findings reveal a profile of yohimbine's behavioral effects that is consistent with that of psychostimulant reinforcing drugs.
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Affiliation(s)
- Briana Renda
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada
| | - Francesco Leri
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.
- Department of Psychology, University of Toronto, Scarborough, ON, Canada.
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Clark PJ, Migovich VM, Das S, Xi W, Kortagere S, España RA. Hypocretin Receptor 1 Blockade Early in Abstinence Prevents Incubation of Cocaine Seeking and Normalizes Dopamine Transmission. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.30.625912. [PMID: 39651183 PMCID: PMC11623669 DOI: 10.1101/2024.11.30.625912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Abstinence from cocaine use has been shown to elicit a progressive intensification or incubation of cocaine craving/seeking that is posited to contribute to propensity for relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking and thereby reduce the likelihood of relapse. In the present studies, we first examined if incubation of cocaine seeking was associated with aberrant dopamine transmission in the nucleus accumbens after seven days of abstinence from intermittent access to cocaine. Given the extensive evidence that hypocretins/orexins regulate motivation for cocaine, we then examined to what extent hypocretin receptor 1 antagonism on the first day of abstinence prevented incubation of cocaine seeking and dopamine adaptations later in abstinence. Results indicated that abstinence from intermittent access to cocaine engendered robust incubation of cocaine seeking in both female and male rats. We also observed aberrant dopamine transmission, but only in rats that displayed incubation of cocaine seeking. Further, we showed that a single injection of the hypocretin receptor 1 antagonist, RTIOX-276, on the first day of abstinence prevented incubation of cocaine seeking and aberrant dopamine transmission. These findings suggest that hypocretin receptor 1 antagonism may serve as a viable therapeutic for reducing cocaine craving/seeking, thus reducing the likelihood of relapse.
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Mohammadkhani A, Mitchell C, James MH, Borgland SL, Dayas CV. Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation. Br J Pharmacol 2024; 181:4430-4449. [PMID: 39317446 PMCID: PMC11458361 DOI: 10.1111/bph.17325] [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: 07/30/2023] [Revised: 06/17/2024] [Accepted: 06/28/2024] [Indexed: 09/26/2024] Open
Abstract
The orexin (also known as hypocretin) system, consisting of neuropeptides orexin-A and orexin-B, was discovered over 25 years ago and was immediately identified as a central regulator of sleep and wakefulness. These peptides interact with two G-protein coupled receptors, orexin 1 (OX1) and orexin 2 (OX2) receptors which are capable of coupling to all heterotrimeric G-protein subfamilies, but primarily transduce increases in calcium signalling. Orexin neurons are regulated by a variety of transmitter systems and environmental stimuli that signal reward availability, including food and drug related cues. Orexin neurons are also activated by anticipation, stress, cues predicting motivationally relevant information, including those predicting drugs of abuse, and engage neuromodulatory systems, including dopamine neurons of the ventral tegmental area (VTA) to respond to these signals. As such, orexin neurons have been characterized as motivational activators that coordinate a range of functions, including feeding and arousal, that allow the individual to respond to motivationally relevant information, critical for survival. This review focuses on the role of orexins in appetitive motivation and highlights a role for these neuropeptides in pathologies characterized by inappropriately high levels of motivated arousal (overeating, anxiety and substance use disorders) versus those in which motivation is impaired (depression).
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Affiliation(s)
- Aida Mohammadkhani
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, Alberta, Canada
| | - Caitlin Mitchell
- School of Biomedical Sciences and Pharmacy, University of Newcastle, University Drive, Callaghan, New South Wales, Australia
- The Hunter Medical Research, New Lambton Heights, New South Wales, Australia
| | - Morgan H James
- Department of Psychiatry and Brain Health Institute, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA
| | - Stephanie L Borgland
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, The University of Calgary, Calgary, Alberta, Canada
| | - Christopher V Dayas
- School of Biomedical Sciences and Pharmacy, University of Newcastle, University Drive, Callaghan, New South Wales, Australia
- The Hunter Medical Research, New Lambton Heights, New South Wales, Australia
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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.
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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
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Bjorness TE, Greene RW. Orexin-mediated motivated arousal and reward seeking. Peptides 2024; 180:171280. [PMID: 39159833 DOI: 10.1016/j.peptides.2024.171280] [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: 05/19/2024] [Revised: 08/03/2024] [Accepted: 08/05/2024] [Indexed: 08/21/2024]
Abstract
The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal.
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Affiliation(s)
- Theresa E Bjorness
- Research Service, VA North Texas Health Care System, Dallas, TX 75126, USA; Departments of Psychiatry University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
| | - Robert W Greene
- Departments of Psychiatry University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba 305-8577, Japan
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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.
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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.)
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Illenberger JM, Flores-Ramirez FJ, Pascasio G, Franco M, Mendonsa B, Martin-Fardon R. Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior. J Psychopharmacol 2024; 38:647-660. [PMID: 38888086 PMCID: PMC11407285 DOI: 10.1177/02698811241260989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
BACKGROUND The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. AIMS This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. METHODS Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress. RESULTS The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking. CONCLUSIONS The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder.
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Williams JT, Bolli MH, Brotschi C, Sifferlen T, Steiner MA, Treiber A, Gatfield J, Boss C. Discovery of Nivasorexant (ACT-539313): The First Selective Orexin-1 Receptor Antagonist (SO1RA) Investigated in Clinical Trials. J Med Chem 2024; 67:2337-2348. [PMID: 38331429 DOI: 10.1021/acs.jmedchem.3c01894] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2024]
Abstract
The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant (20) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.
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Affiliation(s)
- Jodi T Williams
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Martin H Bolli
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Christine Brotschi
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Thierry Sifferlen
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Michel A Steiner
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Alexander Treiber
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - John Gatfield
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
| | - Christoph Boss
- Drug Discovery, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland
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11
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Chen KT, Huang MC, Lin C, Chang HM, Kao CF. GxE interaction effects of HCRTR2 single nucleotide polymorphism and adverse childhood experiences on methamphetamine use disorder. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:84-94. [PMID: 38295363 DOI: 10.1080/00952990.2023.2297661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 12/18/2023] [Indexed: 02/02/2024]
Abstract
Background: Methamphetamine use disorder (MUD) is a worldwide health concern. The hypothalamic orexin system regulates stress response and addictive behaviors. The genetic variation in the hypocretin receptor 2 (HCRTR2), rs2653349, is associated with substance use disorder.Objectives: We explored the gene-environment (GxE) interaction of rs2653349 and adverse childhood experiences (ACEs) associated with MUD susceptibility.Methods: Four hundred and one individuals (336 males, 65 females) with MUD and 348 healthy controls (288 males, 60 females) completed a self-report questionnaire evaluating ACEs, encompassing childhood abuse and household dysfunction categories, and were genotyped for SNP rs2653349. Methamphetamine use variables were collected using the Diagnostic Interview for Genetic Studies. We used regression analyses to assess the GxE effect on MUD risk.Results: The MUD group had a comparable genotypic distribution for rs2653349 to the control group, albeit with a higher prevalence and number of types of ACEs, correlating with an increased MUD risk (p < .05). No significant genetic impact of rs2653349 on MUD risk was found. However, we observed a GxE interaction effect between the minor allele of rs2653349 and the number of childhood abuse or household dysfunction types, correlating with a reduced MUD risk (OR = -0.71, p = .04, Benjamini-Hochberg adjusted p = .08 and OR = -0.59, p = .045, Benjamini-Hochberg adjusted p = .09, respectively).Conclusion: HCRTR2 SNP rs2653349 has no significant impact on MUD risk, but ACEs may increase this risk. GxE results suggest that rs2653349 could offer protection against developing MUD in individuals experiencing multiple types of ACEs.
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Affiliation(s)
- Kai-Ting Chen
- Department of General Medicine, Taipei City Hospital, Taipei, Taiwan
| | - Ming-Chyi Huang
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun Lin
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
| | - Hu-Ming Chang
- Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan
| | - Chung-Feng Kao
- Department of Agronomy, College of Agriculture and Natural Resources, National Chung Hsing University, Taichung, Taiwan
- Advanced Plant and Food Crop Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
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12
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Mazaheri S, Zendehdel M, Haghparast A. Restraint stress potentiates sensitivity to the antinociceptive effect of morphine through orexin receptors in the ventral tegmental area. Neuropeptides 2023; 101:102353. [PMID: 37385145 DOI: 10.1016/j.npep.2023.102353] [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: 02/23/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Orexin signaling in the ventral tegmental area (VTA) plays a critical role in stress and addictive behaviors. On the other hand, exposure to stress potentiates behavioral sensitization to drugs of abuse such as morphine. This study aimed to elucidate the role of orexin receptors within the VTA in restraint stress (RS)-induced morphine sensitization. Adult male albino Wistar rats underwent stereotaxic surgery, and two stainless steel guide cannulae were bilaterally implanted into the VTA. Different doses of SB334867 or TCS OX2 29 as orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists were microinjected into the VTA five min before exposure to RS, respectively. A duration of three hours was considered for applying the RS, and 10 min after RS exposure, animals received a subcutaneous injection of an ineffective dose of morphine (1 mg/kg) for three consecutive days followed by a five-day drug/stress-free period. On the ninth day, the tail-flick test evaluated the sensitivity to the antinociceptive effects of morphine. The results demonstrated that the sole application of RS or morphine (1 mg/kg) could not induce morphine sensitization; however, concurrent application of RS and morphine could induce morphine sensitization. Besides, intra-VTA administration of OX1 R or OX2 R antagonists before paired administration of morphine and RS blocked morphine sensitization. The role of OX1 R and OX2 R in the induction of stress-induced morphine sensitization was almost identical. This study provides new insight into the role of orexin signaling in the VTA in the potentiation of morphine sensitization induced by RS and morphine co-administration.
