Orexins in the Midline Thalamus Are Involved in the Expression of Conditioned Place Aversion to Morphine Withdrawal

Total Page:16

File Type:pdf, Size:1020Kb

Orexins in the Midline Thalamus Are Involved in the Expression of Conditioned Place Aversion to Morphine Withdrawal Physiology & Behavior 102 (2011) 42–50 Contents lists available at ScienceDirect Physiology & Behavior journal homepage: www.elsevier.com/locate/phb Orexins in the midline thalamus are involved in the expression of conditioned place aversion to morphine withdrawal Yonghui Li a, Huiying Wang b, Keke Qi b, Xiaoyu Chen c,SaLic, Nan Sui b, Gilbert J. Kirouac c,d,⁎ a Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China and Faculty of Dentistry, University of Manitoba, Winnipeg, Manitoba, Canada b Behavioral Pharmacology Laboratory, Institute of Psychology, Chinese Academy of Sciences, Beijing, China c Department of Oral Biology, Faculty of Dentistry, University of Manitoba, Winnipeg, Manitoba, Canada d Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada article info abstract Article history: Previous studies have implicated the bed nucleus of the stria terminalis, central nucleus of the amygdala and Received 19 July 2010 the shell of the nucleus accumbens (collectively called the extended amygdala) as playing an important role in Received in revised form 1 October 2010 mediating the aversive emotion associated with opioid withdrawal. The paraventricular nucleus of the Accepted 8 October 2010 thalamus (PVT) provides a very dense input to the extended amygdala, and the PVT is densely innervated by orexin neurons, which appear to be involved in producing some of the physical and emotional effects Keywords: associated with morphine withdrawal. In the present study, we confirm that the PVT is densely innervated by Orexin orexin fibers, whereas the regions of the extended amygdala associated with the effects of morphine Hypocretin Morphine withdrawal withdrawal are poorly innervated. Microinjections of the orexin-1 receptor (OX1R) antagonist SB334867 or Thalamus the orexin-2 receptor (OX2R) antagonist TCSOX229 at doses of 5.0 or 15.0 μg into the PVT region did not affect Extended amygdala the acquisition of the conditioned place aversion (CPA) nor the physical effects produced by naloxone- Conditioned place aversion precipitated morphine withdrawal. In contrast, microinjections of TCSOX229 (15.0 μg) in the PVT region significantly attenuated the expression of naloxone-induced CPA while microinjections of SB334867 at the same dose had no effect. The results from these experiments indicate a role for OX2R in the PVT on the expression of CPA associated with morphine withdrawal. Orexins may mediate the aversive effects of morphine withdrawal by engaging the extended amygdala indirectly through the action of orexins on the PVT. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Neuropeptides called orexins have received attention for their importance in regulating behaviors related to drug reward [3,4]. Several Opioid drugs like heroin and morphine produce euphoric effects studies have also shown that orexins may be involved in the withdrawal that can lead to chronic drug use and dependence. In contrast, effects of morphine. First, morphine withdrawal was found to increase abstinence from opiates in dependent individuals produces negative the expression of c-Fos gene or protein in orexin neurons as well as to physiological (nausea, diarrhea, vomiting, tachycardia and sweating) increase orexin mRNA level in the hypothalamus [5–7].Second,orexin and emotional (irritability, anxiety, and dysphoria) states that are knock-out mice display fewer jumps, tremor and diarrhea in naloxone- extremely unpleasant to the drug user [1]. While the physiological precipitated morphine withdrawal [7]. Third, systemic administration of effects produced by opiate withdrawal dissipate over several days, the the orexin-1 receptor (OX1R) antagonist SB334867 attenuated beha- unpleasant emotional effects produced by opioids remain for weeks viors associated with morphine withdrawal in mice, an effect that or months and represent a major factor contributing to relapse [1,2]. appeared to be mediated by a decrease in the activity of neurons in the Consequently, there has been significant interest in identifying the shell of the nucleus accumbens [6]. The same paper reported that only a brain mechanisms that contribute to the negative emotional states few orexin neurons in the hypothalamus innervate the nucleus produced by abstinence of opioid and other addictive drugs with the accumbens, suggesting that