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Affiliation(s)
- Sajad Mazaheri
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morteza Zendehdel
- Department of Physiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
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13
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Peleg-Raibstein D, Viskaitis P, Burdakov D. Eat, seek, rest? An orexin/hypocretin perspective. J Neuroendocrinol 2023; 35:e13259. [PMID: 36994677 DOI: 10.1111/jne.13259] [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: 12/21/2022] [Revised: 03/06/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023]
Abstract
Seeking and ingesting nutrients is an essential cycle of life in all species. In classical neuropsychology these two behaviours are viewed as fundamentally distinct from each other, and known as appetitive and consummatory, respectively. Appetitive behaviour is highly flexible and diverse, but typically involves increased locomotion and spatial exploration. Consummatory behaviour, in contrast, typically requires reduced locomotion. Another long-standing concept is "rest and digest", a hypolocomotive response to calorie intake, thought to facilitate digestion and storage of energy after eating. Here, we note that the classical seek➔ingest➔rest behavioural sequence is not evolutionarily advantageous for all ingested nutrients. Our limited stomach capacity should be invested wisely, rather than spent on the first available nutrient. This is because nutrients are not simply calories: some nutrients are more essential for survival than others. Thus, a key choice that needs to be made soon after ingestion: to eat more and rest, or to terminate eating and search for better food. We offer a perspective on recent work suggesting how nutrient-specific neural responses shape this choice. Specifically, the hypothalamic hypocretin/orexin neurons (HONs) - cells that promote hyperlocomotive explorative behaviours - are rapidly and differentially modulated by different ingested macronutrients. Dietary non-essential (but not essential) amino acids activate HONs, while glucose depresses HONs. This nutrient-specific HON modulation engages distinct reflex arcs, seek➔ingest➔seek and seek➔ingest➔rest, respectively. We propose that these nutri-neural reflexes evolved to facilitate optimal nutrition despite the limitations of our body.
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Affiliation(s)
- Daria Peleg-Raibstein
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
| | - Paulius Viskaitis
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
| | - Denis Burdakov
- ETH Zürich, Department of Health Sciences and Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland
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14
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Black EM, Samels SB, Xu W, Barson JR, Bass CE, Kortagere S, España RA. Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine. ADDICTION NEUROSCIENCE 2023; 7:100104. [PMID: 37854172 PMCID: PMC10583964 DOI: 10.1016/j.addicn.2023.100104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine - suggesting a complex interplay between DA transmission and behavior.
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Affiliation(s)
- Emily M. Black
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Shanna B. Samels
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Wei Xu
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Jessica R. Barson
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Caroline E. Bass
- Department of Pharmacology and Toxicology, Jacobs School of Medicine, State University of New York at Buffalo, Buffalo NY 14214
| | - Sandhya Kortagere
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129
| | - Rodrigo A. España
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129
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15
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Bouâouda H, Jha PK. Orexin and MCH neurons: regulators of sleep and metabolism. Front Neurosci 2023; 17:1230428. [PMID: 37674517 PMCID: PMC10478345 DOI: 10.3389/fnins.2023.1230428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 08/07/2023] [Indexed: 09/08/2023] Open
Abstract
Sleep-wake and fasting-feeding are tightly coupled behavioral states that require coordination between several brain regions. The mammalian lateral hypothalamus (LH) is a functionally and anatomically complex brain region harboring heterogeneous cell populations that regulate sleep, feeding, and energy metabolism. Significant attempts were made to understand the cellular and circuit bases of LH actions. Rapid advancements in genetic and electrophysiological manipulation help to understand the role of discrete LH cell populations. The opposing action of LH orexin/hypocretin and melanin-concentrating hormone (MCH) neurons on metabolic sensing and sleep-wake regulation make them the candidate to explore in detail. This review surveys the molecular, genetic, and neuronal components of orexin and MCH signaling in the regulation of sleep and metabolism.
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Affiliation(s)
- Hanan Bouâouda
- Pharmacology Institute, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Pawan Kumar Jha
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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16
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Strickland JC, Hatton KW, Hays LR, Rayapati AO, Lile JA, Rush CR, Stoops WW. Use of drug purchase tasks in medications development research: orexin system regulation of cocaine and drug demand. Behav Pharmacol 2023; 34:275-286. [PMID: 37403694 PMCID: PMC10328554 DOI: 10.1097/fbp.0000000000000731] [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] [Indexed: 07/06/2023]
Abstract
Commodity purchase tasks provide a useful method for evaluating behavioral economic demand in the human laboratory. Recent research has shown how responding to purchase tasks for blinded drug administration can be used to study abuse liability. This analysis uses data from a human laboratory study to highlight how similar procedures may be particularly useful for understanding momentary changes in drug valuation when screening novel interventions. Eight nontreatment-seeking participants with cocaine use disorder (one with partial data) were enrolled in a cross-over, double-blind, randomized inpatient study. Participants were maintained on the Food and Drug Administration-approved insomnia medication suvorexant (oral; 0, 5, 10, 20 mg/day) in randomized order with experimental sessions completed after at least 3 days of maintenance on each suvorexant dose. Experimental sessions included administration of a sample dose of 0, 10 and 30 mg/70 kg intravenous cocaine. Analyses focused on purchase tasks for the blinded sample dose as well as alcohol, cigarettes and chocolate completed 15 min after the sample dose. As expected based on abuse liability, near zero demand was observed for placebo with dose-related increases in cocaine demand. Suvorexant maintenance increased cocaine demand in a dose-related manner with the greatest increase observed for the 10 mg/kg cocaine dose. Increased demand under suvorexant maintenance was also observed for alcohol. No effect of cocaine administration was observed for alcohol, cigarette, or chocolate demand. These data support the validity of demand procedures for measuring blinded drug demand. Findings also parallel self-administration data from this study by showing increases in cocaine use motivation under suvorexant maintenance.
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Affiliation(s)
- Justin C Strickland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kevin W Hatton
- Department of Anesthesiology, University of Kentucky College of Medicine
| | - Lon R Hays
- Department of Psychiatry, University of Kentucky College of Medicine
| | - Abner O Rayapati
- Department of Psychiatry, University of Kentucky College of Medicine
| | - Joshua A Lile
- Department of Psychiatry, University of Kentucky College of Medicine
- Department of Behavioral Science, University of Kentucky College of Medicine
- Department of Psychology, University of Kentucky College of Arts and Sciences
| | - Craig R Rush
- Department of Psychiatry, University of Kentucky College of Medicine
- Department of Behavioral Science, University of Kentucky College of Medicine
- Department of Psychology, University of Kentucky College of Arts and Sciences
| | - William W Stoops
- Department of Psychiatry, University of Kentucky College of Medicine
- Department of Behavioral Science, University of Kentucky College of Medicine
- Department of Psychology, University of Kentucky College of Arts and Sciences
- Center on Drug and Alcohol Research, University of Kentucky College of Medicine, Lexington, Kentucky, USA
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17
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Koob GF, Vendruscolo L. Theoretical Frameworks and Mechanistic Aspects of Alcohol Addiction: Alcohol Addiction as a Reward Deficit/Stress Surfeit Disorder. Curr Top Behav Neurosci 2023. [PMID: 37421551 DOI: 10.1007/7854_2023_424] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2023]
Abstract
Alcohol use disorder (AUD) can be defined by a compulsion to seek and take alcohol, the loss of control in limiting intake, and the emergence of a negative emotional state when access to alcohol is prevented. Alcohol use disorder impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). Compulsive drug seeking that is associated with AUD can be derived from multiple neuroadaptations, but the thesis argued herein is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of specific neurochemical elements that are involved in reward and stress within basal forebrain structures that involve the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include decreases in reward neurotransmission (e.g., decreases in dopamine and opioid peptide function in the ventral striatum) and the recruitment of brain stress systems (e.g., corticotropin-releasing factor [CRF]) in the extended amygdala, which contributes to hyperkatifeia and greater alcohol intake that is associated with dependence. Glucocorticoids and mineralocorticoids may play a role in sensitizing the extended amygdala CRF system. Other components of brain stress systems in the extended amygdala that may contribute to the negative motivational state of withdrawal include norepinephrine in the bed nucleus of the stria terminalis, dynorphin in the nucleus accumbens, hypocretin and vasopressin in the central nucleus of the amygdala, and neuroimmune modulation. Decreases in the activity of neuropeptide Y, nociception, endocannabinoids, and oxytocin in the extended amygdala may also contribute to hyperkatifeia that is associated with alcohol withdrawal. Such dysregulation of emotional processing may also significantly contribute to pain that is associated with alcohol withdrawal and negative urgency (i.e., impulsivity that is associated with hyperkatifeia during hyperkatifeia). Thus, an overactive brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of AUD. The combination of the loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement that at least partially drives the compulsivity of AUD.
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Affiliation(s)
- George F Koob
- Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
| | - Leandro Vendruscolo
- Integrative Neuroscience Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA
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18
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Ten-Blanco M, Flores Á, Cristino L, Pereda-Pérez I, Berrendero F. Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: from animal to clinical studies. Front Neuroendocrinol 2023; 69:101066. [PMID: 37015302 DOI: 10.1016/j.yfrne.2023.101066] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/15/2023] [Accepted: 03/30/2023] [Indexed: 04/06/2023]
Abstract
Orexins (also known as hypocretins) are neuropeptides located exclusively in hypothalamic neurons that have extensive projections throughout the central nervous system and bind two different G protein-coupled receptors (OX1R and OX2R). Since its discovery in 1998, the orexin system has gained the interest of the scientific community as a potential therapeutic target for the treatment of different pathological conditions. Considering previous basic science research, a dual orexin receptor antagonist, suvorexant, was the first orexin agent to be approved by the US Food and Drug Administration to treat insomnia. In this review, we discuss and update the main preclinical and human studies involving the orexin system with several psychiatric and neurodegenerative diseases. This system constitutes a nice example of how basic scientific research driven by curiosity can be the best route to the generation of new and powerful pharmacological treatments.
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Affiliation(s)
- Marc Ten-Blanco
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Pozuelo de Alarcón, Madrid, Spain
| | - África Flores
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Neurosciences Institute, University of Barcelona and Bellvitge University Hospital-IDIBELL, 08908 L'Hospitalet de Llobregat, Barcelona, Spain
| | - Luigia Cristino
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Pozzuoli, Italy
| | - Inmaculada Pereda-Pérez
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Pozuelo de Alarcón, Madrid, Spain
| | - Fernando Berrendero
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, 28223 Pozuelo de Alarcón, Madrid, Spain.
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19
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Nikbakhtzadeh M, Ranjbar H, Moradbeygi K, Zahedi E, Bayat M, Soti M, Shabani M. Cross-talk between the HPA axis and addiction-related regions in stressful situations. Heliyon 2023; 9:e15525. [PMID: 37151697 PMCID: PMC10161713 DOI: 10.1016/j.heliyon.2023.e15525] [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: 10/17/2022] [Revised: 04/04/2023] [Accepted: 04/12/2023] [Indexed: 05/09/2023] Open
Abstract
Addiction is a worldwide problem that has a negative impact on society by imposing significant costs on health care, public security, and the deactivation of the community economic cycle. Stress is an important risk factor in the development of addiction and relapse vulnerability. Here we review studies that have demonstrated the diverse roles of stress in addiction. Term searches were conducted manually in important reference journals as well as in the Google Scholar and PubMed databases, between 2010 and 2022. In each section of this narrative review, an effort has been made to use pertinent sources. First, we will provide an overview of changes in the Hypothalamus-Pituitary-Adrenal (HPA) axis component following stress, which impact reward-related regions including the ventral tegmental area (VTA) and nucleus accumbens (NAc). Then we will focus on internal factors altered by stress and their effects on drug addiction vulnerability. We conclude that alterations in neuro-inflammatory, neurotrophic, and neurotransmitter factors following stress pathways can impact related mechanisms on craving and relapse susceptibility.
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Affiliation(s)
- Marjan Nikbakhtzadeh
- Department of Physiology, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Hoda Ranjbar
- Neuroscience Research Center of Kerman, Institute of Neuropharmacology, Kerman University of Medical Science, Kerman, Iran
| | | | - Elham Zahedi
- Department of Physiology, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mahnaz Bayat
- Clinical Neurology Research Centre, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Monavareh Soti
- Neuroscience Research Center of Kerman, Institute of Neuropharmacology, Kerman University of Medical Science, Kerman, Iran
- Corresponding author. Neuroscience Research Center, Neuropharmacology institute, Kerman University of Medical Sciences, Kerman, Postal Code: 76198-13159, Iran.
| | - Mohammad Shabani
- Neuroscience Research Center of Kerman, Institute of Neuropharmacology, Kerman University of Medical Science, Kerman, Iran
- Corresponding author. Neuroscience Research Center, Neuropharmacology institute, Kerman University of Medical Sciences, Kerman, Postal Code: 76198-13159, Iran.
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20
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Beckenstrom AC, Coloma PM, Dawson GR, Finlayson AK, Malik A, Post A, Steiner MA, Potenza MN. Use of experimental medicine approaches for the development of novel psychiatric treatments based on orexin receptor modulation. Neurosci Biobehav Rev 2023; 147:105107. [PMID: 36828161 PMCID: PMC10165155 DOI: 10.1016/j.neubiorev.2023.105107] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/08/2023] [Accepted: 02/18/2023] [Indexed: 02/25/2023]
Abstract
Despite progress in understanding the pathological mechanisms underlying psychiatric disorders, translation from animal models into clinical use remains a significant bottleneck. Preclinical studies have implicated the orexin neuropeptide system as a potential target for psychiatric disorders through its role in regulating emotional, cognitive, and behavioral processes. Clinical studies are investigating orexin modulation in addiction and mood disorders. Here we review performance-outcome measures (POMs) arising from experimental medicine research methods which may show promise as markers of efficacy of orexin receptor modulators in humans. POMs provide objective measures of brain function, complementing patient-reported or clinician-observed symptom evaluation, and aid the translation from preclinical to clinical research. Significant challenges include the development, validation, and operationalization of these measures. We suggest that collaborative networks comprising clinical practitioners, academics, individuals working in the pharmaceutical industry, drug regulators, patients, patient advocacy groups, and other relevant stakeholders may provide infrastructure to facilitate validation of experimental medicine approaches in translational research and in the implementation of these approaches in real-world clinical practice.
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Affiliation(s)
- Amy C Beckenstrom
- P1vital Ltd, Manor House, Howbery Business Park, Wallingford OX10 8BA, UK.
| | - Preciosa M Coloma
- Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, Allschwil 4123, Switzerland
| | - Gerard R Dawson
- P1vital Ltd, Manor House, Howbery Business Park, Wallingford OX10 8BA, UK
| | - Ailidh K Finlayson
- P1vital Ltd, Manor House, Howbery Business Park, Wallingford OX10 8BA, UK; Department of Psychology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Asad Malik
- P1vital Ltd, Manor House, Howbery Business Park, Wallingford OX10 8BA, UK
| | - Anke Post
- Corlieve Therapeutics, Swiss Innovation Park, Hegenheimermattweg 167A, 4123 Allschwil, Switzerland
| | | | - Marc N Potenza
- Departments of Psychiatry and Neuroscience and the Child Study Center, Yale School of Medicine, 1 Church Street, Room 726, New Haven, CT 06510, USA; Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519, USA; Connecticut Council on Problem Gambling, Wethersfield, CT, USA; The Wu Tsai Institute, Yale University, 100 College St, New Haven, CT 06510, USA
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21
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Gaulden AD, Tepe EA, Sia E, Rollins SS, McReynolds JR. Repeated footshock stress induces an escalation of cocaine self-administration in male and female rats: Role of the cannabinoid receptor 1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.23.529774. [PMID: 36865137 PMCID: PMC9980083 DOI: 10.1101/2023.02.23.529774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Stress is a significant contributor to the development and progression of substance use disorders (SUDs) and is problematic as it is unavoidable in daily life. Therefore, it is important to understand the neurobiological mechanisms that underlie the influence of stress on drug use. We have previously developed a model to examine the contribution of stress to drug-related behavior by administering a stressor, electric footshock stress, daily at the time of cocaine self-administration in rats resulting in an escalation of cocaine intake. This stress-induced escalation of cocaine intake involves neurobiological mediators of stress and reward such as cannabinoid signaling. However, all of this work has been conducted in male rats. Here we test the hypothesis that repeated daily stress can produce an escalation of cocaine in both male and female rats. We further hypothesize that cannabinoid receptor 1 (CB1R) signaling is recruited by repeated stress to influence cocaine intake in both male and female rats. Male and female Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during a modified short-access paradigm wherein the 2-hr access was separated into 4-30 min self-administration blocks separated by 4-5 min drug free period. Footshock stress produced a significant escalation of cocaine intake similarly in both male and female rats. Female stress-escalated rats did display greater time-out non-reinforced responding and greater "front-loading" behavior. In males, systemic administration of a CB1R inverse agonist/antagonist Rimonabant only attenuated cocaine intake in rats with a history of combined repeated stress and cocaine self-administration. However, in females, Rimonabant attenuated cocaine intake in the no stress control group but only at the highest dose of Rimonabant (3 mg/kg, i.p.) suggesting that females show a greater sensitivity to CB1R antagonism. However, female rats with a history of stress showed even greater sensitivity to CB1R antagonism as both doses of Rimonabant (1, 3 mg/kg) attenuated cocaine intake in stress-escalated rats similar to males. Altogether these data demonstrate that stress can produce significant changes in cocaine self-administration and suggests that repeated stress at the time of cocaine self-administration recruits CB1Rs to regulate cocaine-taking behavior across sexes.