orexins influence neurotransmission in hope that novel pharmacological targets can be identified to prevent this area of the striatum via an indirect projection [6]. relapse. The paraventricular nucleus of the midline thalamus (PVT) is densely innervated by orexin fibers [8,9] and is a major source of glutamatergic afferents to the shell of the nucleus accumbens, dorsolateral bed nucleus of the stria terminalis and the central nucleus of the amygdala [10–13]. ⁎ Corresponding author. Tel.: +1 204 977 5696; fax: +1 204 789 3913. These areas of the basal forebrain are collectively called the extended E-mail address: [email protected] (G.J. Kirouac). amygdala [14–17] and represent an anatomical macrostructure important 0031-9384/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2010.10.006 Y. Li et al. / Physiology & Behavior 102 (2011) 42–50 43 for mediating both the physical and emotional effects of morphine containing 5% normal donkey serum, 0.3% Triton X-100 and 0.1% sodium withdrawal [6,18–21]. In fact, the entire extended amygdala is a large azide followed by incubation in rabbit antiserum against OXA (1:3000, and complex area of the basal forebrain involved in the integration of diluted in pre-incubation solution; Chemicon, Temacula, CA; catalogue the motivational and physiological responses associated with emotions #AB3704) or goat antiserum against OXB overnight (1:500, diluted in [22–24]. Subregions of the extended amygdala including the shell of the pre-incubation solution; Santa Cruz Biotech Inc., Santa Cruz, CA; nucleus accumbens, lateral bed nucleus of the stria terminalis and the catalogue No. sc 8071). The sections were then rinsed for 3×10 min central nucleus of the amygdala have been identified as being especially in PBS, followed by placing the sections in either biotinylated donkey important for mediating the different effects of morphine withdrawal anti-rabbit or donkey anti-goat (1:500; Jackson Immunoresearch, West [6,18,19,21,25,26]. However, it is questionable if the release of orexins in Grove, PA) antisera for 2 h. Then sections were rinsed thoroughly and the extended amygdala mediates the effect of morphine withdrawal incubated with an avidin-biotin complex (ABC) solution (Elite ABC kit; because most of the critical areas of the extended amygdala activated by Vector Laboratories, Burlingame, CA). After three more rinsing steps, morphine withdrawal appear to be poorly innervated by orexin fibers sections were reacted with 3,3 diaminobenzidine tetrachloride (DAB) [6,27]. As such, the PVT, with its dense projections to those areas of the with nickel intensification (Vector DAB Kit, Vector Laboratories extended amygdala activated by morphine withdrawal, represents a Burlingame, CA) to produce a black reaction product. The DAB reaction potential site where orexins could act to produce the physiological and was terminated by rinsing the sections with PBS and the sections were emotional effects associated with morphine withdrawal. mounted on slides, air dried and cover-slipped with Fluka DPX The present study was done to determine if blockade of orexin mountant. Sections of the forebrain were examined and photographed receptors in the PVT with antagonists for the OX1R or the orexin-2 under magnification using an Olympus BX51 microscope equipped with receptors (OX2R) attenuated the symptoms associated with morphine a digital camera (SPOT RT Slicer, Diagnostic Instruments Inc, Sterling withdrawal. This was done by examining the effects of orexin receptor Heights, MI). Calibration bars were inserted using SPOT software antagonists on the acute physical symptoms and conditioned place (Version 3.2, Diagnostic Instruments) and images were transferred to aversion (CPA) produced by naloxone-induced precipitated morphine Adobe Photoshop 5.5 to optimize light and contrast levels. withdrawal. The CPA paradigm involves Pavlovian conditioning where the negative emotional state an animal experiences during morphine 2.3. Behavioral experiments withdrawal is paired with the particular environment where the emotional state occurs [28]. Re-exposure of the animal to the paired 2.3.1. Surgery environment leads to the experience of a negative emotional state and Rats were anesthetized with equithesin (0.3 ml/100 g, i.p.) and the avoidance of that environment [28]. In this case, CPA can be used to placed in a Stoelting stereotaxic frame. Stainless steel guide cannula investigate the neural mechanisms involved in the expression of (23 gauge, Plastics One, Roanoke, VA, USA) were unilaterally negative emotions link to opioid withdrawal. We also compared the implanted into the posterior aspect of the PVT (3.1 mm posterior to density of orexin-A (OXA) and orexin-B (OXB) fibers in the PVT and the bregma, 1.3 mm lateral to the midline, and 4.0 mm ventral to the extended amgydala to re-examine the extent of orexin innervation of skull, at 10˚ angle, with the incisor bar set at 3.3 mm below intraaural key areas of the forebrain linked to the negative emotional and aversive line). The guide cannula was secured with three small screws attached state associated
Recommended publications
  • Neuroendocrine and Sympathetic Responses to an Orexin Receptor Antagonist, SB-649868, and Alprazolam Following Insulin-Induced Hypoglycemia in Humans
    Psychopharmacology (2014) 231:3817–3828 DOI 10.1007/s00213-014-3520-7 ORIGINAL INVESTIGATION Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB-649868, and Alprazolam following insulin-induced hypoglycemia in humans Ameera X. Patel & Sam R. Miller & Pradeep J. Nathan & Ponmani Kanakaraj & Antonella Napolitano & Philip Lawrence & Annelize Koch & Edward T. Bullmore Received: 8 October 2013 /Accepted: 24 February 2014 /Published online: 26 April 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract it has previously been validated using the insulin tolerance test Rationale The orexin-hypocretin system is important for (ITT) model in humans. translating peripheral metabolic signals and central neuronal Results Of the primary endpoints, ITT induced defined in- inputs to a diverse range of behaviors, from feeding, motiva- creases in pulse rate, plasma cortisol, and adrenocorticotropic tion and arousal, to sleep and wakefulness. Orexin signaling is hormone in the placebo condition, but these responses were thus an exciting potential therapeutic target for disorders of not significantly impacted by alprazolam or SB-649868 pre- sleep, feeding, addiction, and stress. treatment. Of the secondary endpoints, ITT induced a defined Objectives/methods Here, we investigated the low dose phar- increase in plasma concentrations of adrenaline, noradrena- macology of orexin receptor antagonist, SB-649868, on neu- line, growth hormone (GH), and prolactin in the placebo roendocrine, sympathetic nervous system, and behavioral re- condition. Alprazolam pre-treatment significantly reduced sponses to insulin-induced hypoglycemic stress, in 24 healthy the GH response to ITT (p<0.003), the peak electromyogra- male subjects (aged 18–45 years; BMI 19.0–25.9 kg/m2), phy (p<0.0001) and galvanic skin response (GSR, p=0.04)to using a randomized, double-blind, placebo-controlled, acoustic startle, the resting GSR (p=0.01), and increased within-subject crossover design.
    [Show full text]
  • Orexin Receptor Antagonists As Therapeutic Agents for Insomnia
    REVIEW ARTICLE published: 25 December 2013 doi: 10.3389/fphar.2013.00163 Orexin receptor antagonists as therapeutic agents for insomnia Ana C. Equihua 1, Alberto K. De La Herrán-Arita 2 and Rene Drucker-Colin 1* 1 Neuropatología Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, México 2 Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA, USA Edited by: Insomnia is a common clinical condition characterized by difficulty initiating or maintaining Christopher J. Winrow, Merck, USA sleep, or non-restorative sleep with impairment of daytime functioning. Currently, Reviewed by: treatment for insomnia involves a combination of cognitive behavioral therapy (CBTi) Matthew R. Ebben, Weill Medical and pharmacological therapy. Among pharmacological interventions, the most evidence College of Cornell University, USA Gabriella Gobbi, McGill University, exists for benzodiazepine (BZD) receptor agonist drugs (GABAA receptor), although Canada concerns persist regarding their safety and their limited efficacy. The use of these Matt Carter, University of hypnotic medications must be carefully monitored for adverse effects. Orexin (hypocretin) Washington, USA neuropeptides have been shown to regulate transitions between wakefulness and Michihiro Mieda, Kanazawa University, Japan sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the *Correspondence: development of a new class of pharmacological agents that antagonize the physiological Rene Drucker-Colin, Departamento effects of orexin. The development of these agents may lead to novel therapies for de Neurociencias, Instituto de insomnia without the side effect profile of hypnotics (e.g., impaired cognition, disturbed Fisiología Celular, Universidad arousal, and motor balance difficulties). However, antagonizing a system that regulates Nacional Autónoma de México, Circuito exterior S/N, Apdo.