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22
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Veisi A, Khaleghzadeh-Ahangar H, Fattahi M, Haghparast A. The Role of Orexin-1 Receptors Within the Hippocampal CA1 Area in the Extinction and Reinstatement of Methamphetamine-Seeking Behaviors. Neurochem Res 2023; 48:671-680. [PMID: 36284025 DOI: 10.1007/s11064-022-03793-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/08/2022] [Accepted: 10/13/2022] [Indexed: 02/04/2023]
Abstract
Psychostimulant addiction is a chronic brain disorder with high relapse rates, requiring new therapeutic strategies. The orexin system is highly implicated in processing reward and addiction through connections with critical areas such as the hippocampus. This study investigated the role of orexin-1 receptors (OX1R) within the CA1 subregion of the hippocampus in the extinction and reinstatement of the methamphetamine-induced conditioned place preference. After cannulae implantation, recovery, and establishing the methamphetamine place preference, 98 male Wistar rats received different doses of bilateral intra-CA1 selective OX1R antagonist, SB334867 (1, 3, 10, and 30 nmol/0.5 μl DMSO per side) during the 10-day extinction period (daily) or after extinction phase, just on the reinstatement day (single dose) in separate experimental and control groups. The findings indicated that bilateral microinjection of SB334867 into the CA1 area during the extinction period could significantly reduce the extinction latency and maintenance of rewarding aspects of methamphetamine dose-dependently (3, 10, and 30 nmol). In another set of experiments, a single dose of bilateral intra-CA1 SB334867 administration on the reinstatement phase prevented the methamphetamine-induced reinstatement of drug-seeking behaviors at the high doses (10, and 30 nmol). The present study provided more evidence for the implication of hippocampal OX1R in the maintenance of rewarding and reinforcing properties of methamphetamine and its role in the relapse of methamphetamine-seeking behavior. Further investigations on the role of the orexin system, including the orexin-2 receptors in treating addiction, are needed to introduce its antagonists as effective therapeutic options for psychostimulant addiction.
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Affiliation(s)
- Ali Veisi
- Department of Physiology, Behbahan Faculty of Medical Sciences, Behbahan, Iran
| | - Hossein Khaleghzadeh-Ahangar
- Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
- Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mojdeh Fattahi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O.Box 19615-1178, Tehran, Iran
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O.Box 19615-1178, Tehran, Iran.
- School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran.
- Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
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23
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Tyree SM, Jennings KJ, Gonzalez OC, Li SB, Nicholson JR, von Heimendahl M, de Lecea L. Optogenetic and pharmacological interventions link hypocretin neurons to impulsivity in mice. Commun Biol 2023; 6:74. [PMID: 36658362 PMCID: PMC9852239 DOI: 10.1038/s42003-023-04409-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.
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Affiliation(s)
- Susan M. Tyree
- grid.168010.e0000000419368956Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA USA ,Present Address: Atlantia Clinical Trials, Cork, Ireland
| | - Kimberly J. Jennings
- grid.168010.e0000000419368956Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA USA ,grid.55460.320000000121548364Present Address: University of Texas, Austin, TX USA
| | - Oscar C. Gonzalez
- grid.168010.e0000000419368956Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA USA
| | - Shi-bin Li
- grid.168010.e0000000419368956Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA USA
| | - Janet R. Nicholson
- grid.420061.10000 0001 2171 7500Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Moritz von Heimendahl
- grid.420061.10000 0001 2171 7500Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany
| | - Luis de Lecea
- grid.168010.e0000000419368956Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford, CA USA
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Amirteymori H, Karimi-Haghighi S, Mirmohammadi M, Majidinezhad M, Khosrowabadi E, Haghparast A. Hypocretin/orexin system in the nucleus accumbens as a promising player in the extinction and reinstatement of methamphetamine-induced CPP. Prog Neuropsychopharmacol Biol Psychiatry 2023; 120:110616. [PMID: 35988849 DOI: 10.1016/j.pnpbp.2022.110616] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 08/13/2022] [Accepted: 08/14/2022] [Indexed: 10/15/2022]
Abstract
One of the main obstacles in treating psychostimulant addiction is relapse even after long-term abstinence. The nucleus accumbens (NAc) is located in the basal forebrain, responsible for regulating several behaviors, specifically reward-related effect of psychostimulants. In the current study, an unbiased place conditioning paradigm was performed to inquire the role of the hypocretin/orexin system in the NAc in the extinction and reinstatement of methamphetamine (Meth)-induced conditioned place preference (CPP). Similar to previous investigations, rats were conditioned with Meth (1 mg/kg; sc) for five consecutive days to elicit CPP. The rats underwent Meth conditioning protocol received SB334867 or TCS OX2 29, an orexin receptor 1 (OXr1) antagonist or orexin receptor 2 (OXr2) antagonist (0, 3, 10, and 30 nmol/0.5 μL DMSO %12) in the NAc during the extinction period to elucidate the role of OXrs on the extinction of Meth-induced CPP. Meanwhile, extinguished rats received SB334867 or TCS OX2 29 (0, 1, 3, 10, and 30 nmol/0.5 μL DMSO %12) in the NAc prior to an effective priming dose of Meth to evaluate the impact of OXr antagonists on the reinstatement of Meth-induced CPP. The current data pointed out intra-NAc microinjection of SB334867 or TCS OX2 29 blocked both extinction and reinstatement of Meth-induced CPP. In addition, the OXr1 antagonist was more potent than the OXr2 antagonist to suppress both extinction and reinstatement phases of Meth-induced CPP. Based on the current data, the OX system in the NAc is extensively implicated in the reward properties of Meth; therefore, modulation of this system has therapeutic potential in treating psychostimulant use disorders.
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Affiliation(s)
- Haleh Amirteymori
- 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
| | - Mahboobeh Mirmohammadi
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Majidinezhad
- Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elahe Khosrowabadi
- 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; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran.
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Muacevic A, Adler JR. Physiological Role of Orexin/Hypocretin in the Human Body in Motivated Behavior: A Comprehensive Review. Cureus 2023; 15:e34009. [PMID: 36814741 PMCID: PMC9939734 DOI: 10.7759/cureus.34009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/20/2023] [Indexed: 01/22/2023] Open
Abstract
Neurohormones are neurosecretory materials released by neurosecretory cells that serve both as neuromodulators in the brain and spinal cord and as circulating regulatory hormones. They serve a wide range of functions, including homeostasis, development, and modulation of neuronal and muscle activity. In the hypothalamus, neurohormones called hypocretins are created that were discovered in the late nineties. Orexin receptors (OXRs) have been shown to enhance synaptic signaling in the central nervous system at the cellular level. The orexins improve stimulated neural activity in the hippocampus, which, in turn, aids with spatial memory, learning, and mood. They present themselves as mediators for the hypothalamic functions. They have been shown to regulate sleep-wake cycles, arousal mechanisms, addiction, sympathetic nerve activity (SNA), blood pressure, and thermogenesis. Its role in storing brown adipose tissue has implications for thermal homeostasis. The significant role of orexins is seen in tumorigenesis when orexin A (OrxA) and orexin B (OrxB) induce apoptosis in fast-growing tumor cells. Orexin-null subjects show clinical narcolepsy, indicating that orexins were responsible for keeping them awake. Orexin microinjections in mice brains stimulated increased physical activity, thus possibly countering diet-induced obesity. Physical activity significantly increased plasma orexin-A levels, which facilitated the process of energy homeostasis. The amount of adrenocorticotropic hormone (ACTH) increases in stress conditions, which further facilitates the release of the stress hormone cortisol. No increase in the ACTH hormone is seen in stressed mice administered with orexin receptor 2 (OX2R) antagonists thus showing orexin's role in stress reaction. As a result of linking hypocretin/orexin to various physiological procedures, increased research into the medicinal potential of drugs targeting these receptors is emerging. We summed up in this review the recent advances in our understanding of how orexin and its receptor system play an essential role in clinical and pathological functions. This research summarizes a new area for research in human medicine, providing the possibility of controlling a vast array of physiological functions through intra-cerebroventricular injections of a single neuropeptide.