    [Show full text]
  • OREXIN ANTAGONISTS BELSOMRA (Suvorexant), DAYVIGO (Lemborexant)
    OREXIN ANTAGONISTS BELSOMRA (suvorexant), DAYVIGO (lemborexant) RATIONALE FOR INCLUSION IN PA PROGRAM Background Belsomra (suvorexant) and Dayvigo (lemborexant) are orexin receptor antagonists used to treat difficulty in falling and staying asleep (insomnia). Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake (1-2). Regulatory Status FDA-approved indication: Orexin receptor antagonists are indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance (1-2). Orexin Antagonists are contraindicated in patients with narcolepsy (1-2). Orexin Antagonists are central nervous system (CNS) depressants that can impair daytime wakefulness even when used as prescribed. Medications that treat insomnia can cause next-day drowsiness and impair driving and other activities that require alertness. Orexin Antagonists can impair driving skills and may increase the risk of falling asleep while driving. People can be impaired even when they feel fully awake. Patients should also be made aware of the potential for next-day driving impairment, because there is individual variation in sensitivity to the drug (1-2). The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or mental illness that should be evaluated (1-2). Warnings and precautions that should be discussed with the patient on Orexin Antagonist therapy include adverse reactions on abnormal thinking and behavioral changes (such as amnesia, anxiety, hallucinations and other neuropsychiatric symptoms), complex behaviors (such as sleep- driving, preparing and eating food, or making phone calls), dose-dependent increase in suicidal ideation, and sleep paralysis which is the inability to move or speak for up to several minutes during sleep-wake transitions (1-2).
    [Show full text]
  • Ep 2330124 A2
    (19) TZZ ¥¥Z_ T (11) EP 2 330 124 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.06.2011 Bulletin 2011/23 C07K 14/575 (2006.01) (21) Application number: 10012149.0 (22) Date of filing: 11.08.2006 (84) Designated Contracting States: • Lewis, Diana AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Diego, CA 92121 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Soares, Christopher J. SK TR San Diego, CA 92121 (US) • Ghosh, Soumitra S. (30) Priority: 11.08.2005 US 201664 San Diego, CA 92121 (US) 17.08.2005 US 206903 • D’Souza, Lawrence 12.12.2005 US 301744 San Diego, CA 92121 (US) • Parkes, David G. (62) Document number(s) of the earlier application(s) in San Diego, CA 92121 (US) accordance with Art. 76 EPC: • Mack, Christine M. 06801467.9 / 1 922 336 San Diego, CA 92121 (US) • Forood, Behrouz Bruce (71) Applicant: Amylin Pharmaceuticals Inc. San Diego, CA 92121 (US) San Diego, CA 92121 (US) (74) Representative: Gowshall, Jonathan Vallance et al (72) Inventors: Forrester & Boehmert • Levy, Odile Esther Pettenkoferstrasse 20-22 San Diego, CA 92121 (US) 80336 München (DE) • Hanley, Michael R. San Diego, CA 92121 (US) Remarks: • Jodka, Carolyn M. This application was filed on 30-09-2010 as a San Diego, CA 92121 (US) divisional application to the application mentioned under INID code 62. (54) Hybrid polypeptides with selectable properties (57) The present invention relates generally to novel, tions and disorders include, but are not limited to, hyper- selectable hybrid polypeptides useful as agents for the tension, dyslipidemia, cardiovascular disease, eating treatment and prevention of metabolic diseases and dis- disorders, insulin-resistance, obesity, and diabetes mel- orders which can be alleviated by control plasma glucose litus of any kind, including type 1, type 2, and gestational levels, insulin levels, and/or insulin secretion, such as diabetes.