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Abstract
Sleep health is an important factor across several physical and mental health disorders, and a growing scientific consensus has identified sleep as a critical component of opioid use disorder (OUD), both in the active disease state and during OUD recovery. The goal of this narrative review is to collate the literature on sleep, opioid use, and OUD as a means of identifying therapeutic targets to improve OUD treatment outcomes. Sleep disturbance is common and often severe in persons with OUD, especially during opioid withdrawal, but also in persons on opioid maintenance therapies. There is ample evidence that sleep disturbances including reduced total sleep time, disrupted sleep continuity, and poor sleep quality often accompany negative OUD treatment outcomes. Sleep disturbances are bidirectionally associated with several other factors related to negative treatment outcomes, including chronic stress, stress reactivity, low positive affect, high negative affect, chronic pain, and drug craving. This constellation of outcome variables represents a more comprehensive appraisal of the quality of life and quality of recovery than is typically assessed in OUD clinical trials. To date, there are very few clinical trials or experimental studies aimed at improving sleep health in OUD patients, either as a means of improving stress, affect, and craving outcomes, or as a potential mechanistic target to reduce opioid withdrawal and drug use behaviors. As such, the direct impact of sleep improvement in OUD patients is largely unknown, yet mechanistic and clinical research suggests that therapeutic interventions that target sleep are a promising avenue to improve OUD treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Varallo G, Musetti A, D’Anselmo A, Gori A, Giusti EM, Pizza F, Castelnuovo G, Plazzi G, Franceschini C. Exploring Addictive Online Behaviors in Patients with Narcolepsy Type 1. Healthcare (Basel) 2022; 10:2169. [PMID: 36360510 PMCID: PMC9690789 DOI: 10.3390/healthcare10112169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/20/2022] [Accepted: 10/27/2022] [Indexed: 09/08/2024] Open
Abstract
BACKGROUND Narcolepsy type 1 (NT1) is a rare neurological sleep disorder caused by the loss of neurons that produce hypocretin-a peptide that plays a crucial role in addictive behaviors. We aimed to compare, for the first time, levels of problematic online gaming, problematic social media use, and compulsive Internet use between NT1 patients and healthy controls (HC), and to evaluate the association between anxiety, depression, and emotion dysregulation with addictive online behaviors in NT1 patients. METHODS A total of 43 patients with NT1 and 86 sex- and age-matched HC participated in an online cross-sectional survey. RESULTS NT1 patients did not differ from HC in terms of problematic social media use and compulsive Internet use but displayed higher levels of problematic online gaming compared to HC. Higher levels of emotion dysregulation were significantly associated with higher levels of problematic social media use and compulsive Internet use, while none of the tested factors were associated with problematic online gaming. CONCLUSION NT1 patients and HC had similar levels of problematic social media use and compulsive Internet use, but NT1 patients showed higher levels of problematic online gaming. Emotion dysregulation might be an intervention target for reducing compulsive Internet use and problematic social media use.
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Affiliation(s)
- Giorgia Varallo
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Alessandro Musetti
- Department of Humanities, Social Sciences and Cultural Industries, University of Parma, 43121 Parma, Italy
| | - Anita D’Anselmo
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40123 Bologna, Italy
| | - Alessio Gori
- Department of Health Sciences, University of Florence, Via di San Salvi 12, Pad. 26, 50135 Florence, Italy
- Integrated Psychodynamic Psychotherapy Institute (IPPI), 50122 Florence, Italy
| | - Emanuele Maria Giusti
- Psychology Research Laboratory, IRCCS Istituto Auxologico Italiano, Ospedale San Luca, 20149 Milan, Italy
- Department of Psychology, Catholic University of Milan, 20123 Milan, Italy
| | - Fabio Pizza
- Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, 40123 Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB), 40139 Bologna, Italy
| | - Gianluca Castelnuovo
- Department of Psychology, Catholic University of Milan, 20123 Milan, Italy
- Psychology Research Laboratory, IRCCS Istituto Auxologico Italiano, Ospedale San Giuseppe, 28824 Verbania, Italy
| | - Giuseppe Plazzi
- IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB), 40139 Bologna, Italy
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
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Aldridge GM, Zarin TA, Brandner AJ, George O, Gilpin NW, Repunte-Canonigo V, Sanna PP, Koob GF, Vendruscolo LF, Schmeichel BE. Effects of single and dual hypocretin-receptor blockade or knockdown of hypocretin projections to the central amygdala on alcohol drinking in dependent male rats. ADDICTION NEUROSCIENCE 2022; 3:100028. [PMID: 35965958 PMCID: PMC9365098 DOI: 10.1016/j.addicn.2022.100028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.
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Affiliation(s)
- Gabriel M. Aldridge
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Tyler A. Zarin
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Adam J. Brandner
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Olivier George
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Psychiatry, School of Medicine, University of California, San Diego, San Diego, CA, USA
| | - Nicholas W. Gilpin
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Vez Repunte-Canonigo
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, United States
| | - Pietro P. Sanna
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, United States
| | - George F. Koob
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
| | - Leandro F. Vendruscolo
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
| | - Brooke E. Schmeichel
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
- Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA
- Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA
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29
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O'Connor RM, Kenny PJ. Utility of 'substance use disorder' as a heuristic for understanding overeating and obesity. Prog Neuropsychopharmacol Biol Psychiatry 2022; 118:110580. [PMID: 35636576 DOI: 10.1016/j.pnpbp.2022.110580] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 02/07/2023]
Abstract
Rates of obesity and obesity-associated diseases have increased dramatically in countries with developed economies. Substance use disorders (SUDs) are characterized by the persistent use of the substance despite negative consequences. It has been hypothesized that overconsumption of palatable energy dense food can elicit SUD-like maladaptive behaviors that contribute to persistent caloric intake beyond homeostatic need even in the face of negative consequences. Palatable food and drugs of abuse act on many of the same motivation-related circuits in the brain, and can induce, at least superficially, similar molecular, cellular, and physiological adaptations on these circuits. As such, applying knowledge about the neurobiological mechanisms of SUDs may serve as useful heuristic to better understand the persistent overconsumption of palatable food that contributes to obesity. However, many important differences exist between the actions of drugs of abuse and palatable food in the brain. This warrants caution when attributing weight gain and obesity to the manifestation of a putative SUD-related behavioral disorder. Here, we describe similarities and differences between compulsive drug use in SUDs and overconsumption in obesity and consider the merit of the concept of "food addiction".
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Affiliation(s)
- Richard M O'Connor
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, United States of America
| | - Paul J Kenny
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, United States of America.
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Donegan D, Kanzler CM, Büscher J, Viskaitis P, Bracey EF, Lambercy O, Burdakov D. Hypothalamic Control of Forelimb Motor Adaptation. J Neurosci 2022; 42:6243-6257. [PMID: 35790405 PMCID: PMC9374158 DOI: 10.1523/jneurosci.0705-22.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 06/12/2022] [Indexed: 11/21/2022] Open
Abstract
The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation.SIGNIFICANCE STATEMENT The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.
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Affiliation(s)
- Dane Donegan
- Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland
| | - Christoph M Kanzler
- Rehabilitation Engineering Laboratory (RELab), Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Zürich 8008, Switzerland
| | - Julia Büscher
- Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland
| | - Paulius Viskaitis
- Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland
| | - Ed F Bracey
- Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland
| | - Olivier Lambercy
- Rehabilitation Engineering Laboratory (RELab), Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Zürich 8008, Switzerland
| | - Denis Burdakov
- Neurobehavioral Dynamics Laboratory, Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich, Schwerzenbach 8603, Switzerland
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31
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Douton JE, Acharya NK, Stoltzfus B, Sun D, Grigson PS, Nyland JE. Acute glucagon-like peptide-1 receptor agonist liraglutide prevents cue-, stress-, and drug-induced heroin-seeking in rats. Behav Pharmacol 2022; 33:364-378. [PMID: 35695511 PMCID: PMC9308649 DOI: 10.1097/fbp.0000000000000685] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Substance use disorder is challenging to treat due to its relapsing nature. In the last decade, opioid use disorder has been a threat to public health, being declared an epidemic by the Centers for Disease Control and Prevention. This is a tragic situation, considering there currently are only three effective, yet not ideal, treatments to prevent relapse to opioids. Recent research has shown that hormones that modulate hunger and satiety also can modulate motivated behavior for drugs of abuse. For example, the short-acting analog of glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates homeostatic feeding, has been shown to reduce responding for rewarding stimuli such as food, cocaine, heroin, and nicotine when administered over several days or weeks. This may serve as an effective adjuvant during treatment; however, whether it would be effective when used acutely to bridge a patient between cessation of use and onset of medication for the treatment of an opioid addiction is unknown. Here, we tested the acute effects of the longer acting GLP-1 analog, liraglutide, on heroin-seeking. In rats with heroin self-administration experience, we found that subcutaneous administration of an acute dose of 0.3-mg/kg liraglutide was effective in preventing drug-seeking after exposure to three major precipitators: drug-associated cues, stress (yohimbine-induced), and the drug itself. Finally, we confirmed that the reduction in drug-seeking is not due to a locomotor impairment, as liraglutide did not significantly alter performance in a rotarod test. As such, acute use of GLP-1 analogs may serve as a new and effective nonopioid bridge to treatment.