    [Show full text]
  • Drug Information Center Highlights of FDA Activities – 12/1/19 – 12/31/19
    Drug Information Center Highlights of FDA Activities – 12/1/19 – 12/31/19 FDA Drug Safety Communications & Drug Information Updates: Ranitidine and Nizatidine Updates: Detection of N‐nitrosodimethylamine (NDMA) 12/4/19 The FDA maintains a site with updates and press announcements on NDMA testing in ranitidine products and ranitidine recalls. They are requiring manufacturers test all lots of ranitidine and nizatidine prior to release. FDA Launches CURE ID App for Health Care Professionals 12/5/19 The FDA launched an internet repository for health care professionals to report their experience treating difficult‐ to‐treat infectious diseases with novel uses of existing FDA‐approved drugs. The CURE ID repository, accessible through a website, a smartphone or other medical device, is designed to enable crowdsourcing of medical information that may guide use of life‐saving interventions and facilitate development of new drugs. The application may be accessed at https://cure.ncats.io or by downloading “CURE ID” from the App or Play Store. NDMA Impurities Found in Metformin Outside the U.S.: Drug Information Update 12/6/19 The FDA is aware that low levels of NDMA have been detected in some metformin products available in other countries. The levels reported have been within the range naturally occurring in some foods and water. Currently no metformin product has been recalled in the U.S.; the FDA is working with manufacturers to test samples and will recall products if the levels are found to contain NDMA at levels above the acceptable daily intake limit of 96 ng. Public Safety Alert Due to Marketing of Unapproved Exosome Products 12/6/19 The FDA notified patients and healthcare practitioners of serious adverse effects experienced by patients who were treated with unapproved products marketed as containing exosomes, and issued a reminder that there are currently no FDA‐approved exosome products and any such use should be through a clinical trial with a product with an Investigational New Drug Application.
    [Show full text]
  • Orexin and Psychoneurobiology: a Hidden Treasure Hayder M
    Chapter Orexin and Psychoneurobiology: A Hidden Treasure Hayder M. Alkuraishy, Ali I. Al-Gareeb and Naseer A. Al-Harchan Abstract Orexin is a neuropeptide secreted from the lateral hypothalamus and prefrontal cortex concerned in wakefulness and excitement. This study aimed to review the pos- sible neurobiological effect of orexin. A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. Orexin plays a vital role in activation of learn- ing, memory acquisition, and consolidation through activation of the monoaminergic system, which affects cognitive flexibility and cognitive function. Orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of the cen- tral corticotropin-releasing hormone (CRH). Cerebrospinal (CSF) and serum orexin serum levels are reduced in depression, schizophrenia, and narcolepsy. However, high orexin serum levels are revealed in drug addictions. Regarding neurodegenerative brain diseases, CSF and serum orexin levels are reduced in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Orexin antagonist leads to significant reduction of sympathetic overactivity during withdrawal syndrome. Also, orexin antagonist improves sleep pattern. The orexinergic system is involved in different psychiatric and neurological disorders; therefore targeting of this system could be a possible novel pathway in the management of these disorders. In addition measurement of CSF and serum orexin levels might predict the relapse and withdrawal of addict patients. Keywords: orexin, sleep disorders, psychiatric disorders, neurodegenerative disorders 1. Introduction Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.
    [Show full text]
  • Belsomra®: a Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia
    Pharmacy and Wellness Review Volume 7 Issue 1 Article 1 January 2016 Belsomra®: A Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia Shane Bogusz Ohio Northern University Steven Blake Ohio Northern University Michaela Wolford Ohio Northern University Victoria Cho Ohio Northern University Manoranjan D'Souza Ohio Northern University, [email protected] Follow this and additional works at: https://digitalcommons.onu.edu/paw_review Part of the Medical Pharmacology Commons, Nervous System Diseases Commons, Neurology Commons, and the Pharmaceutics and Drug Design Commons This Article is brought to you for free and open access by the ONU Journals and Publications at DigitalCommons@ONU. It has been accepted for inclusion in Pharmacy and Wellness Review by an authorized editor of DigitalCommons@ONU. For more information, please contact [email protected]. CNS Belsomra®: A Novel Dual Orexin Receptor Antagonist for the Treatment of Insomnia Shane Bogusz, Steven Blake, Michaela Wolford, Victoria Cho, Manoranjan D'Souza, M.D., Ph.D. Key Terms This knowledge-based activity is targeted for all pharmacists Belsomra®; Benzodiazepine; Dual Orexin Receptor Antago­ and is acceptable for 1.0 hour (0.1 CEU) of continuing nist; DORA, Insomnia, Insomnia Treatment, Orexin, education credit. This course requires completion Suvorexant of the program evaluation and at least a 70 percent grade on the program assessment questions. Introduction Insomnia refers to a disease state that involves persistent ACPE Universal Activity Number (UAN): 0048-0000-16-005-HOl-P difficulty falling asleep and/or frequent awakenings during sleep. Over 35 percent of the adult population exhibits one or To complete the continuing education program and receive more symptoms associated with insomnia, with 12 percent credit, please go to www.raabecollegeofpharmacy.org/PAW/.
    [Show full text]
  • Lemborexant for Insomnia
    Out of the Pipeline Lemborexant for insomnia David N. Neubauer, MD emborexant, FDA-approved for the Table 1 New agent treatment of insomnia, has demon- Fast facts about lemborexant promotes sleep strated efficacy in improving both sleep by suppressing L 1 Brand name: Dayvigo onset and sleep maintenance. This novel the wake drive compound is now the second approved Class: Dual orexin receptor antagonist supported by the insomnia medication classed as a dual orexin Indication: Insomnia characterized by difficulties with sleep onset and/or sleep orexin system receptor antagonist (Table 1). This targeted maintenance mechanism of action aims to enhance sleep Approval date: December 20, 2019 while limiting the adverse effects associated Availability date: June 2020 with traditional hypnotics. Manufacturer: Eisai Inc., Woodcliff Lake, New Jersey Clinical implications Dosage forms: 5-mg and 10-mg tablets Insomnia symptoms affect approximately Recommended dosage: 5 mg taken one-third of the general population at least immediately before going to bed with at least occasionally. Approximately 10% of indi- 7 hours remaining before the planned time viduals meet DSM-5 criteria for insomnia of awakening, no more than once per night. The dosage may be increased to 10 mg taken disorder, which require nighttime sleep once per night based on clinical response and difficulty and daytime consequences tolerance persisting for a minimum of 3 months.2 The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially similar mechanisms of action. There is 1 mood, anxiety, substance use, and stress- melatonin receptor agonist (ramelteon) and and trauma-related disorders.
    [Show full text]
  • Integration of Reward Signalling and Appetite Regulating Peptide Systems
    British Journal of DOI:10.1111/bph.13321 BJP www.brjpharmacol.org Pharmacology REVIEW Correspondence Amy C. Reichelt, PhD, School of Psychology, UNSWAustralia, NSW 2052, Australia. Integration of reward signalling E-mail: [email protected] --------------------------------------------------------- and appetite regulating peptide Received 3 June 2015 Revised systems in the control of 28 July 2015 Accepted food-cue responses 27 August 2015 A C Reichelt1,2, R F Westbrook1 and M J Morris2 1School of Psychology, UNSW Sydney, Sydney, UNSW, Australia, and 2School of Medical Sciences, UNSW Sydney, Sydney, UNSW, Australia Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over-consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over-consumption seen in obesity and binge-eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviours and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone.