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Affiliation(s)
- Joaquin E Douton
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Nikhil K Acharya
- Department of Neural and Behavioral Sciences, Penn State College of Medicine
| | - Brooke Stoltzfus
- Department of Neural and Behavioral Sciences, Penn State College of Medicine
| | - Dongxiao Sun
- Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Patricia S Grigson
- Department of Neural and Behavioral Sciences, Penn State College of Medicine
| | - Jennifer E Nyland
- Department of Neural and Behavioral Sciences, Penn State College of Medicine
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32
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Gao XB, Horvath TL. From Molecule to Behavior: Hypocretin/orexin Revisited From a Sex-dependent Perspective. Endocr Rev 2022; 43:743-760. [PMID: 34792130 PMCID: PMC9277634 DOI: 10.1210/endrev/bnab042] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Indexed: 11/19/2022]
Abstract
The hypocretin/orexin (Hcrt/Orx) system in the perifornical lateral hypothalamus has been recognized as a critical node in a complex network of neuronal systems controlling both physiology and behavior in vertebrates. Our understanding of the Hcrt/Orx system and its array of functions and actions has grown exponentially in merely 2 decades. This review will examine the latest progress in discerning the roles played by the Hcrt/Orx system in regulating homeostatic functions and in executing instinctive and learned behaviors. Furthermore, the gaps that currently exist in our knowledge of sex-related differences in this field of study are discussed.
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Affiliation(s)
- Xiao-Bing Gao
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Tamas L Horvath
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
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33
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Flores-Ramirez FJ, Matzeu A, Sánchez-Marín L, Martin-Fardon R. Blockade of corticotropin-releasing factor-1 receptors in the infralimbic cortex prevents stress-induced reinstatement of alcohol seeking in male Wistar rats: Evidence of interaction between CRF 1 and orexin receptor signaling. Neuropharmacology 2022; 210:109046. [PMID: 35341789 PMCID: PMC9176217 DOI: 10.1016/j.neuropharm.2022.109046] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/11/2022] [Accepted: 03/21/2022] [Indexed: 10/18/2022]
Abstract
Alcohol use dysregulates responsivity to stress, which is mediated by corticotropin-releasing factor (CRF). With repeated cycles of alcohol use, the hypothalamic-pituitary-adrenal axis becomes hyporesponsive, rendering individuals vulnerable to the reinstatement of alcohol-seeking behavior during stressful episodes. Orexin (Orx; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and interacts with CRF. The infralimbic cortex (IL) is a CRF-rich region. Anatomical evidence suggests that CRF and Orx interact in this area. To test the behavioral implication of CRF and Orx transmission in the IL during the stress-induced reinstatement of alcohol-seeking behavior, male Wistar rats were trained to self-administer 10% alcohol for 3 weeks. The rats then underwent two weeks of extinction training (identical to the alcohol self-administration sessions, but alcohol was withheld). The day after the last extinction session, the rats received a bilateral intra-IL injection of the CRF1 receptor antagonist CP154,526 (0.6 μg/0.5 μl/side), the dual Orx receptor antagonist TCS1102 (15 μg/0.5 μl/side), or their combination and then were tested for the footshock stress-induced reinstatement of alcohol-seeking behavior. CP154,526 significantly prevented reinstatement, but TCS1102 did not produce such an effect. Interestingly, the co-administration of TCS1102 and CP154,526 reversed the effect of CP154,526 alone, and footshock stress induced a significant increase in Crhr1 and Hcrtr2 mRNA expression in the IL. These results demonstrate a functional interaction between Orx receptor and CRF1 receptor signaling and suggest that CRF1 receptor antagonism may ameliorate stress-induced alcohol-seeking behavior.
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Affiliation(s)
| | - Alessandra Matzeu
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Laura Sánchez-Marín
- Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, Spain
| | - Rémi Martin-Fardon
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Dunigan AI, Roseberry AG. Actions of feeding-related peptides on the mesolimbic dopamine system in regulation of natural and drug rewards. ADDICTION NEUROSCIENCE 2022; 2:100011. [PMID: 37220637 PMCID: PMC10201992 DOI: 10.1016/j.addicn.2022.100011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The mesolimbic dopamine system is the primary neural circuit mediating motivation, reinforcement, and reward-related behavior. The activity of this system and multiple behaviors controlled by it are affected by changes in feeding and body weight, such as fasting, food restriction, or the development of obesity. Multiple different peptides and hormones that have been implicated in the control of feeding and body weight interact with the mesolimbic dopamine system to regulate many different dopamine-dependent, reward-related behaviors. In this review, we summarize the effects of a selected set of feeding-related peptides and hormones acting within the ventral tegmental area and nucleus accumbens to alter feeding, as well as food, drug, and social reward.
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Affiliation(s)
- Anna I. Dunigan
- Department of Biology and Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA
| | - Aaron G. Roseberry
- Department of Biology and Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303, USA
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35
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Spinieli RL, Ben Musa R, Cornelius-Green J, Hasser EM, Cummings KJ. Orexin facilitates the ventilatory and behavioral responses of rats to hypoxia. Am J Physiol Regul Integr Comp Physiol 2022; 322:R581-R596. [PMID: 35380477 PMCID: PMC9109809 DOI: 10.1152/ajpregu.00334.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 02/03/2023]
Abstract
Orexin neurons are sensitive to CO2 and contribute to cardiorespiratory homeostasis as well as sensorimotor control. Whether orexin facilitates respiratory and behavioral responses to acute hypoxia is unclear. We hypothesized that orexin neurons are activated by acute hypoxia and that orexin facilitates the hypoxic ventilatory response (HVR), as well as the arterial blood pressure (ABP) and behavioral (movement) responses to acute hypoxia. We further hypothesized that orexin has greater effects in the active phase of the rat circadian cycle, when orexin neurons have high activity. Using whole body plethysmography with EEG, EMG, and the dual-orexin receptor (OxR) antagonist suvorexant (20 mg/kg ip), we determined the effect of OxR blockade on the respiratory, ABP, and behavioral responses of adult rats to acute, graded hypoxia ([Formula: see text]= 0.15, 0.13, 0.11, and 0.09) and hyperoxic hypercapnia ([Formula: see text]= 0.05; [Formula: see text]= 0.95). OxR blockade had no effect on eupnea. OxR blockade significantly reduced the HVR in both inactive and active phases, with a stronger effect in the active phase. OxR blockade reduced the behavioral response to acute hypoxia in the active phase. The central component of the ventilatory and the ABP responses to hypercapnia were reduced by OxR blockade solely in the inactive phase. In the inactive phase, hypoxia activated ∼10% of orexin neurons in the perifornical hypothalamus. These data suggest that orexin neurons participate in the peripheral chemoreflex to facilitate the ventilatory and behavioral responses to acute hypoxia in rats, particularly in the active phase. Orexin also facilitates central chemoreflex responses to CO2 in the inactive phase.
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Affiliation(s)
- Richard L Spinieli
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Ruwaida Ben Musa
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Jennifer Cornelius-Green
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Eileen M Hasser
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Kevin J Cummings
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
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Abstract
SignificanceAnxiety disorders are among the most prevalent mental illnesses worldwide. Despite significant advances in their treatment, many patients remain treatment resistant. Thus, new treatment modalities and targets are much needed. Therefore, we developed a deep brain stimulation therapy that targets a recently identified anxiety center in the lateral hypothalamus. We show that this therapy rapidly silences anxiety-implicated neurons and immediately relieves diverse anxiety symptoms in a variety of stressful situations. This therapeutic effect occurs without acute or chronic side effects that are typical of many existing treatments, such as physical sedation or memory deficits. These findings identify a clinically applicable new therapeutic strategy for helping patients to manage treatment-resistant anxiety.