    [Show full text]
  • Role of Catecholamine Pathways in Action of Orexin B Induced Open Field Activity by Nucleus Accumbens in Wistar Rats
    Pharmacogn J. 2018; 10(4):628-632 A Multifaceted Journal in the field of Natural Products and Pharmacognosy Original Article www.phcogj.com | www.journalonweb.com/pj | www.phcog.net Role of Catecholamine Pathways in Action of Orexin B Induced Open Field Activity by Nucleus Accumbens in Wistar Rats Rashmi Kaup Shiva1, Ganaraja Bolumbu2*, Santosh Mayannavar3, Dharnappa Poojari3 ABSTRACT Aims: To elucidate whether exploratory behaviour changes following Orexin B infusion in NAc is mediated through catecholamines in male Wistar rats. Methods: Inbred male Wistar rats (n= 24) were divided into three groups. Control, Treated 1 (Orexin B) and Treated 2 (Orexin B antagonist) groups. Using stereotaxic method, guide cannula was set in place bilaterally to reach Nucleus Accumbens. Orexin B and its antagonist, TCS-OX2-29 were infused in separate groups of overnight fasted rats. Following open field activity, catecholamines (Dopamine, Adrenaline, and Noradrenaline) were estimated in brain tissue homogenate by ELISA. Data were expressed as mean±SEM (ANOVA; Student-Newman Keuls test,).p<0.05 were considered as statistically significant. Results: Orexin B infusion significantly increased Rashmi Kaup Shiva1, noradrenaline levels in Nucleus accumbens when compared to controls. TCS-OX2-29 signifi- Ganaraja Bolambu2*, cantly decreased noradrenaline in Nucleus accumbens during open field exploration activity. 3 Adrenaline was not altered significantly during open field activity. Conclusion: These results SantoshMayannavar suggest that Orexin B, which plays a role in the regulation of motor and exploratory behaviour 1 when infused in NAc mediates these actions through noradrenergic neurotransmission in Department of Physiology, Centre for Nucleus Accumbens. Basic Sciences, Kasturba Medical Key words: Adrenaline, Dopamine, Nucleus Accumbens, Noradrenaline, Orexin B, TCS- College (A unit of Manipal Academy of Higher Education (MAHE), Manipal), OX2-29.
    [Show full text]
  • MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice
    molecules Article MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice Jean A. Boutin 1,*,† , Magali Jullian 2, Lukasz Frankiewicz 2,‡, Mathieu Galibert 2, Philippe Gloanec 3, Thierry Le Diguarher 4, Philippe Dupuis 5, Amber Ko 6, Laurent Ripoll 1, Marc Bertrand 4, Anne Pecquery 5, Gilles Ferry 7 and Karine Puget 2 1 Institut de Recherches Internationales Servier, 92284 Suresnes, France; [email protected] 2 Genepep SA, 34430 Saint Jean de Vedas, France; [email protected] (M.J.); [email protected] (L.F.); [email protected] (M.G.); [email protected] (K.P.) 3 Institut de Recherches Servier, 92150 Suresnes, France; [email protected] 4 Technologie Servier, 45520 Gidy, France; [email protected] (T.L.D.); [email protected] (M.B.) 5 Eurofins Discovery, 86600 Celle l’Evescault, France; PhilippeDupuis@eurofins.com (P.D.); AnnePecquery@eurofins.com (A.P.) 6 Eurofins Discovery, New Taipei City 24891, Taiwan; AmberKo@eurofins.com 7 Institut de Recherches Servier, 78290 Croissy-sur-Seine, France; [email protected] * Correspondence: [email protected] † Current affiliation: PHARMADEV (Pharmacochimie et biologie pour le développement), Faculté de Pharmacie, 31000 Toulouse, France. ‡ Current affiliation: Gyros Protein Technologies AB, 751 83 Uppsala, Sweden. Citation: Boutin, J.A.; Jullian, M.; Abstract: Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the Frankiewicz, L.; Galibert, M.; Gloanec, brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite P.; Le Diguarher, T.; Dupuis, P.; Ko, A.; and/or energy homeostasis.
    [Show full text]
  • The Dual Hypocretin Receptor Antagonist Almorexant Is Permissive for Activation of Wake-Promoting Systems
    Neuropsychopharmacology (2016) 41, 1144–1155 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems 1 1 1 1 1 Gregory S Parks , Deepti R Warrier , Lars Dittrich , Michael D Schwartz , Jeremiah B Palmerston , 2 1 ,1 Thomas C Neylan , Stephen R Morairty and Thomas S Kilduff* 1 2 SRI International, Center for Neuroscience, Biosciences Division, Menlo Park, CA, USA; Department of Psychiatry, SF VA Medical Center/NCIRE/ University of California, San Francisco, CA, USA The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake- promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos+ cells in the locus coeruleus (LC).
    [Show full text]