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Matzeu A, Martin-Fardon R. Understanding the Role of Orexin Neuropeptides in Drug Addiction: Preclinical Studies and Translational Value. Front Behav Neurosci 2022; 15:787595. [PMID: 35126069 PMCID: PMC8811192 DOI: 10.3389/fnbeh.2021.787595] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/29/2021] [Indexed: 12/22/2022] Open
Abstract
Orexins (also known as hypocretins) are neuropeptides that participate in the regulation of energy metabolism, homeostasis, sleep, feeding, stress responses, arousal, and reward. Particularly relevant to the scope of the present review is the involvement of the orexin system in brain mechanisms that regulate motivation, especially highly motivated behavior, arousal, and stress, making it an ideal target for studying addiction and discovering treatments. Drug abuse and misuse are thought to induce maladaptive changes in the orexin system, and these changes might promote and maintain uncontrolled drug intake and contribute to relapse. Dysfunctional changes in this neuropeptidergic system that are caused by drug use might also be responsible for alterations of feeding behavior and the sleep-wake cycle that are commonly disrupted in subjects with substance use disorder. Drug addiction has often been associated with an increase in activity of the orexin system, suggesting that orexin receptor antagonists may be a promising pharmacological treatment for substance use disorder. Substantial evidence has shown that single orexin receptor antagonists that are specific to either orexin receptor 1 or 2 can be beneficial against drug intake and relapse. Interest in the efficacy of dual orexin receptor antagonists, which were primarily developed to treat insomnia, has grown in the field of drug addiction. Treatments that target the orexin system may be a promising strategy to reduce drug intake, mitigate relapse vulnerability, and restore “normal” physiological functions, including feeding and sleep. The present review discusses preclinical and clinical evidence of the involvement of orexins in drug addiction and possible beneficial pharmacotherapeutic effects of orexin receptor antagonists to treat substance use disorder.
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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Vaseghi S, Zarrabian S, Haghparast A. Reviewing the role of the orexinergic system and stressors in modulating mood and reward-related behaviors. Neurosci Biobehav Rev 2021; 133:104516. [PMID: 34973302 DOI: 10.1016/j.neubiorev.2021.104516] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 01/22/2023]
Abstract
In this review study, we aimed to introduce the orexinergic system as an important signaling pathway involved in a variety of cognitive functions such as memory, motivation, and reward-related behaviors. This study focused on the role of orexinergic system in modulating reward-related behavior, with or without the presence of stressors. Cross-talk between the reward system and orexinergic signaling was also investigated, especially orexinergic signaling in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the hippocampus. Furthermore, we discussed the role of the orexinergic system in modulating mood states and mental illnesses such as depression, anxiety, panic, and posttraumatic stress disorder (PTSD). Here, we narrowed down our focus on the orexinergic signaling in three brain regions: the VTA, NAc, and the hippocampus (CA1 region and dentate gyrus) for their prominent role in reward-related behaviors and memory. It was concluded that the orexinergic system is critically involved in reward-related behavior and significantly alters stress responses and stress-related psychiatric and mood disorders.
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Affiliation(s)
- Salar Vaseghi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
| | - Shahram Zarrabian
- Department of Anatomical Sciences & Cognitive Neuroscience, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O. Box 19615-1178, Tehran, Iran.
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40
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Coleman P, de Lecea L, Gotter A, Hagan J, Hoyer D, Kilduff T, Kukkonen JP, Porter R, Renger J, Siegel JM, Sutcliffe G, Upton N, Winrow CJ. Orexin receptors in GtoPdb v.2021.3. IUPHAR/BPS GUIDE TO PHARMACOLOGY CITE 2021; 2021. [PMID: 34927075 DOI: 10.2218/gtopdb/f51/2021.3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [42]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [109]. Currently the only orexin receptor ligands in clinical use are suvorexant and lemborexant, which are used as hypnotics. Orexin receptor crystal structures have been solved [134, 133, 54, 117, 46].
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41
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Peleg-Raibstein D, Burdakov D. Do orexin/hypocretin neurons signal stress or reward? Peptides 2021; 145:170629. [PMID: 34416308 DOI: 10.1016/j.peptides.2021.170629] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/14/2021] [Indexed: 12/23/2022]
Abstract
Hypothalamic neurons that produce the peptide transmitters orexins/hypocretins (HONs) broadcast their predominantly neuroexcitatory outputs to the entire brain via their extremely wide axonal projections. HONs were originally reported to be activated by food deprivation, and to stimulate arousal, energy expenditure, and eating. This led to extensive studies of HONs in the context of nutrient-sensing and energy balance control. While activation of HONs by body energy depletion continues to be supported by experimental evidence, it has also become clear that HONs are robustly activated not only by nutrient depletion, but also by diverse sensory stimuli (both neutral and those associated with rewarding or aversive events), seemingly unrelated to each other or to energy balance. One theory that could unify these findings is that all these stimuli signal "stress" - defined either as a potentially harmful state, or an awareness of reward deficiency. If HON activity is conceptualized as a cumulative representation of stress, then many of the reported HONs outputs - including EEG arousal, sympathetic activation, place avoidance, and exploratory behaviours - could be viewed as logical stress-counteracting responses. We discuss evidence for and against this unifying theory of HON function, including the alterations in HON activity observed in anxiety and depression disorders. We propose that, in order to orchestrate stress-countering responses, HONs need to coactivate motivation and aversion brain systems, and the impact of HON stimulation on affective states may be perceived as rewarding or aversive depending on the baseline HON activity.
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Affiliation(s)
| | - Denis Burdakov
- Department of Health Sciences and Technology, ETH Zürich, Switzerland.
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42
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Sleep dysregulation in binge eating disorder and "food addiction": the orexin (hypocretin) system as a potential neurobiological link. Neuropsychopharmacology 2021; 46:2051-2061. [PMID: 34145404 PMCID: PMC8505614 DOI: 10.1038/s41386-021-01052-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022]
Abstract
It has been proposed that binge eating reflects a pathological compulsion driven by the "addictive" properties of foods. Proponents of this argument highlight the large degree of phenomenological and diagnostic overlap between binge eating disorder (BED) and substance use disorders (SUDs), including loss of control over how much is consumed and repeated unsuccessful attempts to abstain from consumption, as well as commonalities in brain structures involved in food and drug craving. To date, very little attention has been given to an additional behavioral symptom that BED shares with SUDs-sleep dysregulation-and the extent to which this may contribute to the pathophysiology of BED. Here, we review studies examining sleep outcomes in patients with BED, which collectively point to a heightened incidence of sleep abnormalities in BED. We identify the orexin (hypocretin) system as a potential neurobiological link between compulsive eating and sleep dysregulation in BED, and provide a comprehensive update on the evidence linking this system to these processes. Finally, drawing on evidence from the SUD literature indicating that the orexin system exhibits significant plasticity in response to drugs of abuse, we hypothesize that chronic palatable food consumption likewise increases orexin system activity, resulting in dysregulated sleep/wake patterns. Poor sleep, in turn, is predicted to exacerbate binge eating, contributing to a cycle of uncontrolled food consumption. By extension, we suggest that pharmacotherapies normalizing orexin signaling, which are currently being trialed for the treatment of SUDs, might also have utility in the clinical management of BED.
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43
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Zhan D, Perrer DA, Decker AM, Langston TL, Mavanji V, Harris DL, Kotz CM, Zhang Y. Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists. J Med Chem 2021; 64:8806-8825. [PMID: 34101446 PMCID: PMC8994207 DOI: 10.1021/acs.jmedchem.1c00841] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.
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Affiliation(s)
- Dehui Zhan
- Research Triangle Institute, Research Triangle Park, North Carolina 27709
| | - David A. Perrer
- Research Triangle Institute, Research Triangle Park, North Carolina 27709
| | - Ann M. Decker
- Research Triangle Institute, Research Triangle Park, North Carolina 27709
| | | | - Vijayakumar Mavanji
- Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417
| | - Danni L. Harris
- Research Triangle Institute, Research Triangle Park, North Carolina 27709
| | - Catherine M. Kotz
- Research Service, Veterans Affairs Health Care System, Minneapolis, MN 55417
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455
- Geriatric, Research, Education and Clinical Center, Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417
| | - Yanan Zhang
- Research Triangle Institute, Research Triangle Park, North Carolina 27709
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44
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Fragale JE, James MH, Avila JA, Spaeth AM, Aurora RN, Langleben D, Aston-Jones G. The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System. FRONTIERS OF NEUROLOGY AND NEUROSCIENCE 2021; 45:117-127. [PMID: 34052815 PMCID: PMC8324012 DOI: 10.1159/000514965] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 02/02/2021] [Indexed: 01/06/2023]
Abstract
Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus that regulate various behavioral and physiological processes, including sleep-wakefulness and motivated drug taking. Given its dual role in sleep and addiction, the orexin system represents a promising therapeutic target for treating SUDs and their comorbid sleep deficits. Here, we review the literature on the role of the orexin system in sleep and drug addiction and discuss the therapeutic potential of orexin receptor antagonists for SUDs. We argue that orexin receptor antagonists may be effective therapeutics for treating addiction because they target orexin's regulation of sleep (top-down) and motivation (bottom-up) pathways.
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Affiliation(s)
- Jennifer E Fragale
- Brain Health Institute, Rutgers Biomedical Health Sciences, Rutgers University, Piscataway, New Jersey, USA
| | - Morgan H James
- Brain Health Institute, Rutgers Biomedical Health Sciences, Rutgers University, Piscataway, New Jersey, USA
| | - Jorge A Avila
- Brain Health Institute, Rutgers Biomedical Health Sciences, Rutgers University, Piscataway, New Jersey, USA
| | - Andrea M Spaeth
- Department of Kinesiology and Health, Rutgers University, New Brunswick, New Jersey, USA
| | - R Nisha Aurora
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| | - Daniel Langleben
- Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Gary Aston-Jones
- Brain Health Institute, Rutgers Biomedical Health Sciences, Rutgers University, Piscataway, New Jersey, USA
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45
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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.
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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
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46
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Abstract
Drug addiction is a chronic relapsing disorder, and a significant amount of research has been devoted to understand the factors that contribute to the development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide an overview of various theories of addiction to drugs of abuse and the neurobiology involved in elements of the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the role of the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the contribution of these pathways and associated circuits to conditioned responses, drug craving, and loss of behavioral control that may underlie drug relapse. By enhancing the understanding of the neurobiological factors that mediate drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals.
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Affiliation(s)
- Matthew W Feltenstein
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA
| | - Ronald E See
- Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA
- Department of Psychology, Westmont College, Santa Barbara, California 93108, USA
| | - Rita A Fuchs
- Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164-7620, USA
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47
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Concetti C, Burdakov D. Orexin/Hypocretin and MCH Neurons: Cognitive and Motor Roles Beyond Arousal. Front Neurosci 2021; 15:639313. [PMID: 33828450 PMCID: PMC8019792 DOI: 10.3389/fnins.2021.639313] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 03/01/2021] [Indexed: 02/01/2023] Open
Abstract
The lateral hypothalamus (LH) is classically implicated in sleep-wake control. It is the main source of orexin/hypocretin and melanin-concentrating hormone (MCH) neuropeptides in the brain, which have been both implicated in arousal state switching. These neuropeptides are produced by non-overlapping LH neurons, which both project widely throughout the brain, where release of orexin and MCH activates specific postsynaptic G-protein-coupled receptors. Optogenetic manipulations of orexin and MCH neurons during sleep indicate that they promote awakening and REM sleep, respectively. However, recordings from orexin and MCH neurons in awake, moving animals suggest that they also act outside sleep/wake switching. Here, we review recent studies showing that both orexin and MCH neurons can rapidly (sub-second-timescale) change their firing when awake animals experience external stimuli, or during self-paced exploration of objects and places. However, the sensory-behavioral correlates of orexin and MCH neural activation can be quite different. Orexin neurons are generally more dynamic, with about 2/3rds of them activated before and during self-initiated running, and most activated by sensory stimulation across sensory modalities. MCH neurons are activated in a more select manner, for example upon self-paced investigation of novel objects and by certain other novel stimuli. We discuss optogenetic and chemogenetic manipulations of orexin and MCH neurons, which combined with pharmacological blockade of orexin and MCH receptors, imply that these rapid LH dynamics shape fundamental cognitive and motor processes due to orexin and MCH neuropeptide actions in the awake brain. Finally, we contemplate whether the awake control of psychomotor brain functions by orexin and MCH are distinct from their “arousal” effects.
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Affiliation(s)
- Cristina Concetti
- Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland
| | - Denis Burdakov
- Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland
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48
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Drug addiction co-morbidity with alcohol: Neurobiological insights. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2021; 157:409-472. [PMID: 33648675 DOI: 10.1016/bs.irn.2020.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Addiction is a chronic disorder that consists of a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages involve, respectively, neuroadaptations in brain circuits involved in incentive salience and habit formation, stress surfeit and reward deficit, and executive function. Much research on addiction focuses on the neurobiology underlying single drug use. However, alcohol use disorder (AUD) can be co-morbid with substance use disorder (SUD), called dual dependence. The limited epidemiological data on dual dependence indicates that there is a large population of individuals suffering from addiction who are dependent on more than one drug and/or alcohol, yet dual dependence remains understudied in addiction research. Here, we review neurobiological data on neurotransmitter and neuropeptide systems that are known to contribute to addiction pathology and how the involvement of these systems is consistent or divergent across drug classes. In particular, we highlight the dopamine, opioid, corticotropin-releasing factor, norepinephrine, hypocretin/orexin, glucocorticoid, neuroimmune signaling, endocannabinoid, glutamate, and GABA systems. We also discuss the limited research on these systems in dual dependence. Collectively, these studies demonstrate that the use of multiple drugs can produce neuroadaptations that are distinct from single drug use. Further investigation into the neurobiology of dual dependence is necessary to develop effective treatments for addiction to multiple drugs.
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Tan Y, Hang F, Liu ZW, Stoiljkovic M, Wu M, Tu Y, Han W, Lee AM, Kelley C, Hajós M, Lu L, de Lecea L, De Araujo I, Picciotto MR, Horvath TL, Gao XB. Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice. J Clin Invest 2021; 130:4985-4998. [PMID: 32516139 DOI: 10.1172/jci130889] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 06/03/2020] [Indexed: 12/27/2022] Open
Abstract
The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking, and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress-coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seeking, and altered stress response) in obese animals.
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Affiliation(s)
- Ying Tan
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Department of Neurosurgery, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Fu Hang
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Guangxi Reproductive Medical Research Center, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhong-Wu Liu
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Milan Stoiljkovic
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mingxing Wu
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Department of Ophthalmology, Second Affiliate Hospital of Chongqing Medical University, Chongqing, China
| | - Yue Tu
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.,Department of Traditional Chinese Medicine Health Preservation, Second Clinic Medical School, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Wenfei Han
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Angela M Lee
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Craig Kelley
- Joint Biomedical Engineering Program, SUNY Downstate and NYU Tandon, Brooklyn, New York, USA
| | - Mihály Hajós
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Luis de Lecea
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California, USA
| | - Ivan De Araujo
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marina R Picciotto
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Tamas L Horvath
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xiao-Bing Gao
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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50
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Tunisi L, D'Angelo L, Fernández-Rilo AC, Forte N, Piscitelli F, Imperatore R, de Girolamo P, Di Marzo V, Cristino L. Orexin-A/Hypocretin-1 Controls the VTA-NAc Mesolimbic Pathway via Endocannabinoid-Mediated Disinhibition of Dopaminergic Neurons in Obese Mice. Front Synaptic Neurosci 2021; 13:622405. [PMID: 33613258 PMCID: PMC7890184 DOI: 10.3389/fnsyn.2021.622405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/11/2021] [Indexed: 01/27/2023] Open
Abstract
Disinhibition of orexin-A/hypocretin-1 (OX-A) release occurs to several output areas of the lateral hypothalamus (LH) in the brain of leptin knockout obese ob/ob mice. In this study, we have investigated whether a similar increase of OX-A release occurs to the ventral tegmental area (VTA), an orexinergic LH output area with functional effects on dopaminergic signaling at the mesolimbic circuit. By confocal and correlative light and electron microscopy (CLEM) morphological studies coupled to molecular, biochemical, and pharmacological approaches, we investigated OX-A-mediated dopaminergic signaling at the LH-VTA-nucleus accumbens (NAc) pathway in obese ob/ob mice compared to wild-type (wt) lean littermates. We found an elevation of OX-A trafficking and release to the VTA of ob/ob mice and consequent orexin receptor-1 (OX1R)-mediated over-activation of dopaminergic (DA) neurons via phospholipase C (PLC)/diacylglycerol lipase (DAGL-α)-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). In fact, by retrograde signaling to cannabinoid receptor type 1 (CB1R) at inhibitory inputs to DA neurons, 2-AG inhibited GABA release thus inducing an increase in DA concentration in the VTA and NAc of ob/ob mice. This effect was prevented by the OX1R antagonist SB-334867 (30 mg/Kg, i.p.), or the CB1R antagonist AM251 (10 mg/Kg, i.p.) and mimicked by OX-A injection (40 μg/Kg, i.p.) in wt lean mice. Enhanced DA signaling to the NAc in ob/ob mice, or in OX-A-injected wt mice, was accompanied by β-arrestin2-mediated desensitization of dopamine D2 receptor (D2R) in a manner prevented by SB-334867 or the D2R antagonist L741 (1.5 mg/Kg, i.p.). These results further support the role of OX-A signaling in the control of neuroadaptive responses, such as compulsive reward-seeking behavior or binge-like consumption of high palatable food, and suggest that aberrant OX-A trafficking to the DA neurons in the VTA of ob/ob mice influences the D2R response at NAc, a main target area of the mesolimbic pathway, via 2-AG/CB1-mediated retrograde signaling.
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Affiliation(s)
- Lea Tunisi
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.,Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy
| | - Livia D'Angelo
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy
| | - Alba Clara Fernández-Rilo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
| | - Nicola Forte
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Québec City, QC, Canada
| | - Fabiana Piscitelli
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
| | - Roberta Imperatore
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Paolo de Girolamo
- Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Naples, Italy
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Québec City, QC, Canada.,Heart and Lung Research Institute of Université Laval, and Institute for Nutrition and Functional Foods, Université Laval, Québec City, QC, Canada
| | - Luigia Cristino
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
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